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id stringlengths 24 24	contexts_ids listlengths 1 157	split stringclasses 1 value	question stringlengths 13 215	type stringclasses 4 values	answer stringlengths 2 3.15k	exact_answer stringlengths 1 3.15k	contexts listlengths 1 157	concepts stringlengths 3 7.42k
5a897601fcd1d6a10c000008	[ 12007552, 22516994, 24705033, 8235662, 23172751, 28123902, 11480850, 16761499, 28116652, 12945718, 10955328, 15468356, 16354890, 25861457, 27365721, 17477466, 19762400, 16681575, 10685800, 28243944, 7993706, 2195948, 16150398, 27795838 ]	train	A SLEDAI score is associated with Systemic Lupus Erythematosus. What is a SLEDAI score?	summary	Disease activity of Systemic Lupus Erythematosis was evaluated according to the SLE Disease Activity Index (SLEDAI) score which score disease activity based on a number of parameters.	Disease activity of Systemic Lupus Erythematosis was evaluated according to the SLE Disease Activity Index (SLEDAI) score which score disease activity based on a number of parameters.	[ "Both the revised Systemic Lupus Activity Measure (SLAM-R) and the Systemic Lupus \nErythematosus Disease Activity Index (SLEDAI) are valid and reliable measures of \ndisease activity in systemic lupus erythematosus (SLE). However, more study of \ntheir responsiveness is needed. The purpose of this study was to compare the \nresponsiveness of SLAM-R and SLEDAI to disease activity changes relevant to \nphysicians and patients. Patients were evaluated monthly for up to 12 months. At \neach visit, the physician completed SLAM-R and SLEDAI. Patients and physicians \nassessed whether relevant improvement or worsening of disease activity had \noccurred since the previous visit. Based on repeated measurements, effect size \n(ES), standardized response mean (SRM), and control-standardized response mean \n(CSRM) were calculated for each response category, with bootstrap-based 95% \nconfidence intervals (CIs). Seventy-six patients contributed 471 score changes. \nFor physicians' responses, the CSRMs for SLAM-R and SLEDAI were -0.47 versus \n-0.42 for improvement, 0.04 versus 0.003 for no change, and 0.65 versus 0.66 for \ndeterioration. For patients, the CSRMs for SLAM-R and SLEDAI were -0.31 versus \n-0.18 for improvement, -0.08 versus 0.06 for no change, and 0.48 versus 0.05 for \ndeterioration. Only for SLAM-R did the 95% CIs exclude zero when improvement or \ndeterioration were detected. Similar results were found for ES and SRM. Both \nSLAM-R and SLEDAI are responsive to changes in SLE disease activity important to \nphysicians. Only SLAM-R is responsive to changes important to patients. These \ndifferences may result from the inclusion of subjective SLE manifestations in \nSLAM-R.", "OBJECTIVE: To evaluate the outcomes of pregnancies in patients with systemic \nlupus erythematosus (SLE).\nMETHODS: A retrospective observation was made on 41 patients with SLE delivered \nin our hospital and the disease activity of the patients and neonatal conditions \nwere followed up for one year after delivery. The impact of the disease \nduration, the use of cyclophosphamide, the highest systematic lupus \nerythematosus disease activity index (SLEDAI) score during the disease and the \nantepartum SLEDAI score to the outcome of delivery were analyzed.\nRESULTS: The disease duration of SLE was (3.5±3.1) years, the highest SLEDAI \nscore during the disease was 10.6±3.1. The antepartum SLEDAI score was 6.2±1.6, \nthe postpartum SLEDAI score was 6.4±2.9. The SLEDAI score in one year after \ndelivery was 5.4±2.1, which in patients with disease duration more than 4 years \nwas higher than that in patients with disease duration less than 4 years \n(P=0.03). All the deliveries were live births. The gestational age at birth was \n(37.6±3.3) weeks, and the body weight was (2 510.0±756.9) g. These figures were \nsignificantly lower than those of the healthy women (P=0.03 and P=0.008, \nrespectively). Four (9.8%) newborns were diagnosed as neonatal lupus.\nCONCLUSION: The risks of premature and low weight baby rates are increased in \npatients with SLE. The proper timing of pregnancy and conception will improve \npregnancy outcomes.", "Systemic lupus erythematosus (SLE) is a connective tissue disease characterized \nby the formation of autoantibodies and immune complexes. Lupus nephritis is one \nof the hallmark features of SLE. CXCL10 is a chemokine secreted by IFNg- \nstimulated endothelial cells and has been shown to be involved in the \npathological processes of autoimmune diseases. The objective was to measure \nurinary CXCL10 in SLE patients, to compare levels between nephritis and \nnon-nephritis groups and to study its correlation with other variables. Sixty \nlupus patients were enrolled in our trial. Thirty patients had lupus nephritis \nand the other 30 were without evidence of lupus nephritis. Thirty healthy \nsubjects were willing to participate as a healthy control group. Renal biopsy \nwas performed for lupus nephritis group. Urinary CXCL10 was measured using the \nELISA technique. Serum creatinine, C3, C4 and 24 h urinary proteins were \nmeasured. Lupus activity was assessed using systemic lupus erythematosus disease \nactivity index (SLEDAI) scoring system. Renal activity was measured using renal \nactivity scoring system. CXCL10 was significantly higher in lupus nephritis \npatients than in lupus patients without nephritis. CXCL10 was significantly \ncorrelated with renal activity score, 24 hours urinary proteins and the SLEDAI \nscore. It is highly valid predictor of SLE nephritis with high sensitivity and \nspecificity. CXCL 10 a highly sensitive and specific non-invasive diagnostic \ntool for lupus nephritis patients.", "The course and prognostic value of disease activity measured by the validated \nSystemic Lupus Erythematosus Disease Activity Index (SLEDAI) was investigated in \n68 newly diagnosed black Caribbean cases. A high percentage of patients had \nclinical renal involvement (78%). Disease activity at onset was mild to moderate \n(SLEDAI < or = 10) in 36% of patients; about half never reached a higher SLEDAI \nscore, whereas the other half advanced to higher disease activity (SLEDAI > 10). \nSLEDAI scores decreased significantly over time from diagnosis. Within 3 months \nafter disease onset, 54% of patients reached their maximum SLEDAI scores. There \nwere no differences in clinical features or survival between these patients and \nthose with later (mean, 35 months) maximum disease activity, although the latter \nhad more frequent disease flares. Overall survival was poor (91% and 56% at 1 \nand 5 years, respectively). High persistent disease activity (weighted average \nof SLEDAI scores > 10) was independently associated with decreased survival, \nwhereas a high initial SLEDAI, a high maximum SLEDAI, and an increase number of \nflares were not. The main cause of death was infection, which often was \nassociated with active disease (mean SLEDAI at death, 16 +/- 8.9). SLEDAI was a \npractical and reliable way of evaluating disease activity but was of limited \nprognostic value.", "OBJECTIVES: To evaluate treatment with the peptide-based agent, Lupuzor, in a \ndouble-blind, randomised, placebo-controlled study of patients with systemic \nlupus erythematosus.\nMETHODS: Patients who met ≥4 of the American College of Rheumatology criteria, \nhad a score of ≥6 on the Systemic Lupus Erythematosus Disease Activity Index \n2000 (SLEDAI-2K) and did not have an A score on the British Isles Lupus \nAssessment Group (BILAG)-2004 scale were eligible. 149 intention-to-treat (ITT) \npatients were randomly assigned to receive Lupuzor (200 μg) subcutaneously every \n4 weeks (n=49; group 1) or every 2 weeks (n=51; group 2) or placebo (n=49; group \n3) in addition to standard of care (SOC). A target population (136 ITT patients) \nconsisting of patients having a clinical SLEDAI score ≥6 at week 0 was \nconsidered. The clinical SLEDAI score is the SLEDAI-2K score obtained by \nomitting low complement and increased DNA binding components.\nRESULTS: In the ITT overall population, 53.1% in group 1 (p=0.048), 45.1% in \ngroup 2 (p=0.18) and 36.2% in the placebo group achieved an SLE Responder Index \n(SRI) response at week 12. In the target population, the results were more \nimpressive: 61.9% in group 1 (p=0.016), 48.0% in group 2 (p=0.18) and 38.6% in \nthe placebo group achieved an SRI response at week 12. An interim analysis \nincluding 114 patients from the target population demonstrated an even better \nefficacy (according to SLEDAI score) in group 1 compared with placebo (67.6% vs \n41.5% (p<0.025) at week 12 and 84.2% vs 45.8% (p<0.025) at week 24). The most \ncommon adverse event was a mild injection-site erythema.\nCONCLUSIONS: Lupuzor/200 µg given three times at 4-week intervals during 12 \nweeks in addition to SOC is efficacious and generally well tolerated.", "To determine the expression of mTOR, Becline-1, LC3 and p62 in the peripheral \nblood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) and assess \ntheir relationship with disease activity and immunologic features. The \nexpression of mTOR, Becline-1, LC3 and p62 was detected by RT-PCR in 81 SLE \nsubjects and 86 age- and sex-matched healthy controls. Data regarding \ndemographics and clinical parameters were collected. Disease activity of SLE was \nevaluated according to the SLE Disease Activity Index (SLEDAI) score. \nIndependent sample t-test was used to analyze the expression of mTOR, Becline-1, \nLC3, and p62 in the two groups. Pearson's or Spearman's correlation was \nperformed to analyze their relationship with disease activity and immunologic \nfeatures. The mean levels of Becline-1, LC3 and p62 mRNA were significantly \nhigher in SLE patients than the controls (9.96×10-4 vs 7.38×10-4 for Becline-1 \nwith P<0.001; 4.04×10-5 vs 2.62×10-5 for LC3 with P<0.001; 9.51×10-4 vs \n7.59×10-4 for p62 with P=0.008). However, the levels of mTOR mRNA in SLE \npatients were not significantly different from that in controls. Correlation \nanalysis showed that Becline-1, LC3 and p62 mRNA levels correlated positively \nwith SLEDAI, IgG and ds-DNA, negatively with C3. Our results suggested that \nautophagosomes formation were activated and their degradation were blocked in \nSLE. Moreover, the maintenance of autophagy balance can improve disease activity \nand immune disorders in SLE patients.", "The objective of this study was to assess the incidence and risk factors of \ninfections in 200 SLE outpatients. All outpatients with active or inactive SLE \nwithout infections in the previous month were included. They were assessed every \n3 months. Major infections were those requiring hospitalization and parental \nantibiotic therapy; minor infections required oral or topical therapy. \nSociodemographic, disease activity using the Systemic Lupus Erythematosus \nDisease Activity Index (SLEDAI), therapy and laboratory variables were \nevaluated. After a follow-up of 22+/-7 months, 65 (32%) patients had infections; \n35% of those were major. The most common sites for infection were urinary (26%), \nskin (23%), systemic (12%), and vaginal (9%). At infection onset, 50 of 65 \npatients (77%) had disease activity, with a mean SLEDAI score of 6.1. The \nvariables significantly associated with infection in the univariate analyses \nwere the presence of disease activity, SLEDAI score, renal activity, prednisone \ndose, and IV cyclophosphamide. The only variable associated with infection in \nthe multivariate analyses was a SLEDAI score of 4 or higher. Most infections in \nSLE outpatients were single, minor, non-life threatening, and associated with \ndisease activity independently of sociodemographic and therapeutic factors.", "Mononuclear cells play a cardinal role in the pathogenesis of systemic lupus \nerythematosus (SLE). A high urine cytology score has been reported to be \nassociated with lupus nephritis in relapse. The objective of this study was to \nexamine the urinary mononuclear cell population of patients with lupus \nnephritis, and explore its correlation with lupus disease activity. We studied \n12 patients with active lupus nephritis, 17 patients with lupus nephritis in \nremission, 12 SLE patients with no history of renal disease and 13 healthy \nsubjects. Clinical disease activity was quantified by the SLE Disease Activity \nIndex (SLEDAI). Mononuclear cell species in the urinary sediment were examined \nby immunocytochemistry. Patients with active lupus nephritis had significantly \nmore mononuclear cells in the urinary sediment. The number of CD3+ cell was \nsignificantly elevated in the active lupus nephritis than the others (P < \n0.001), while there was no significant difference in the number of CD20+ and \nCD56+ cell among patient groups. The total urinary mononuclear cell correlated \nsignificantly with the overall SLEDAI score (r = 0.58, P < 0.001) as well as the \nrenal score (r = 0.57, P < 0.001). The number of urinary CD3+, but not CD20+ or \nCD56+, cell significantly correlated with the overall SLEDAI score (r = 0.46, P \n= 0.003) as well as the renal score (r = 0.40, p = 0.011). In nine patients with \nrenal biopsy, the histological activity index correlated with the total urinary \nmononuclear cell (r = 0.75, P = 0.02), CD3+ (r = 0.69, P = 0.04) and CD20+ cell \n(r = 0.69, P = 0.04). We conclude that urinary mononuclear cell was markedly \nelevated in patients with active lupus, and the urinary mononuclear cell count \ncorrelated significantly with the SLEDAI score and histological activity. CD3+ \nand CD20+ cells are the major component of urinary mononuclear cell in SLE \npatients and their number correlates with lupus disease activity.", "We sought to evaluate a possible link between parvovirus B19 infection and the \nclinical and laboratory expression of systemic lupus erythematosus (SLE). SLE \npatients were examined to evaluate their clinical status and disease activity. A \ncomplete Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was \nobtained for each patient. In addition, we determined the level of systemic \ninvolvement throughout the course of the disease. Blood levels of IgM and IgG \nantibodies to parvovirus B19, levels of anti-dsDNA, C3, and C4 were measured. A \nPCR real-time assay was used to determine the presence of parvovirus B19 genetic \nmaterial. The viral genome was found in sera of 2 of 51(3.9%) patients with SLE. \nThere was no correlation between viral serology and the clinical and serological \nparameters of the disease. More SLE patients with secondary antiphospholipid \nsyndrome (APS) had IgG and IgM antibodies to the virus (p < 0.029 and p < 0.018, \nrespectively). These patients also had a higher titer of IgG antibodies to \nparvovirus B19 compared to SLE patients without APS. In this group of SLE \npatients, no association was found between parvovirus infection and the presence \nor activity of SLE. The results of the study suggest an association between \nparvovirus infection and antibody production directed against phospholipids.", "The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the most \ncommonly used measure of disease activity for children with systemic lupus \nerythematosus (SLE). For headaches to be scored in the SLEDAI as a symptom of \nactive disease, they have to be nonresponsive to narcotic analgesia. This may \naffect the overall estimation of disease activity, especially because headaches \nare common among children with SLE and narcotic analgesia is rarely used for \nheadache therapy in paediatrics. Moreover, the importance of headaches for the \ndevelopment of damage and their relation to other clinical parameters and \noutcomes has not been well described for children with SLE. We reviewed the \nmedical charts of an inception cohort of children (n = 63) who were newly \ndiagnosed with SLE. Information on headaches and other disease parameters was \nobtained. Disease activity and damage were measured using the SLEDAI and the \nSystemic Lupus International Collaboration Clinics/American College of \nRheumatology Damage Index (SDI), respectively. It has been shown that the \naccumulated burden of active disease as measured by serial SLEDAI scores over \ntime is one of the best predictors of eventual damage to children with SLE. \nNew-onset or significant increase of severe and/or persistent headaches (LHA) \nwere reported in 43% of the patients during a mean follow-up of 3.6 years. LHA \noccurred preferentially among patients with elevated levels of antiphospholipid \nantibodies (aPL) (P < 0.02) and only 6% of all LHA episodes were treated with \nnarcotics and thus considered for the measurement of disease activity in the \nSLEDAI. LHA were unrelated to proxy-measures of disease activity, such as the \nneed to intensify therapies. When used in children, the insensitivity of the \nSLEDAI to capture LHA did not seem to decrease the responsiveness of the SLEDAI \nto detect clinically important worsening of disease, or negatively impact on its \nability to predict damage.", "OBJECTIVE: To evaluate the prevalence, disease course, and survival of patients \nwith systemic lupus erythematosus (SLE) in a population of over 120,000 North \nAmerican Indians (NAI), and contrast the results to those in the non-Indian \npopulation.\nMETHODS: The regional arthritis center database and the medical records of all \nrheumatologists, hematologists, nephrologists, and general internists with > 1 \npatient with SLE were searched for cases of SLE diagnosed between 1980 and 1996. \nA random survey of 20% of family physicians serving this population suggested \nthat > 85% of all SLE cases were identified. Demographics, SLE Disease Activity \nIndex (SLEDAI) scores, Systemic Lupus International Collaborating \nClinics/American College of Rheumatology (SLICC/ACR) damage scores. clinical \nmanifestations, and therapy for NAI were contrasted with the results in \nCaucasians (CAUC).\nRESULTS: We identified 257 cases meeting the ACR criteria for SLE diagnosed \nbetween 1980 and 1996. There were 49 NAI cases, resulting in a prevalence of \n42.3/100,000, compared to a prevalence of 20.6/100,000 for the remainder of the \npopulation. NAI patients were younger at diagnosis, had higher SLEDAI scores at \ndiagnosis, and had more frequent vasculitis, proteinuria and cellular casts. \nThere were no treatment differences at diagnosis or at 2 years, but NAI patients \nwere significantly more likely to receive treatment with prednisone or \nimmunosuppressives at the last clinic visit. The NAI patients had similar damage \nscores at diagnosis, but significantly higher scores at 2 years and at the last \nclinic visit. NAI ethnicity increased the likelihood of death more than 4-fold.\nCONCLUSION: The prevalence of SLE was increased 2-fold in the NAI population. \nNAI patients had higher SLEDAI scores at diagnosis and more frequent vasculitis \nand renal involvement, required more treatment later in the disease course, \naccumulated more damage following diagnosis, and had increased fatality.", "OBJECTIVE: To assess the validity, reliability, and feasibility of the Systemic \nLupus Activity Measure-Revised (SLAM-R), the Mexican version of the Systemic \nLupus Erythematosus Disease Activity Index (MEX-SLEDAI), and a Modified \nSLEDAI-2000 (SLEDAI-2K) compared with the SLEDAI-2K in a multiethnic population \nof patients with SLE.\nMETHODS: We studied 92 SLE patients from 3 US geographic areas (Alabama, Texas, \nand Puerto Rico). Assessment occurred during regular outpatient, inpatient, or \nstudy encounters. A trained physician scored the 4 instruments and also assessed \ndisease activity globally [physician global assessment (PGA)]. Convergent (with \nSLEDAI-2K) and construct validity (with PGA) were determined by Spearman rank \n(rs) correlation test. Level of agreement between the instruments was assessed \nusing Bland-Altman plots. Discriminant validity (distinguishing clearly active \nvs mildly/nonactive disease) was assessed considering the SLEDAI-2K (and the \nPGA) as the gold standard. Feasibility was explored by cost analyses.\nRESULTS: The SLAM-R, the MEX-SLEDAI, and the Modified SLEDAI-2K were highly \ncorrelated with the SLEDAI-2K (rs = 0.566, 0.755, 0.924, respectively) and with \nthe PGA (rs = 0.650, 0.540, 0.634, respectively). The 3 instruments showed good \nagreement with the SLEDAI-2K (Bland-Altman plots). The Modified SLEDAI-2K had \nbetter discriminant validity than the SLAM-R and the MEX-SLEDAI. The Modified \nSLEDAI-2K was the least expensive instrument.\nCONCLUSION: The SLAM-R, the MEX-SLEDAI, and the Modified SLEDAI-2K are adequate \noptions for assessment of SLE disease activity; they are also less costly than \nthe SLEDAI-2K.", "BACKGROUND: The effects of estrogen-containing contraceptives on disease \nactivity in women with systemic lupus erythematosus have not been determined.\nMETHODS: We conducted a single-blind clinical trial involving 162 women with \nsystemic lupus erythematosus who were randomly assigned to combined oral \ncontraceptives, a progestin-only pill, or a copper intrauterine device (IUD). \nDisease activity was assessed at 0, 1, 2, 3, 6, 9, and 12 months according to \nthe Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The primary \noutcome was global disease activity, which we estimated by measuring the area \nunder the SLEDAI curve. Secondary outcomes included the maximum SLEDAI score, \nchange in SLEDAI score, incidence of lupus flares, median time to first flare, \nsystemic lupus erythematosus treatment, and adverse events. The results were \nanalyzed by the intention-to-treat method.\nRESULTS: At baseline, all demographic features and disease characteristics were \nsimilar in the three groups. The mean (+/-SD) SLEDAI score was 6.1+/-5.6 in the \ngroup assigned to combined oral contraceptives, 6.4+/-4.6 in the group assigned \nto the progestin-only pill, and 5.0+/-5.3 in the group assigned to the IUD (54 \npatients in each group) (P=0.36). Disease activity remained mild and stable in \nall groups throughout the trial. There were no significant differences among the \ngroups during the trial in global or maximum disease activity, incidence or \nprobability of flares, or medication use. The median time to the first flare was \nthree months in all groups. Thromboses occurred in four patients (two in each of \nthe two groups receiving hormones), and severe infections were more frequent in \nthe IUD group. One patient receiving combined oral contraceptives died from \namoxicillin-related severe neutropenia.\nCONCLUSIONS: Global disease activity, maximum SLEDAI score, incidence of flares, \ntime to first flare, and incidence of adverse events were similar among women \nwith systemic lupus erythematosus, irrespective of the type of contraceptive \nthey were using.", "OBJECTIVE: Current disease activity measures for systemic lupus erythematosus \n(SLE) are difficult to score or interpret and problematic for use in clinical \npractice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in \nLupus (REAL) is a pilot application composed of anchored visual analogue scores \n(0-100 mm each) for each organ affected by lupus. This study evaluated the use \nof LFA-REAL in capturing SLE disease activity.\nMETHODS: In a preliminary test of LFA-REAL, this simplified, organ-based system \nwas compared with the most widely used outcome measures in clinical trials, the \nBritish Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease \nActivity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus \nNational Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The \nlevel of agreement was analysed using Spearman rank correlations.\nRESULTS: 91 patients with SLE with mild to severe disease activity were \nevaluated, their median SLEDAI score was 4.0 (range 0-28) and BILAG score 8.0 \n(0-32). The median SS-PGA was 38 mm (4-92) versus the total REAL 50 mm (0-268), \nwhich expands in range by additive organ scores. Thirty-three patients had \nmoderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median \nSS-PGA score of this group was 66 mm (50-92) versus median REAL score of 100 mm \n(59-268), confirming ability to detect a wider distribution of scores at higher \ndisease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA \n(correlation coefficient=0.816, 0.933 and 0.903, respectively; p<0.001 for all). \nIndividual LFA-REAL organ scores for musculoskeletal and mucocutaneous also \ncorrelated with corresponding BILAG domain scores (correlation coefficient=0.925 \nand 0.934, p<0.001).\nCONCLUSIONS: In this preliminary exercise, there were strong correlations \nbetween LFA-REAL and validated lupus disease activity indices. Further \ndevelopment may be valuable for consistent scoring in clinical trials, grading \noptimal assessment of change in disease activity and reliable monitoring of \npatients in practice.", "BACKGROUND: Therapeutic decisions in systemic lupus erythematosus (SLE) are \nbased on the disease activity and nature of organ involvement. There are various \nclinical and laboratory methods to assess the lupus flares.\nMETHODS: Fifty one SLE patients with active disease (lupus flare) were studied. \nSystemic lupus erythematosus disease activity index (SLEDAI), C3, C4 and \nanti-double stranded DNA levels were estimated and repeated monthly till \nremission. After remission these tests were done three monthly. Values of \nserological parameters were then correlated with SLEDAI score.\nRESULT: Thirteen (25.4%) patients had predominantly renal involvement while 38 \n(74.6%) patients had non-renal affliction. Musculoskeletal and mucocutaneous \nsymptoms were the commonest features of lupus flare (90%). It was observed that \n12 out of 13 (92.3%) patients with active renal involvement had low C3 levels \nand 11 (84.6%) had low C4 levels. The anti-dsDNA levels were elevated in all \npatients with predominant renal flare. In non-renal flare anti-dsDNA titre was \nraised only in 35% cases. Low C3 and C4 levels were noticed in 43% and 53% of \nnon-renal flares respectively. Significant positive correlation was noticed \nbetween SLEDAI score and anti-dsDNA levels (0.01 level two-tailed prediction) \nand a significant negative correlation was observed with SLEDAI and C3, C4 \nlevels (0.01 and 0.05 levels, two-tailed prediction) in our patients. On \nsubgroup analysis it was noticed that this correlation is stronger for renal \nlupus. Negative correlation of SLEDAI and complement levels was not observed in \nnon-renal flares.\nCONCLUSION: Calculation of SLEDAI is a vital clinical tool for assessment of SLE \npatients. Serial estimation of anti-dsDNA titre, C3 and C4 levels help us \ndiagnose lupus flare and make appropriate therapeutic decisions in patients with \nhigh SLEDAI score.", "OBJECTIVE: To determine the flare rate and the change in Safety of Estrogens in \nLupus Erythematosus: National Assessment Systemic Lupus Erythematosus Disease \nActivity Index (SELENA SLEDAI) score with disease flare in pediatric systemic \nlupus erythematosus (pSLE).\nMETHODS: A retrospective chart review of 62 patients with pSLE (ages 5-20 yrs). \nA flare was defined as the start of, or increase in, the dose of corticosteroids \nand/or the addition of an immunosuppressive medication. All pre-flare, flare, \nand post-flare visits were recorded with a SELENA SLEDAI score calculated for \neach visit. The flare rate was calculated by dividing the total number of flares \nin the cohort by the total followup years.\nRESULTS: Sixty-two patients were eligible. Forty-seven patients had 112 flares. \nThe average number of flares/patient was 1.8 +/- 2.0 and the mean inter-flare \ntime was 15.4 +/- 17.9 months. The flare rate in pSLE was 0.46 \nflares/patient-year of followup. The median time to first flare from the date of \ndiagnosis was 14.3 months. Patients with cytopenia, pleuritis, or pericarditis, \nor a positive antibody to Smith nuclear antigen at the time of diagnosis had a \nsignificantly higher flare rate than those who did not. The average SELENA \nSLEDAI score at presentation was 12.5 +/- 5.4, at the pre-flare visit 6.3 +/- \n3.5, and during a flare 7.9 +/- 5.1.\nCONCLUSION: This is the first large study to report a flare rate (0.46 \nflares/patient-year of followup) in pSLE. The flare rate was similar to what has \nbeen reported in pSLE previously but significantly lower than that reported in \nadults with lupus. The average change in the SELENA SLEDAI score with disease \nflare is 2 points.", "The objective of this study is to determine if digital vasculitis (DV), a \nclinical manifestation with a high systemic lupus erythematosus disease activity \nindex (SLEDAI) score, is associated with lupus severity. DV and other clinical \nmanifestations defined according to the SLEDAI were evaluated in 168 consecutive \npatients with systemic lupus erythematosus (SLE). Two groups were defined \naccording to presence (DV+, n = 27) or absence of DV (DV-, n = 141) at the time \nof evaluation. The exclusion criterion was the presence of antiphospholipid \nsyndrome (Sapporo's criteria). The two groups were comparable with regard to age \n(P = 0.09), gender (P = 1.00), white race (P = 0.81), and disease duration (P = \n0.78). Compared to the DV- group, the DV+ group had a significantly higher \nfrequency of mucocutaneous manifestations (66.7 vs. 39.0%, P = 0.01), \nhaematological abnormalities (22.2 vs. 6.4%, P = 0.02) and constitutional \nsymptoms (11.1 vs. 0.7%, P = 0.01). Renal and neurological involvements were \nsimilar in both groups (P = 0.57 and P = 1.00, respectively). The evaluation of \neach SLEDAI parameter confirmed that the DV+ group had higher frequencies of \nmild manifestations, such as new rash (P = 0.02), alopecia (P = 0.02), oral \nulcers (P = 0.045), fever (P = 0.01) and leucopenia (P = 0.005). In contrast, \nboth groups had similarly increased anti-dsDNA (P = 0.78) and decreased \ncomplement levels (P = 0.29). In conclusion, DV in patients with SLE identifies \na subgroup of a mild disease. The high 'weighted' index attributed to this \nalteration in the SLEDAI score should therefore be revised.", "BACKGROUND: Lupus band test still has no clearly defined position within either \ndiagnostic or disease activity measuring tools for systemic lupus erythematosus \n(SLE).\nOBJECTIVES: We tested the hypothesis that positive LBT correlates with global \nactivity of SLE measured by the SLE Disease Activity Index (SLEDAI) score.\nMETHODS: In total, 90 SLE patients who underwent biopsy of sunprotected \nnon-lesional (SPNL) skin were studied prospectively. The skin specimen was \nprocessed for standard direct immunofluorescence. The patients were classified \ninto groups as negative and positive LBT, and the latter were further subdivided \non the basis of the type and morphology of the deposits. Every patient was \nthoroughly examined and assigned a SLEDAI score. The relationship between LBT \nfindings and SLEDAI score was analysed.\nRESULTS: The disease was significantly more active in patients with positive LBT \nand in those with a higher number of deposited immunoreactants. Almost all \npatients with renal involvement had a positive LBT.\nCONCLUSIONS: LBT on SPNL skin may be a good marker of severe disease at \npresentation, particularly when three immunoglobulins are found at the \ndermoepidermal junction.", "OBJECTIVE: To determine whether Systemic Lupus Erythematosus Disease Activity \nIndex (SLEDAI) scores correlate with the clinician's impression of level of \ndisease activity.\nMETHODS: In total, 230 patients with SLE followed at the University of Toronto \nLupus Clinic who had 5 visits 3 months apart in 1992-93 were studied. At each \nvisit a standard protocol was completed. A clinician who did not know the \npatients or their SLEDAI scores evaluated each patient record and assigned a \nclinical activity level. \"Flare\" was defined by new or increased therapy for \nactive disease, an expression of concern, or use of the term \"flare\" in the \nphysician's notes. The SLEDAI score was calculated from the database.\nRESULTS: SLEDAI scores described a range of clinical activity as recognized by \nthe clinician. Median SLEDAI scores ranged from 2 (inactive disease) to 8 \n(persistently active or flare). When the clinician assessed the patient to be \nimproved, the median SLEDAI score decreased by 2. When the clinician assessed \nthat the patient was experiencing a flare, the SLEDAI score increased by a \nmedian of 4.\nCONCLUSION: Based on our data we propose the following outcomes for patients \nwith SLE: flare, an increase in SLEDAI > 3; improvement is a reduction in SLEDAI \nof > 3; persistently active disease is change in SLEDAI +/- 3; and remission a \nSLEDAI of 0. These outcomes will allow a more complete description of a \npatient's response to therapeutic intervention in a responder index.", "Author information:\n(1)Programa de Doctorado en Farmacologia, Centro Universitario de Ciencias de la \nSalud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, Col. Independencia, \n44340, Guadalajara, Jalisco, Mexico.\n(2)Unidad de Investigación Biomédica 02 (UIEC), UMAE Hospital de Especialidades, \nCentro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, \nAvenida Belisario Domínguez 1000, Col. Independencia Oriente, 44340, \nGuadalajara, Jalisco, Mexico.\n(3)Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de \nCiencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, Col. \nIndependencia, 44340, Guadalajara, Jalisco, Mexico.\n(4)Departamento de Fisiología, Centro Universitario de Ciencias de la Salud \n(CUCS), Universidad de Guadalajara, Sierra Mojada 950, Col. Independencia, \n44340, Guadalajara, Jalisco, Mexico.\n(5)Laboratorio de Investigación y Desarrollo Farmacéutico, Centro Universitario \nde Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino \nGarcía Barragán 421, 44430, Guadalajara, Jalisco, Mexico.\n(6)Departamento de Inmunología y Reumatología, Hospital General de Occidente, \nSecretaria de Salud, Av Zoquipan 1050, Seattle, 45170, Zapopan, Jalisco, Mexico.\n(7)Programa Internacional de Medicina, Universidad de Autónoma de Guadalajara, \nAv. Patria 1201, Col. Lomas del Valle, 45129, Zapopan, Jalisco, Mexico.\n(8)Unidad Médica Familiar 4 y 8, Departamento de Epidemiologia, Instituto \nMexicano del Seguro Social (IMSS), Fidel Velázquez Sánchez 1531, Atemajac del \nValle, 44218, Guadalajara, Jalisco, Mexico.\n(9)Programa de Doctorado en Farmacologia, Centro Universitario de Ciencias de la \nSalud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, Col. Independencia, \n44340, Guadalajara, Jalisco, Mexico. dralauragonzalez@prodigy.net.mx.\n(10)Departamento de Medicina Interna-Reumatología, Instituto Mexicano del Seguro \nSocial (IMSS), Hospital General Regional 110, Av Circunvalación Oblatos 2208, \nColonia Circunvalación Oblatos, 44716, Guadalajara, Jalisco, Mexico. \ndralauragonzalez@prodigy.net.mx.\n(11), Avenida Salto del Agua 2192, Colonia Jardines del Country, 44210, \nGuadalajara, Mexico. dralauragonzalez@prodigy.net.mx.", "In this article, assessment of disease activity in systemic lupus erythematosus \n(SLE), including available instruments and their use in patients with SLE, is \ndiscussed. Several validated measures, including the SLAM (Systemic Lupus \nActivity Measure), SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), \nLAI (Lupus Activity Index), ECLAM (European Consensus Lupus Activity \nMeasurement), and that of the BILAG (British Isles Lupus Activity Group) are now \navailable and should be included in studies of new laboratory measures, \ntherapeutic trials, and studies of outcome and prognosis. The prognosis of SLE \nhas improved over the past 4 decades, including 20-year survival rates. With \nimproved survival, other outcome measures such as specific organ function and \nhealth status need to be considered. Administration of hydroxychloroquine \nremains an important part of therapy for SLE. The use of cyclophosphamide should \nbe reserved for severe manifestations of the disease. Newer forms of therapy, \nparticularly immunotherapy, have been tested in animal models.", "It is difficult to measure clinical disease activity in systemic lupus \nerythematosus because many organs can be involved simultaneously and the \ncorresponding symptoms are not easy to quantify. Disease activity is poorly \ndefined and there is no consensus on what disease activity means or how it \nshould be measured. More than 60 systems have been devised but none of them is \ncommonly used because they do not have the 3 characteristics necessary for such \na tool: validity, reliability and sensitivity. Three recent systems, BILAG \n(British Isles Lupus Assessment Group), SLEDAI (Systemic Lupus Erythematosus \nDisease Activity Index) and SLAM (Systemic Lupus Activity Measures) are very \nvalid. Comparisons of their reproducibility are in progress; however, more \ninformation is needed concerning their sensitivity and the feasibility of making \nthese systems easy to manage for physicians.", "The assessment of disease activity in systemic lupus erythematosus (SLE) is a \ntask faced by clinicians in every day care, but it is also required for clinical \nresearch and in randomised controlled trials. It is crucial to distinguish \ndisease activity from infection, chronic damage and co-morbid disease. Over the \npast 20 years, many indices have been developed to objectively measure lupus \ndisease activity and several of these have been validated. The most widely used \nindices are the British Isles Lupus Assessment Group (BILAG) index, the European \nConsensus Lupus Activity Measurement (ECLAM), the Systemic Lupus Activity \nMeasure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) \nand the Lupus Activity Index (LAI). All these indices have been validated and \nhave excellent reliability, validity and responsiveness to change. In addition \nto the assessment of disease activity, the evaluation of damage using the \nvalidated SLICC/ACR damage index and health-related quality of life is advised \nfor clinical research.", "BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune \nconnective-tissue disease involving multiple organs and systems. Some evidence \nhas demonstrated that disease activity could be associated with increased risk \nof organ damage.\nOBJECTIVES: The aim of this study was to determine the association between \nsystemic lupus erythematosus Disease Activity Index (SLEDAI) scores and \nsubclinical cardiac involvement.\nMETHODS: This cross-sectional study was conducted on 45 SLE patients (88% \nfemale; mean age: 31.2 ± 8.2 years) from 2011 to 2013 in Mashhad, Iran. The \npatients had no clinical signs and symptoms of cardiac problems or risk factors \nfor cardiovascular disease and were selected consecutively. All patients \nunderwent complete echocardiographic examinations (using two dimensional (2D) \ntissue Doppler and 2D speckle tracking). Disease activity was evaluated by using \nthe SLEDAI.\nRESULTS: Patients with higher SLEDAI scores had higher pulmonary artery pressure \nrates (r = 0.34; P = 0.024; 95% CI (0.086 to 0.595)) and SLE durations (r = \n0.43; P = 0.004; 95% CI (0.165 to 0.664). The correlation between disease \nduration and left ventricular mass was also significant (r = 0.43; P = 0.009; \n95% CI (0.172 to 0.681)), even after adjusting for age (r = 0.405; P = 0.016). \nThere was no correlation between SLEDAI scores or disease duration and the \nleft/right ventricle systolic function parameters. This was true while assessing \nthe right ventricle's diastolic function. A statistically significant \ncorrelation was found between mitral E/E' as an index of left ventricle \ndiastolic impairment and the SLEDAI scores (r = 0.33; P = 0.037; 95% CI (0.074 \nto 0.574)) along with disease duration (r = 0.45; P = 0.004; 95% CI (0.130 to \n0.662); adjusted for age: r = 0.478; P = 0.002).\nCONCLUSIONS: Echocardiography is a useful noninvasive technique for screening \nsubclinical heart problems in SLE patients. Although disease activity in general \nshould suggest a closer follow-up, regular scanning would enable earlier \ndetection of cardiovascular involvement and should not be confined to cases with \nhigher SLEDAI indices or longer disease durations." ]	['http://www.disease-ontology.org/api/metadata/DOID:8857', 'http://www.disease-ontology.org/api/metadata/DOID:9074', 'https://meshb.nlm.nih.gov/record/ui?ui=D008180']
5a96c886fcd1d6a10c00002a	[ 24690977, 28319627 ]	train	A bite from the Lone Star Tick Amblyomma americanum, can cause the victim to become allergic to red meat, yes or no?	yesno	Conditions such as Southern tick-associated rash illness and anaphylaxis to red meat following tick bites have been attributed to the lone star tick, Ambyomma ameriacanum.	yes	[ "Delayed hypersensitivity disorders and food allergies are often challenging for \nthe clinician and patient alike. A recent discovery of an IgE antibody specific \nto galactose-α-1,3-galactose, which is a carbohydrate abundantly expressed on \ncells and tissues of beef, pork, and lamb, adds one more tool to aid the \nclinician in making the appropriate diagnosis. A link has been discovered \nbetween the bite of the Lone Star Tick (Amblyomma americanum) and the \ndevelopment of sensitivity to galactose-α-1,3-galactose. With a high prevalence \nof Lone Star Tick populations inhabiting major U.S. Army Installations, and the \ntype of duty required by our Service members, it could potentially affect \nsusceptible individuals. We describe a case of an active duty soldier who went 4 \nyears searching for this elusive diagnosis and connection and discuss why it \nshould remain in the differential diagnosis when treating military health care \nbeneficiaries.", "Amblyomma americanum, also known as the lone star tick, is found in much of the \neastern United States. Since the mid-20th century, the lone star tick has been \nimplicated in human disease. Today, A americanum remains an important vector for \ntick-borne illness. In addition to others, species of Rickettsia, Ehrlichia, and \nBorrelia are all transmitted by the lone star tick. Recently described \nconditions such as Southern tick-associated rash illness and anaphylaxis to red \nmeat following tick bites have been attributed to the lone star tick. Impressive \nlocal reactions also can result after bites from A americanum. Early treatment \nof tick-borne illness is crucial to ensure good patient outcomes. Tick-control \nmeasures also are an important part of disease management in endemic areas. We \ndiscuss the tick's biology, human illnesses associated with A americanum, and \nmethods to control tick numbers and eliminate disease in local reservoirs." ]	['https://meshb.nlm.nih.gov/record/ui?ui=D017282']
602346eb1cb411341a000090	[ 33139264, 34245216, 34522691, 34377156, 34051880, 34798793, 33442538, 33213161, 34189869, 33549983, 33663220, 34853653, 34771637, 32984090, 32349374, 34167423 ]	train	A combination of which two drugs was tested in the IMbrave150 trial?	list	IMbrave150 trial tested a combination of atezolizumab and bevacizumab for advanced hepatocellular carcinoma.	['atezolizumab', 'bevacizumab']	[ "On May 29, 2020, the FDA approved atezolizumab for use in combination with \nbevacizumab, for the treatment of adult patients with unresectable locally \nadvanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic \ntreatment. The approval was based on data from Study IMbrave150, which randomly \nallocated (2:1) patients to receive either atezolizumab plus bevacizumab \n(atezolizumab-bevacizumab) or sorafenib. Overall survival (OS) and independently \nassessed progression-free survival (PFS) in the intent-to-treat population were \nthe primary endpoints. At the time of the primary analysis, the estimated median \nOS could not be estimated in the atezolizumab-bevacizumab arm and was 13.2 \nmonths in the sorafenib arm [HR, 0.58; 95% confidence interval (CI), 0.42-0.79]. \nThe estimated median PFS was 6.8 months (95% CI, 5.8-8.3) and 4.3 months (95% \nCI, 4.0-5.6) in the atezolizumab-bevacizumab and sorafenib arms, respectively. \nAdverse reactions occurring in >20% of patients receiving \natezolizumab-bevacizumab were hypertension, fatigue/asthenia, and proteinuria. \nAdverse reactions occurring in >20% of patients receiving sorafenib were \npalmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased \nappetite. Hemorrhage was reported more frequently in patients receiving \natezolizumab-bevacizumab (25%) than in patients receiving sorafenib (17%). An \nevaluation for the presence of varices is recommended within 6 months of \ninitiation of atezolizumab-bevacizumab in patients with HCC. Approval of \natezolizumab-bevacizumab is likely to change the treatment paradigm for HCC, \ngiven that treatment with atezolizumab-bevacizumab resulted in improved OS and \nPFS compared with sorafenib, an accepted standard of care for first-line \ntreatment of patients with unresectable HCC.See related commentary by Castet et \nal., p. 1827.", "AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of \natezolizumab plus bevacizumab for patients with unresectable hepatocellular \ncarcinoma (HCC). In this study, we evaluated this therapeutic combination in a \nreal-world setting, with a focus on patients who did not meet the IMbrave150 \neligibility criteria.\nMETHODS: In this multicenter study, patients with unresectable HCC treated with \natezolizumab plus bevacizumab between October 2020 and May 2021 were screened. \nIn patients who did not meet IMbrave150 eligibility criteria, treatment \nresponses and safety at 6 and 12 weeks were evaluated.\nRESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including \n46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of \nthese patients had a history of systemic therapy (44/46). The objective response \nrate and disease control rate observed using Response Evaluation Criteria in \nSolid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, \nrespectively; these rates were similar between patients who met and did not meet \nthe IMbrave150 criteria. Ten patients experienced progressive disease (PD) at \n6 weeks. Portal vein tumor thrombosis was significantly associated with PD \n(p = 0.039); none of the 15 patients with hepatitis B virus-related HCC \nexperienced PD (p = 0.050). The most common adverse events of grade 3 or higher \nwere aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile \nwas similar between patients who met and did not meet the IMbrave150 criteria.\nCONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not \nmeet the IMbrave150 criteria; however, the combination therapy showed good \nsafety and efficacy at the early treatment phase.", "Portal vein involvement is considered one of the most fearful complications of \nhepatocellular carcinoma (HCC). Portal vein tumor thrombosis (PVTT) is \nassociated with aggressive tumor biology (high grade), high tumor burden (number \nand size of lesions), high levels of serum markers (AFP), poor liver function \n(deranged LFT), and poor performance status of patients. The Barcelona Clinic \nLiver Cancer staging system places HCC patients with PVTT in advanced stage \n(BCLC Stage-C). This group contains a fairly heterogeneous patient population, \npreviously considered candidates for palliative systemic therapy with sorafenib. \nHowever, this provided modest overall survival (OS) benefit. The results of a \nrecent Phase III (IMbrave150) trial favor the combination of atezolizumab and \nbevacizumab over sorafenib as a standard of care in advanced unresectable HCC. \nWhile only lenvatinib proved to be non-inferior against sorafenib in a phase III \n(REFLECT trial), regorafenib (RESORCE trial), ramucirumab (REACH-2), and \ncabozantinib (CELESTIAL) have been approved second-line therapy in phase III \nclinical trials. Recently, the data on the prospect of other modalities in the \nmanagement of HCC with PVTT is mounting with favorable results. Targeting \nmultiple pathways in the HCC cascade using a combination of drugs and other \nmodalities such as RT, TACE, TARE, and HAIC appear effective for systemic and \nloco-regional control. The quest for the ideal combination therapy and the \nsequence set is still widely unanswered and prospective trials are lacking. With \nthe armament of available therapeutic options and the advances and refinements \nin the delivery system, down-staging patients to make them eligible for curative \nresection has been reported. In a rapidly evolving treatment landscape, \nperforming surgery when appropriate, in the form of LR and even LT to achieve \ncure does not seem farfetched. Likewise, adjuvant therapy and prompt management \nof the recurrences holds the key to prolong OS and DFS. This review discusses \nthe management options of HCC patients with PVTT.", "In light of positive efficacy and safety findings from the IMbrave150 trial of \natezolizumab plus bevacizumab, this novel combination has become the preferred \nfirst-line standard of care for patients with unresectable hepatocellular \ncarcinoma (HCC). Several additional trials are ongoing that combine an immune \ncheckpoint inhibitor with another agent such as a multiple kinase inhibitor or \nantiangiogenic agent. Therefore, the range of first-line treatment options for \nunresectable HCC is likely to increase, and healthcare providers need succinct \ninformation about the use of such combinations, including their efficacy and key \naspects of their safety profiles. Here, we review efficacy and safety data on \ncombination immunotherapies and offer guidance on monitoring and managing \nadverse events, especially those associated with atezolizumab plus bevacizumab. \nBecause of their underlying liver disease and high likelihood of portal \nhypertension, patients with unresectable HCC are at particular risk of \ngastrointestinal bleeding, and this risk may be exacerbated by treatments that \ninclude antiangiogenic agents. Healthcare providers also need to be alert to the \nrisks of proteinuria and hypertension, colitis, hepatitis, and reactivation of \nhepatitis B or C virus infection. They should also be aware of the possibility \nof rarer but potentially life-threatening adverse events such as pneumonitis and \ncardiovascular events. Awareness of the risks associated with these therapies \nand knowledge of adverse event monitoring and management will become \nincreasingly important as the therapeutic range broadens in unresectable HCC.", "BACKGROUND: Understanding patients' experience of cancer treatment is important. \nWe aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus \nbevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma \nin the IMbrave150 trial, which has already shown significant overall survival \nand progression-free survival benefits with this combination therapy.\nMETHODS: We did an open-label, randomised, phase 3 trial in 111 hospitals and \ncancer centres across 17 countries or regions. We included patients aged 18 \nyears or older with systemic, treatment-naive, histologically, cytologically, or \nclinically confirmed unresectable hepatocellular carcinoma and an Eastern \nCooperative Oncology Group (ECOG) performance status of 0 or 1, with disease \nthat was not amenable to curative surgical or locoregional therapies, or \nprogressive disease after surgical or locoregional therapies. Participants were \nrandomly assigned (2:1; using permuted block randomisation [blocks of six], \nstratified by geographical region; macrovascular invasion, extrahepatic spread, \nor both; baseline alpha-fetoprotein concentration; and ECOG performance status) \nto receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once \nevery 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical \nbenefit or unacceptable toxicity. The independent review facility for tumour \nassessment was masked to the treatment allocation. Previously reported coprimary \nendpoints were overall survival and independently assessed progression-free \nsurvival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified \nsecondary and exploratory analyses descriptively evaluated treatment effects on \npatient-reported quality of life, functioning, and disease symptoms per the \nEuropean Organisation for Research and Treatment of Cancer (EORTC) \nquality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life \nquestionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed \ndeterioration of PROs was analysed in the intention-to-treat population; all \nother analyses were done in the PRO-evaluable population (patients who had a \nbaseline PRO assessment and at least one assessment after baseline). The trial \nis ongoing; enrolment is closed. This trial is registered with \nClinicalTrials.gov, NCT03434379.\nFINDINGS: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened \nand 501 patients were enrolled and randomly assigned to atezolizumab plus \nbevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus \nbevacizumab group and 145 patients in the sorafenib group were included in the \nPRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was \n8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater \nfor 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab \nplus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 \ncompletion rates were 90% or greater for 20 of 24 cycles in the atezolizumab \nplus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib \ngroup (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab \nreduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom \nscales that were prespecified for analysis (appetite loss [hazard ratio (HR) \n0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], \npain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific \nsymptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] \nand pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of \ntreatment cycle five (after which attrition in the sorafenib group was more than \n50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab \nplus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 \n(20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role \nfunctioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning.\nINTERPRETATION: Prespecified analyses of PRO data showed clinically meaningful \nbenefits in terms of patient-reported quality of life, functioning, and disease \nsymptoms with atezolizumab plus bevacizumab compared with sorafenib, \nstrengthening the combination therapy's positive benefit-risk profile versus \nthat of sorafenib in patients with unresectable hepatocellular carcinoma.\nFUNDING: F Hoffmann-La Roche and Genentech.", "INTRODUCTION: The treatment algorithm of advanced hepatocellular carcinoma (HCC) \nhas evolved since the introduction of immunotherapy. The IMbrave150 trial set \natezolizumab-bevacizumab as a new standard-of-care first-line treatment for \nunresectable HCC patients. However, for patients with intermediate or advanced \nstage with portal vein thrombosis but without distant metastases, 90Yttrium \ntransarterial radioembolization (90Y-TARE) is considered the treatment of \nchoice.\nAREAS COVERED: We discuss the main evidence regarding the use of 90Y-TARE in \nHCC, the recent progress of immunotherapy in this tumor, and the preclinical \nrationale of combining VEGF blockade with the other two treatment strategies.\nEXPERT OPINION: HCC has an extremely heterogeneous tumor immune \nmicroenvironment. This may explain the inconsistent outcomes obtained with \nimmune-checkpoint inhibitors. The identification of patients who could benefit \nmost from immunotherapy is crucial; however, reliable markers of response are \nlacking. Radiation therapy and VEGF inhibition have an established synergism \nwith immunotherapy, mainly linked to enhanced antigen presentation and reduced \nimmunosuppressive immune infiltrate. Combining an immune-checkpoint inhibitor \nwith VEGF blockade and 90Y-TARE might hence overcome primary resistances \nobserved when each of these treatments is administerd alone.", "Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since \nthe introduction of the molecular targeted agent sorafenib in 2007. Sorafenib \nincreased the available treatment options for patients with extrahepatic spread \nand vascular invasion and improved survival in patients with advanced HCC; \nhowever, various shortcomings such as low response rates and relatively high \ntoxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at \ndeveloping new molecular targeted agents to provide more treatment options and \nsecond-line agents for patients with disease progression or intolerance to \nsorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all \nfirst-line and second-line clinical trials conducted during this period failed. \nHowever, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and \nregorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in \nquick succession from clinical trials and became available for clinical use. In \naddition, nivolumab and pembrolizumab were approved as second-line agents after \nsorafenib. A recent phase III trial (IMbrave150) showed that combination \nimmunotherapy with atezolizumab plus bevacizumab increases overall survival \ncompared with sorafenib therapy; Food and Drug Agency already approved this \ncombination therapy, and worldwide approval is expected soon. This review \ndescribes the recent advances in systemic therapy and the use of tyrosine kinase \ninhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal \nantibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors \n(nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the \nsimilarity of their efficacy and safety profiles to those in the general \npopulation.", "Hepatocellular carcinoma remains a serious global disease. Its incidence is \nincreasing. Standard procedures have been developed for each stage. The \ncomplexity of this disease shows that the selection of patients in stage 0/A for \ndifferent types of surgical treatment is very complicated. Treatment methods of \nstage B, especially locoregional treatment represented by TACE (transarterial \nchemoembolization or radioembolization of TARE), radiofrequency ablation and \nothers, move freely to lower and higher stages as adjunctive therapy. Lenvatinib \ncan replace TACE with equal efficacy in cases where locoregional treatment \ncannot be used. Until 2016, the only systemic treatment option for stage C was \nsorafenib. Lenvatinib became a second-line drug to show non-inferiority to \nsorafenib in OS. Retrospective analyzes revealed that patients who responded to \nthe treatment with lenvatinib or sorafenib had a median survival of over 22 \nmonths. Sequential treatment with sorafenib and regorafenib in the RESOURCE \nstudy with a median survival of more than 24 months was similar. Ramucirumab was \neffective only in patients with high AFP levels. The study demonstrated the \nimportance of selecting patients according to prognostic factors (extrahepatic \nspread and vascular invasion). Second-line cabozantinib has shown the same \nbenefit as regorafenib. In the second line, immunotherapy represented by anti \nPD-1 antibodies nivolumab and pembrolizumab was used. Sequential administration \nafter sorafenib prolonged the median overall survival of about 22 months. We \ncurrently have sorafenib and lenvatinib in the first line, regorafenib, \ncabozantinib, ramucirumab (AFP 400 μg/L), pembrolizumab and nivolumab in \nthe second line. The possibilities of monotherapy have been exhausted. The \ndiscovery of a synergistic effect of angiogenesis inhibitors, which convert a \ncold tumor into a hot one and facilitate the efficacy of anti-PD-1 / anti-PDL-1 \nantibodies, has led to a highly effective combination therapy. In study \nIMbrave150, the combination of atezolizumab and bevacizumab was successfully \nused compared to sorafenib in the first-line treatment. Additional studies are \ncurrently underway using other tyrosin kinase inhibitors - regorafenib, \nlenvatinib and cabozantinib - in combination with nivolumab, ipilimumab and \npembrolizumab. This development of treatment at all stages evoked with renewed \nurgency the need to find a suitable way to search for the early stages of HCC \nand to create a more effective system for selecting patients for the most \nappropriate treatment.", "BACKGROUND: IMbrave150 is a phase III trial that assessed \natezolizumab + bevacizumab (ATEZO/BEV) versus sorafenib (SOR) in patients with \nunresectable hepatocellular carcinoma (HCC) and demonstrated a significant \nimprovement in clinical outcomes. Exploratory analyses characterized objective \nresponse rate (ORR), depth (DpR), and duration of response (DoR), and patients \nwith a complete response (CR).\nMETHODS: Patients were randomized 2:1 to intravenous ATEZO (1200 mg) + BEV \n(15 mg/kg) every 3 weeks or oral SOR (400 mg) twice daily. Tumors were evaluated \nusing Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and \nHCC-modified RECIST (mRECIST). ORR by prior treatment and largest baseline liver \nlesion size, DoR, time to response (TTR), and complete response (TTCR) were \nanalyzed.\nRESULTS: For both criteria, responses favored ATEZO/BEV versus SOR regardless of \nprior treatment and in patients with lesions ≥3 cm. Median TTR was 2.8 months \nper RECIST 1.1 (range: 1.2-12.3 months) and 2.8 months per mRECIST (range: \n1.1-12.3 months) with ATEZO/BEV. Patients receiving ATEZO/BEV had a greater DpR, \nper both criteria, across baseline liver lesion sizes. Characteristics of \ncomplete responders were similar to those of the intent-to-treat population. In \ncomplete responders receiving ATEZO/BEV per mRECIST versus RECIST 1.1, \nrespectively, median TTCR was shorter (5.5 vs. 7.0 months), mean baseline sum of \nlesion diameter was longer (5.0 [SD, 5.1] vs. 2.6 [SD, 1.4] cm), and mean \nlargest liver lesion size was larger (4.8 [SD, 4.2] vs. 2.3 [SD, 1.0] cm).\nCONCLUSIONS: These data highlight the improved ORR, DpR, and CR rates with \nATEZO/BEV in unresectable HCC.", "Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver \ncancer worldwide, and the overall survival of patients with unresectable disease \nis poor. In the last five years, immune checkpoint inhibitors (ICIs) have \nrevolutionized the treatment scenario of several hematological and solid tumors, \nand these agents have been actively explored in unresectable HCC. Firstly, \npromising findings of phase I and II clinical studies reporting durable \nresponses and a tolerable safety profile have led to the assessment of ICIs as \nsingle agents in phase III clinical studies; however, the latter have provided \ncontroversial results, and the activity of ICI monotherapy seems limited to a \nsmall subgroup of patients. Conversely, the IMbrave150 trial recently showed \nthat, among patients with previously untreated unresectable HCC, treatment with \natezolizumab plus bevacizumab resulted in significantly longer overall survival \nand progression-free survival compared to sorafenib monotherapy. In addition, \nthe activity of several other ICIs is under investigation, as combination \nimmunotherapy as well as combinations of immunotherapy with antiangiogenic \nagents. Nonetheless, there are currently no validated predictive biomarkers able \nto guide treatment choice in this setting, where the identification of specific \npredictors of response to ICIs represents a major challenge. In this review, we \naim to provide a critical overview of recent evidence on biochemical predictors \nof response to ICIs in patients with unresectable HCC, especially focusing on \nPD-L1, TMB, MSI, and other emerging biomarkers.", "Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause \nof cancer-related deaths. Although early-stage disease may be curable by \nresection, liver transplantation or ablation, many patients present with \nunresectable disease and have a poor prognosis. Combination treatment with \natezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent \nIMbrave150 study was shown to be effective with an acceptable safety profile in \npatients with unresectable HCC. Herein, we discuss this novel combination in the \ncontext of the liver immune environment, summarize the mechanism and \npharmacokinetics of atezolizumab and bevacizumab, and examine recent data on \nother immune checkpoint inhibitor combination strategies as well as future \ndirections in the treatment of patients with advanced HCC.", "BACKGROUND: Despite the use of current standard therapy, the prognosis of \npatients with unresectable hepatocellular carcinoma (HCC) is poor, with median \nsurvival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer \n[BCLC] stage B) and 6-8 mo for advanced HCC (BCLC stage C). Although patients \nwith early-stage HCC are usually suitable for therapies with curative intention, \nup to 70% of patients experience relapse within 5 years. In the past decade, the \nUnited States Food and Drug Administration has approved different immunogenic \ntreatment options for advanced HCC, the most common type of liver cancer among \nadults. Nevertheless, no treatment is useful in the adjuvant setting. Since \n2007, the multi-kinase inhibitor sorafenib has been used as a first-line \ntargeted drug to address the increased mortality and incidence rates of HCC. \nHowever, in 2020, the IMbrave150 trial demonstrated that combination therapy of \natezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab \n(anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a \nsingle anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer \nmonotherapy for HCC treatment.\nAIM: To conduct a systematic literature review to evaluate the evidence \nsupporting the efficacy and safety of atezolizumab/bevacizumab as preferred \nfirst-line drug therapy over the conventional sorafenib or atezolizumab \nmonotherapies, which are used to improve survival outcomes and reduce disease \nprogression in patients with unresectable HCC and non-decompensated liver \ndisease.\nMETHODS: A comprehensive literature review was conducted using the PubMed, \nScopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, \nand CINAHL databases to identify studies that met the inclusion criteria using \nrelevant MeSH terms. This systematic review was conducted according to the \nPreferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines \nand risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis.\nRESULTS: In the atezolizumab/bevacizumab group, an improvement in overall tumor \nresponse, reduction of disease progression, and longer progression-free survival \nwere observed compared to monotherapy with either sorafenib or atezolizumab. \nHypertension and proteinuria were the most common adverse events, and the rates \nof adverse events were comparable to those with the monotherapy. Of the studies, \nthere were two completed trials and two ongoing trials analyzed using high \nquality and low bias. A more thorough analysis was only performed on the \ncompleted trials.\nCONCLUSION: Treatment of HCC with atezolizumab/bevacizumab combination therapy \nwas confirmed to be an effective first-line treatment to improve survival in \npatients with unresectable HCC and non-decompensated liver disease compared to \nmonotherapy with either sorafenib or atezolizumab.", "Atezolizumab plus bevacizumab combination therapy was approved worldwide for use \nin 2020. A 30% objective response rate with 8% complete response (CR) was \nachieved in a phase 3 IMbrave150 trial. Here, the change in the treatment \nstrategy for hepatocellular carcinoma (HCC) using atezolizumab plus bevacizumab \ncombination therapy is reviewed. The phase 3 IMbrave150 clinical trial was \nsuccessful because of the direct antitumor effect of bevacizumab, which shifted \nthe suppressive immune microenvironment to a responsive immune microenvironment, \nin addition to its synergistic effects when combined with atezolizumab. The \nanalysis of CR cases was effective in patients with poor conditions, \nparticularly tumor invasion in the main portal trunk (Vp4), making the \ncombination therapy a breakthrough for HCC treatment. The response rate of the \ncombination therapy was 44% against intermediate-stage HCC. Such a strong \ntumor-reduction effect paves the way for curative conversion (ABC conversion) \ntherapy and, therefore, treatment strategies for intermediate-stage HCC may \nundergo a significant shift in the future. As these treatment strategies are \neffective in maintaining liver function, even in elderly patients, the \ntransition frequency to second-line treatments could also be improved. These \nstrategies may be effective against nonalcoholic steatohepatitis-related \nhepatocellular carcinoma and WNT/β-catenin mutations to a certain degree.", "For over a decade, sorafenib remained the only systemic agent with proven \nclinical efficacy for patients with advanced hepatocellular carcinoma (HCC). \nRecent years have seen a proliferation of agents. In the first line, lenvatinib \nwas found to be non-inferior to sorafenib in terms of overall survival (OS), \nwith significantly better progression-free survival and objective response rate. \nMeanwhile, encouraging efficacy signals were observed in phase I/II studies of \nimmune checkpoint inhibitors as monotherapy in HCC. Although subsequent phase \nIII trials failed to demonstrate statistically significant benefit in OS, other \nclinically meaningful outcomes were observed, including long-term disease \ncontrol with a favorable toxicity profile. In addition, a synergistic response \nhas been postulated based on the interplay between antiangiogenic molecular \ntargeted agents and immunotherapy. On this basis, interest has turned toward \ncombination strategies of immunotherapy with these standard-of-care medications \nin the hope of improving treatment efficacy for advanced HCC, while maintaining \ntolerable safety profiles. Indeed, preliminary results from phase I studies of \nlenvatinib plus pembrolizumab and atezolizumab plus bevacizumab have proved \nfavorable, prompting phase III investigations in the frontline setting, and for \natezolizumab plus bevacizumab, these positive findings have been substantiated \nby recent reporting of phase III data from IMbrave150. In this review, we will \npresent the currently available data on combination therapy atezolizumab plus \nbevacizumab in advanced HCC, and compare these findings to other promising \ncombination treatments, most notably that of lenvatinib plus pembrolizumab.", "A successful phase III trial for the combination of atezolizumab and bevacizumab \n(the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been \nreported. This is groundbreaking because nivolumab and pembrolizumab, both \nprogrammed cell death-1 (PD-1) antibodies, have failed to show efficacy as \nfirst- and second-line therapeutics, respectively, in phase III clinical trials. \nImmunotherapy with a combination of atezolizumab and bevacizumab resulted in \nbetter survival than treatment with sorafenib for the first time since sorafenib \nwas approved in 2007. The high efficacy of the combination of PD-1/programmed \ndeath ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) antibodies \nis not only due to their additive effects on tumor growth, but also to their \nreprogramming of the immunosuppressive microenvironment into an \nimmunostimulatory microenvironment. These results were confirmed in a phase Ib \ntrial that showed significantly longer progression-free survival in the \natezolizumab plus bevacizumab group than in patients that received atezolizumab \nalone. These results demonstrate that immunotherapy with a combination of \nPD-1/PD-L1 and VEGF inhibitors is effective and may result in a reprogramming of \nthe tumor microenvironment. The results of an ongoing phase III trial of a PD-1 \nantibody in combination with the VEGF receptor tyrosine kinase inhibitor (TKI) \nare highly anticipated.", "Introduction: The treatment of unresectable hepatocellular carcinoma (HCC) has \nradically changed after the approval of the combination of atezolizumab plus \nbevacizumab as first-line treatment. A strong preclinical rationale exists to \nsupport the combination of bevacizumab, an anti-vascular endothelial growth \nfactor monoclonal antibody (mAb), and atezolizumab, an anti-programmed death \nligand 1 mAb. The efficacy of the combination was first assessed in the phase Ib \nGO30140 study, and the combination was then proven superior to the prior \nstandard of care, sorafenib, in the phase III IMbrave150 trial.Areas covered: \nThis article focuses on the mechanism of action of atezolizumab and bevacizumab, \ntheir synergistic action, and the two clinical trials leading to approval. We \nalso collected the body of post-hoc analyses and meta-analyses to help guide the \ndecision-making process in terms of patient selection and subsequent \ntreatments.Expert opinion: Atezolizumab plus bevacizumab are the current \nstandard of care for first-line treatment of unresectable or metastatic HCC and \ntreatment-naïve patient should be treated with the combination, unless \ncontraindications to the drugs. Since all the available agents for further lines \nof treatment have been approved for sorafenib-pretreated patients, prospective \ntrials, post-hoc analyses, and real-world data assessing valid treatment \nsequencing are strongly needed." ]	nan
515d7693298dcd4e5100000c	[ 22954629, 12872232, 20641139, 12422360, 12915006 ]	train	A common problem in proteomics is the contamination of samples with exogenous proteins (often from other species). These proteins can be found in specific databases. List some contaminants.	list	Some common contaminants in proteomics are proteases (used for the digestion of the proteins), keratins (usually from the skin), proteins originated from the serum of the culture media and antibodies if used in the experiment.	['Proteases', 'Keratins', 'Bovine serum proteins', 'Antibodies']	[ "Mass spectrometry is widely used in bioanalysis, including the fields of \nmetabolomics and proteomics, to simultaneously measure large numbers of \nmolecules in complex biological samples. Contaminants routinely occur within \nthese samples, for example, originating from the solvents or plasticware. \nIdentification of these contaminants is crucial to enable their removal before \ndata analysis, in particular to maintain the validity of conclusions drawn from \nuni- and multivariate statistical analyses. Although efforts have been made to \nreport contaminants within mass spectra, this information is fragmented and its \naccessibility is relatively limited. In response to the needs of the \nbioanalytical community, here we report the creation of an extensive manually \nwell-annotated database of currently known small molecule contaminants.\nAVAILABILITY: The Mass spectrometry Contaminants Database (MaConDa) is freely \navailable and accessible through all major browsers or by using the MaConDa web \nservice http://www.maconda.bham.ac.uk.", "Unmatched masses are often observed in the experimental peptide mass spectra \nwhen database searching is performed with the ProFound program. Comparison \nbetween theoretical and experimental mass spectra of standard proteins shows \nthat contamination accounts for most of the unmatched masses. In this \nretrospective analysis, the top 100 most probable contaminating masses, as \nlisted in order of their probability, are statistically filtered out from 118 \ndifferent experimental peptide mass fingerprinting (PMF) maps. Most of the \ninterfering masses originate from trypsin autolysis and human keratins. \nSubtraction of known contaminants from raw data and using cleaner masses for \nsearching can enhance protein identification by PMF.", "Cell culture is a fundamental tool in proteomics where mammalian cells are \ncultured in vitro using a growth medium often supplemented with 5-15% FBS. \nContamination by bovine proteins is difficult to avoid because of adherence to \nthe plastic vessel and the cultured cells. We have generated peptides from \nbovine serum using four sample preparation methods and analyzed the peptides by \nhigh mass accuracy LC-MS/MS. Distinguishing between bovine and human peptides is \ndifficult because of a considerable overlap of identical tryptic peptide \nsequences. Pitfalls in interpretation, different database search strategies to \nminimize erroneous identifications and an augmented contaminant database are \npresented.", "FindPept (http://www.expasy.org/tools/findpept.html) is a software tool designed \nto identify the origin of peptide masses obtained by peptide mass fingerprinting \nwhich are not matched by existing protein identification tools. It identifies \nmasses resulting from unspecific proteolytic cleavage, missed cleavage, protease \nautolysis or keratin contaminants. It also takes into account post-translational \nmodifications derived from the annotation of the SWISS-PROT database or supplied \nby the user, and chemical modifications of peptides. Based on a number of \nexperimental examples, we show that the commonly held rules for the specificity \nof tryptic cleavage are an oversimplification, mainly because of effects of \nneighboring residues, experimental conditions, and contaminants present in the \nenzyme sample.", "Immunoprecipitation (IP) and coimmunoprecipitation (co-IP) are key techniques \nfor studying protein-protein interactions. These methods utilize immobilized \nProtein A or Protein G to isolate antibody-bound target antigens. The main \ndisadvantage of traditional IP and co-IP is that the conditions used to elute \nthe precipitated antigen also release the antibody thus contaminating the \nantigen and destroying the antibody support. To overcome these problems, we \ndescribe two methods to generate a reusable antibody support by cross-linking \nthe antibody to immobilized Protein A or Protein G, or by coupling it directly \nto the resin (see Scheme 1). Antibody cross-linking can be done in 1 h while \nantibody coupling requires 4 h. IP or co-IP is accomplished by incubating the \nantibody resin with the protein sample. Washes and elutions are carried out in a \nspin column to reduce resin loss and decrease assay time. Target proteins are \neluted with 0.1 M glycine (pH 2.8) and the resin-bound antibody is \nre-equilibrated in phosphate-buffered saline (PBS) for reuse. Our studies have \ndemonstrated that the immobilization efficiency for the antibody coupling method \nwas similar for several species of antibody. Furthermore, we illustrate that \nusing both methods of antibody immobilization yield IP and co-IP results similar \nto traditional protocols but eliminate the antibody heavy and light chain \ncontamination." ]	nan
5312280ce3eabad02100000a	[ 11037190, 21968521, 20635402, 8898827, 18463369, 15362573, 22436252, 22426657, 23966756, 9973290, 16723886, 9128751, 20644152, 23077562, 21596366, 21048783, 23713105, 10754001, 15340753, 18576213, 19335127, 17431895, 19918425, 24167642, 15675355, 15675354, 18174554, 16164190, 10757474, 16475235, 17138018, 8937199, 21631222 ]	train	Abnormalities in which chromosomes were linked to the Moyamoya disease?	list	chromosomes 3, 6, 8, 12, 15, 17, 21, X and Y were implicated in the Moyamoya disease.	['3', '6', '8', '12', '15', '17', '21', 'X', 'Y']	[ "Moyamoya disease is a specific chronic cerebrovascular occlusive disease first \nreported by Japanese surgeons in 1957. The disease is characterized by stenosis \nor occlusion of the terminal portions of the bilateral internal carotid arteries \nand abnormal vascular network in the vicinity of the arterial occlusion. It may \ncause ischemic attacks or cerebral infarction, which is more frequent in \nchildren than in adults. In adults, cerebral hemorrhage may occur. The disease \nis distributed in all age groups, but the highest peak is in childhood at less \nthan 10 years of age. The characteristic histopathologic features of the \nsteno-occlusive arteries are fibrocellular thickening of the intima containing \nproliferated smooth muscle cells and prominently tortuous and often duplicated \ninternal elastic lamina. There is usually no atheromatous plaque in the arterial \nwall. Etiology of the disease is still unknown; however, multifactorial \ninheritance is considered possible because of a higher incidence of the disease \nin Japanese and Koreans and approximately 10% of familial occurrence among the \nJapanese. Recent genetic studies suggest some responsible genetic foci in \nchromosomes 3, 6 and 17.", "A 20-year-old woman presented with mental retardation and a history of stroke \nrelated to moyamoya disease at the age of 8 years. She had cognitive impairment \nwhich became more pronounced after the stroke. This patient's parents were first \ncousins and six close family relatives had strokes in their 60s or 70s. The \npatient's 16-year-old sister had learning disability, chronic muscle pain, and \nan ECG suggestive of previous hypoxemic heart injury. The two sisters had \nsimilar dysmorphic facial appearance including a prominent philtrum, bulbous \nnose, and severe acne. They both had increased subcutaneous tissue in their \nfaces, whereas their bodies were slim. Both sisters were found to have elevated \nlevels of rheumatoid factor, C-reactive protein, and erythrocyte sedimentation \nrate on repeat measurements. Partial autoimmunity screening in one of the \npatients was negative. Chromosome analysis and array comparative genomic \nhybridization analyses were also normal. Nerve conduction findings in the \nyounger sister were consistent with distal, predominantly motor, demyelinating \nneuropathy localized to the lower extremities. We propose that these two sisters \nsuffer from a new autosomal recessive syndrome. Carrier status for this \ncondition may predispose to later onset stroke.", "Aortic dilation and dissection are well-recognized cardiac abnormalities in \nwomen with Turner syndrome (TS), although the underlying pathophysiology is not \nfully understood. We report on a 46-year-old Hispanic woman who was previously \ndiagnosed with moyamoya disease on magnetic resonance imaging after a \npresentation with stroke-like symptoms. Her features were consistent with TS and \nchromosome analysis revealed mosaicism in which 17% of the cells showed a \npseudoisodicentric Y chromosome: 45,X (25)/46,X psu idic (Y)(11.2) (5). A \npreceding screening transthoracic echocardiogram had shown a bicuspid aortic \nvalve (BAV) with an aortic diameter of 3.2 cm; at the time of moyamoya \ndiagnosis, the aorta was 3.5 cm with mild aortic stenosis and mild aortic \nregurgitation. Four years later, the patient had had an acute aortic dissection, \nStanford type A, which was repaired successfully. This case report is the third \nindividual with TS associated with moyamoya disease and the first associated \nwith dissection. The small number of cases does not allow detailed analysis \nother than noting patient age (two older than 40 years), karyotype (two others \nassociated with isochrome Xq), and associated cardiac risk factors (one with \nBAV). Although this may be a chance occurrence, we hypothesize that moyamoya \ndisease could be a manifestation of the vasculopathy in TS.", "BACKGROUND AND PURPOSE: Moyamoya disease is a chronic occlusive cerebrovascular \ndisorder characterized by progressive stenosis of the supraclinoid internal \ncarotid artery, with the secondary development of enlarged basal collateral \nvessels. It may occur as a primary disease or as a syndrome in association with \na variety of conditions, and its pathogenesis remains unexplained. There are \nrelatively few reports describing the occurrence of moyamoya in Down syndrome. \nThe aim of this study is to describe the clinical and radiological features of \nmoyamoya syndrome associated with Down syndrome (MM-DS) and to explore theories \nof moyamoya pathogenesis in these patients.\nMETHODS: Seven children with MM-DS underwent brain imaging, transfemoral \nangiography, and serial neurological exams. Neurological deficits, poststroke \nrecovery, radiographic infarct characteristics, and angiographic abnormalities \nwere reviewed.\nRESULTS: The clinical and radiological features of primary moyamoya disease \noverlap with those of MM-DS. Hemiplegia and aphasia were the most common \npresentations. Motor recovery was excellent in five of seven cases. Cerebral \ninfarcts were superficial or deep and can occur in a watershed distribution. \nAngiography demonstrated involvement of the internal carotid artery and its \nbranches bilaterally in all seven cases and the posterior cerebral arteries in \nfour cases.\nCONCLUSIONS: The clinical and radiological features of MM-DS overlap with \nprimary moyamoya disease. We postulate that a protein encoded on chromosome 21 \nmay be related to the pathogenesis of moyamoya disease. Although the neuronal \nsubstrate is abnormal in Down syndrome patients, recovery from hemiplegic stroke \nin patients with MM-DS is comparable to recovery in patients with primary \nmoyamoya.", "BACKGROUND: Moyamoya disease (MMD) is an idiopathic steno-occlusive \ncerebrovascular disease that represents an important cause of stroke. However, \netiology of the disease has remained largely unknown.\nMETHODS: We previously showed that the inheritance pattern of MMD is autosomal \ndominant with incomplete penetrance. Here, we report the genome-wide parametric \nlinkage analysis for MMD in 15 extended Japanese families. We conducted linkage \nanalyses under two diagnostic classifications: narrow and broad. Affected \nmember-only analysis was applied due to incomplete and age-dependent penetrance \nof the disease.\nRESULTS: Under both classifications, significant evidence of linkage was only \nobserved on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) \nscores of 6.57 (under the narrow classification) and 8.07 (under the broad \nclassification) at D17S704. Haplotype analysis revealed segregation of a disease \nhaplotype in all families but one, and informative crossovers enabled mapping of \nthe MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, \nencompassing 94 annotated genes.\nCONCLUSIONS: Our data suggest that there is a major gene locus for autosomal \ndominant moyamoya disease on chromosome 17q25.3.", "Moyamoya disease (MIM 252350) is characterized by stenosis or occlusion of the \nterminal portions of the bilateral internal carotid arteries and by abnormal \nvascular networks at the base of the brain. There is a high incidence of \nmoyamoya disease in Asia, especially in Japan. Multifactorial inheritance is \nestimated with lambda(s)>40. Previous linkage studies have indicated that \nsusceptibility loci for the disease are located on chromosomes 3p, 6q, and 17q. \nIn the present study, we searched for loci linked to the disease in 12 Japanese \nfamilies using 428 microsatellite markers and found significant evidence for \nlinkage to 8q23 [maximum LOD score (MLS) of 3.6] and suggestive evidence for \nlinkage to 12p12 (MLS=2.3). The present study revealed a novel locus for \nmoyamoya disease.", "BACKGROUND: Single-gene disorders related to ischemic stroke seem to be an \nimportant cause of stroke in young patients without known risk factors. To \nidentify new genes responsible of such diseases, we studied a consanguineous \nMoroccan family with three affected individuals displaying hereditary \nleucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis \npigmentosa that appears to segregate in autosomal recessive pattern.\nMETHODS: All family members underwent neurological and radiological \nexaminations. A genome wide search was conducted in this family using the ABI \nPRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate \ngenes within the region linked to the disease were screened for mutations by \ndirect sequencing.\nRESULTS: Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis \nof recombination events and LOD score calculation suggests linkage of the \nresponsible gene in a genetic interval of 11 Mb located between D17S789 and \nD17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven \ncandidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and \nGRIN2C, identified three missense mutations in the FDXR gene which were also \nfound in a homozygous state in three healthy controls, suggesting that these \nvariants are not disease-causing mutations in the family.\nCONCLUSION: A novel locus for leucoencephalopathy with ischemic stroke, \ndysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome \n17q24.2-25.3 in a consanguineous Moroccan family.", "Stroke in trisomy 21 may be due to cardioembolism, atherosclerosis, vasculitis, \nmoyamoya disease, sinus venous thrombosis, internal carotid hypoplasia or \ninfections like endocarditis with septic emboli, meningitis or brain abscess. In \nrare cases, however, stroke etiology remains unexplained. We present a 19 year \nold Caucasian girl with trisomy 21 with a 47XX+21 karyotype who suffered at age \n11 years from a transient ischemic attack with left hemiparesis, and at age \n17 years from an ischemic stroke in the territory of the right cerebral medial \nartery. She suffered from arterial hypertension, obesity and \nhypercholesterolemia. Since blood coagulation studies, immunologic parameters, \nblood cultures, 24-h Holter monitoring, transthoracic and transesophageal \nechocardiography, magnetic resonance angiography of the extra- and intracranial \nvessels, thoracic and abdominal aorta and renal arteries did not provide any \nexplanation for the stroke, implantation of a loop recorder is considered in \norder to detect episodes of clinically silent atrial fibrillation.", "A 14-year-old boy was admitted to our hospital after being diagnosed at a local \nclinic with bilateral carotid artery stenoses (Moyamoya disease) and mild \nthyrotoxicosis. A blood examination showed suppressed TSH and elevated \ntriiodothyronine and thyroxine levels; however, he was negative for \nanti-thyrotropin receptor antibody (TRAB) and thyroid stimulating antibody \n(TSAB). Concern about a possible thyroid crisis led us to administer thiamazole \n(MMI) and potassium iodide (KI), following which \nencephalo-duro-arterio-synangiosis (EDAS) of the left side was performed \nsuccessfully. After about 1 mo, he became positive for TRAB and TSAB. He was \nthought to have Graves' disease and Moyamoya disease coincidentally. Several \nfactors are considered to be involved in the coincidental onset of these two \ndiseases.", "Moyamoya disease is characterized by bilateral stenosis and/or occlusion of the \nterminal portion of the internal carotid artery. Moyamoya disease is prevalent \namong patients <10 years of age. Although most cases appear to be sporadic, \napproximately 10% occur as familial cases. The incidence of familial cases has \nbeen increasing because noninvasive diagnostic equipment, such as \nmagnetic-resonance imaging and magnetic-resonance angiography, can detect the \ndisease in almost all affected patients, including asymptomatic patients, during \nscreening studies. In this study, we performed a total genome search to identify \nthe location of a familial moyamoya disease gene in 16 families, assuming an \nunknown mode of inheritance. A linkage was found between the disease and markers \nlocated at 3p24.2-26. A maximum NPL score of 3.46 was obtained with marker \nD3S3050. This is the first genetic locus found to be involved in the molecular \npathogenesis of familial moyamoya disease.", "OBJECTIVE: The genes encoding tissue inhibitor of metalloproteinase (TIMP) 4 and \nTIMP2 span chromosomes 3p24.2-p26 and 17q25, respectively, which are the \nlocations of familial moyamoya disease (FMMD) genes. We investigated single \nnucleotide polymorphisms of the TIMP2 and TIMP4 genes in FMMD patients to \ndetermine genetic predispositions.\nMETHODS: Eleven blood samples from FMMD patients were recruited. Controls \nincluded 50 blood samples from patients with nonfamilial moyamoya disease (MMD) \nand another 50 blood samples from non-MMD persons. We evaluated the promoter \nregions, exon-intron junctions, and the exons of the TIMP2 and TIMP4 genes by \ndirect sequencing, and compared single nucleotide polymorphisms frequencies \namong the study groups.\nRESULTS: A significantly higher frequency of a heterozygous genotype was found \nin the TIMP2 promoter region at position -418 in FMMD; that is, the G/C \nheterozygous genotype at position -418 was observed in nine of 11 patients with \nFMMD, in 16 out of 50 nonfamilial MMD control participants, and in 14 out of 50 \nnon-MMD control participants (FMMD versus nonfamilial MMD: odds ratio, 9.56; 95% \nconfidence interval, 1.85-49.48; P = 0.005; and FMMD versus non-MMD: odds ratio, \n10.50; 95% confidence interval, 2.02-54.55; P = 0.001). This base at position \n-418 corresponds to the third base of the GAGGCTGGG sequence, an Sp1 binding \nsite. Thus, changes in this position may influence Sp1 binding and subsequent \ntranscription of the gene.\nCONCLUSION: Our findings suggest that the presence of a G/C heterozygous \ngenotype at position -418 in TIMP2 promoter could be a genetic predisposing \nfactor for FMMD.", "Moyamoya disease is a progressive cerebrovascular occlusive disease that occurs \nfrequently in children. The etiology is unknown. We examined changes in \nbiological characteristics and responsiveness to serum mitogens during the in \nvitro cellular aging of arterial smooth muscle cell strains derived from \npatients with moyamoya disease (HMSMC) and compared them with those of cells \nfrom age-matched control patients (HCSMC). HMSMC had a normal human diploid \nchromosome constitution. HMSMC and HCSMC had almost the same in vitro life span \nand the age-related patterns of biological parameters were essentially the same. \nHowever, the doubling time at the early passages was significantly longer in \nmoyamoya SMC than control SMC, although there was no significant difference at \nthe late passages. Furthermore, the poor responsiveness of moyamoya SMC to \nplatelet-derived growth factor was retained throughout the life span in vitro. \nThese results support the hypothesis that functional alterations in vascular \ncells are involved in the mechanism of development of intimal thickening in \nmoyamoya disease.", "OBJECTIVE: We report a detailed description of a family affected by a hereditary \nmultisystem disorder associated with moyamoya syndrome.\nMETHODS: In this family case report, we evaluated 9 members of the same family \noriginating from Algeria. Investigations included neuroimaging, cardiologic and \nophthalmologic evaluation, hormonal testing, hemoglobin electrophoresis, \nchromosomal karyotyping, muscle biopsy for morphology, immunohistochemistry and \nenzyme assays, mtDNA mutation screening, and haplotype analysis of 2 loci \npreviously linked to moyamoya, on chromosomes 10 (ACTA2) and 17.\nRESULTS: Five males related through a maternal lineage were affected, suggesting \nan X-linked inheritance. Four of them had symptomatic moyamoya syndrome with an \nonset of acute neurologic manifestations between 4 and 32 years. \nHypergonadotropic hypogonadism, azoospermia, short stature of postnatal onset \n(-2 to -4 SD in adulthood), premature graying of hair, and dysmorphism were \npresent in all patients. The other features of the disease included early \ncataract in 4, dilated cardiomyopathy in 3, and partial growth hormone \ndeficiency in 2 members. Muscle biopsy data did not reveal signs of a \nmitochondrial disorder. All conditions known to be associated with moyamoya \nsyndrome such as Down syndrome, neurofibromatosis, and sickle cell disease were \nexcluded. We also excluded linkage to the 2 loci previously reported to be \ninvolved in autosomal dominant syndromic and nonsyndromic moyamoya. Carrier \nfemales had normal phenotype and clinical history.\nCONCLUSIONS: These data strongly suggest that this family is affected by a \nhereditary moyamoya multisystem disorder with X-linked recessive pattern of \ninheritance.", "We conducted a case-control study to investigate whether vascular endothelial \ngrowth factor (VEGF -2578, -1154, -634, and 936) and kinase insert domain \ncontaining receptor (KDR -604, 1192, and 1719) polymorphisms are associated with \nmoyamoya disease. Korean patients with moyamoya disease (n = 107, mean age, \n20.9±15.9 years; 66.4% female) and 243 healthy control subjects (mean age, \n23.0±16.1 years; 56.8% female) were included. The subjects were divided into \npediatric and adult groups. Among the 64 surgical patients, we evaluated \ncollateral vessel formation after 2 years and divided patients into good \n(collateral grade A) or poor (collateral grade B and C) groups. The frequencies \nand distributions of four VEGF (-2578, -1154, -634, and 936) and KDR (-604, \n1192, and 1719) polymorphisms were assessed from patients with moyamoya disease \nand compared to the control group. No differences were observed in VEGF -2578, \n-1154, -634, and 936 or KDR -604, 1192, and 1719 polymorphisms between the \ncontrol group and moyamoya disease group. However, we found the -634CC genotype \noccurred less frequently in the pediatric moyamoya group (p = 0.040) whereas the \nKDR -604C/1192A/1719T haplotype increased the risk of pediatric moyamoya (p = \n0.024). Patients with the CC genotype of VEGF -634 had better collateral vessel \nformation after surgery. Our results suggest that the VEGF -634G allele is \nassociated with pediatric moyamoya disease and poor collateral vessel formation.", "Author information:\n(1)INSERM UMR-S-740; Université Paris, 7 Denis Diderot, 10 Avenue de Verdun, \n75010 Paris, France.\n(2)Program in Genomics of Differentiation, National Institute of Child Health \nand Human Development, National Institutes of Health, Bethesda, MD 20892.\n(3)Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier \nLariboisière-Saint-Louis, Service de Neurologie, Centre de Référence des \nMaladies Vasculaires Rares du Cerveau et de l'Oeil, F-75010 Paris, France.\n(4)Hospices Civils de Lyon, Groupe Hospitalier Est, Hôpital Femme-Mère-Enfant, \nService de Neurologie Pédiatrique, 69677 Bron, France.\n(5)Division of Pediatric Endocrinology, Lyon University Pediatric Hospital, \nINSERM U.870, Centre d'Investigation Clinique 201, Université Claude Bernard \nLyon 1, Hospices Civils de Lyon, Lyon, France.\n(6)Department of Neurosurgery, Stanford Stroke Center and Stanford Institute for \nNeuro-Innovation and Translational Neurosciences, Stanford University School of \nMedicine, Stanford, California, USA.\n(7)First Department of Neurology, Eginition Hospital, National and Kapodestrian \nUniversity of Athens, School of Medicine, 11528 Athens, Greece.\n(8)Assistance Publique des Hôpitaux de Paris, Plateforme de Génomique \nConstitutionnelle du Groupe Hospitalo Universitaire Nord, Hôpital Bichat, \nF-75010 Paris, France.\n(9)INSERM UMR-S-740; Université Paris, 7 Denis Diderot, 10 Avenue de Verdun, \n75010 Paris, France; Assistance Publique des Hôpitaux de Paris, Groupe \nHospitalier Lariboisière-Saint-Louis, Laboratoire de Génétique, Centre de \nRéférence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, F-75010 Paris, \nFrance. Electronic address: tournier-lasserve@univ-paris-diderot.fr.", "Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by \nbilateral internal carotid artery stenosis and abnormal collateral vessels. \nAlthough ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A \ngenome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) \nwas performed, comparing 72 Japanese MMD patients with 45 Japanese controls and \nresulting in a strong association of chromosome 17q25-ter with MMD risk. This \nresult was further confirmed by a locus-specific association study using 335 \nSNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the \nRNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes \na really interesting new gene finger protein with an AAA ATPase domain and is \nabundantly expressed in spleen and leukocytes. An RNA in situ hybridization \nanalysis of mouse tissues indicated that mature lymphocytes express higher \nlevels of Rnf213 mRNA than their immature counterparts. Mutational analysis of \nRNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of \nnon-familial MMD cases and 1.4% of controls; this mutation greatly increases the \nrisk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = \n71.7-507.9). Three additional missense mutations were identified in the \np.R4859K-negative patients. These results indicate that RNF213 is the first \nidentified susceptibility gene for MMD.", "A 7-year-old white girl presented with left hemiparesis and ischemic stroke \nsecondary to moyamoya syndrome, a progressive cerebrovascular occlusive disorder \nof uncertain but likely multifactorial etiology. Past medical history revealed \nhearing loss and developmental delay/intellectual disability. Routine karyotype \ndemonstrated extra chromosomal material on 6p. Single nucleotide polymorphism \nmicroarray revealed a previously unreported complex de novo genetic \nrearrangement involving subtelomeric segments on chromosomes 6p and 12q. The \nduplicated/deleted regions included several known OMIM-annotated genes. This \nnovel phenotype and genotype provides information about a possible association \nof genomic copy number variation and moyamoya syndrome. Dosage-sensitive genes \nin the deleted and duplicated segments may be involved in aberrant vascular \nproliferation. Our case also emphasizes the importance of comprehensive \nevaluation of both developmental delay and congenital anomalies such as \nmoyamoya.", "BACKGROUND AND PURPOSE: Moyamoya disease is a cerebrovascular disease of unknown \ncause that mainly affects Japanese children. The incidence of familial \noccurrence accounts for 9% of cases. The characteristic lesions of moyamoya \ndisease are occasionally seen in neurofibromatosis type 1, of which the \ncausative gene (NF1) has been assigned to chromosome 17q11.2.\nMETHODS: To determine whether a gene related to moyamoya disease is located on \nchromosome 17, we conducted microsatellite linkage analyses on 24 families \ncontaining 56 patients with moyamoya disease. Leukocyte DNA extracted from the \nfamily members was subjected to polymerase chain reaction for a total of 22 \nmicrosatellite markers on chromosome 17. The amplified polymerase chain reaction \nfragments were analyzed with GeneScan on an automated sequencer.\nRESULTS: Two-point linkage analysis gave a maximum log(10) odds (LOD) score of \n3.11 at the recombination fraction of 0.00 for the marker at locus D17S939. The \naffected pedigree member method also showed a significantly low P value (<1. \n0x10(-5)) for the 5 adjacent markers at 17q25. Multipoint linkage analysis also \nindicated that the disease gene is contained within the 9-cM region of D17S785 \nto D17S836, with a maximum LOD score of 4. 58.\nCONCLUSIONS: A gene for familial moyamoya disease is located on chromosome \n17q25.", "OBJECTS: The pathogenesis of moyamoya disease is still unknown. The present \nstudy aimed to find out the responsible genes that are located in the 17q25 \nlocus.\nMETHODS: Considering the function, we selected nine genes as candidates from a \ntotal of 65 genes identified in the 9-cM region of D17S785-D17S836 in chromosome \n17q25, and performed sequence analysis on the DNA samples obtained from a \npedigree of familial moyamoya disease, which showed a complete linkage to the \nregion by a haplotype analysis. Also, we attempted to identify candidate genes \nthat have not been known but might be functionally relevant to the disease among \na total of 2,100 expressed sequence tag (EST) sequences using bioinformatics \ntechniques.\nRESULTS AND CONCLUSION: The sequence analysis could detect no mutation in the \nnine genes. Nor could we identify a novel candidate gene by the EST analysis. \nFurther studies using alternative approaches are warranted to clarify the \npathogenesis of moyamoya disease.", "The neurofibromatoses are genetic disorders of the nervous system that primarily \naffect the development and growth of neural (nerve) cell tissues. The \nneurofibromatoses are classified as neurofibromatosis type 1 (NF1) and \nneurofibromatosis type 2 (NF2). NF1 is the more common type of the \nneurofibromatoses. The gene responsible for NF1 is located on the chromosome \nregion 17q11.2 and for familial moyamoya disease on chromosome 17q25. This \narticle reports on a 20-year-old female with neurofibromatosis-1 who developed \nmoyamoya syndrome. More extensive reports and further investigations of such \nfamilies having this combination will certainly provide a better understanding \nof this link in the near future.", "Moyamoya, meaning a \"hazy puff of smoke\" in Japanese, is a chronic, occlusive \ncerebrovascular disease involving bilateral stenosis or occlusion of the \nterminal portion of the internal carotid arteries (ICAs) and/or the proximal \nportions of the anterior cerebral arteries and middle cerebral arteries (MCAs). \nThe Ministry of Health and Welfare of Japan has defined 4 types of moyamoya \ndisease (MMD): ischemic, hemorrhagic, epileptic, and \"other.\" The ischemic type \nhas been shown to predominate in childhood, while the hemorrhagic type is more \noften observed in the adult population. The highest prevalence of MMD is found \nin Japan, with a higher female to male ratio. Studies have shown a possible \ngenetic association of MMD linked to chromosome 17 in Japanese cases as well as \nin cases found in other demographics. During autopsy, intracerebral hematoma is \nfound and most commonly serves as the major cause of death in patients with MMD. \nMoyamoya vessels at the base of the brain are composed of medium-sized or small \nmuscular arteries emanating from the circle of Willis, mainly the intracranial \nportions of ICAs, anterior choroidal arteries, and posterior cerebral arteries, \nforming complex channels that connect with distal positions of the MCAs. Off of \nthese channels are small tortuous and dilated vessels that penetrate into the \nbase of the brain at the site of the thalamoperforate and lenticulostriate \narteries. On angiography, there is the characteristic stenosis or occlusion \nbilaterally at the terminal portion of the ICAs as well as the moyamoya vessels \nat the base of the brain. Six angiographic stages have been described, from \nStage 1, which reveals a narrowing of the carotid forks, to Stage 6, in which \nthe moyamoya vessels disappear and collateral circulation is produced solely \nfrom the external carotid arteries. Cases with milder symptoms are usually \ntreated conservatively; however, more severe symptomatic cases are treated using \nrevascularization procedures. Surgical treatments are divided into 3 types: \ndirect, indirect, and combined/other methods. Direct bypass includes superficial \ntemporal artery-MCA bypass or use of other graft types. Indirect procedures \nbring in circulation to the intracranial regions by introducing newly developed \nvasculature from newly approximated tissues. These procedures may not be enough \nto prevent further ischemia; therefore, a combination of direct and indirect \nprocedures is more suitable. This article will give a review of the \nepidemiology, natural history, pathology, pathophysiology, and diagnostic \ncriteria, including imaging, and briefly describe the surgical treatment of MMD.", "Chromosomal rearrangements causing microdeletions and microduplications are a \nmajor cause of congenital malformation and mental retardation. Because they are \nnot visible by routine chromosome analysis, high resolution whole-genome \ntechnologies are required for the detection and diagnosis of small chromosomal \nabnormalities. Recently, array-comparative genomic hybridization (aCGH) and \nmultiplex ligation-dependent probe amplification (MLPA) have been useful tools \nfor the identification and mapping of deletions and duplications at higher \nresolution and throughput. Smith-Magenis syndrome (SMS) is a multiple congenital \nanomalies/mental retardation syndrome caused by deletion or mutation of the \nretinoic acid induced 1 (RAI1) gene and is often associated with a chromosome \n17p11.2 deletion. We report here on the clinical and molecular analysis of a \n10-year-old girl with SMS and moyamoya disease (occlusion of the circle of \nWillis). We have employed a combination of aCGH, FISH, and MLPA to characterize \nan approximately 6.3 Mb deletion spanning chromosome region 17p11.2-p13.1 in \nthis patient, with the proximal breakpoint within the RAI1 gene. Further, \ninvestigation of the genomic architecture at the breakpoint intervals of this \nlarge deletion documented the presence of palindromic repeat elements that could \npotentially form recombination substrates leading to unequal crossover.", "INTRODUCTION: In this report we discuss an unusual cause of subarachnoid \nhaemorrhage in association with neurofibromatosis.\nCASE PRESENTATION: A previously fit 55-year-old man developed sudden onset \nheadache with loss of consciousness. He was comatose on admission with no focal \nneurological signs. Numerous neurofibromas and café-au-lait patches were noted, \nindicating neurofibromatosis type 1 which had not been previously diagnosed. \nComputer Tomography brain revealed a grade IV subarachnoid haemorrhage in \nassociation with numerous vascular lesions on cerebral angiography.\nCONCLUSION: A rare cause of subarachnoid haemorrhages was identified and is \ndiscussed in detail.", "PATIENT: Male, 42 FINAL DIAGNOSIS: Moyamoya disease (MMD) Symptoms: Aphasia • \nconcentration difficulty • dysarthria • personality change\nMEDICATION: - Clinical Procedure: - Specialty: Radiology.\nOBJECTIVE: Rare disease.\nBACKGROUND: Moyamoya disease (MMD) was first described in 1957 as \"hypoplasia of \nthe bilateral internal carotid arteries.\" The characteristic appearance of the \nassociated network of abnormally dilated collateral vessels on angiography was \nlater likened to \"something hazy, like a puff of cigarette smoke,\" which, in \nJapanese, is Moyamoya. This paper describes the fulminant course of the disease \nin a Hispanic male involving the corpus callosum.\nCASE REPORT: A 42-year-old Hispanic male with progressive aphasia, slow \nmentation, and sudden onset of sensorimotor symptoms with gait disturbance was \nfound to have multiple intracranial supratentorial infarcts of variable stages \nof evolution involving, but not limited to, the anterior corpus callosum, \nfollowed by rapid development of further infarcts. Angiography demonstrated \nright ACA occlusion, left supraclinoid ICA occlusion with a Moyamoya pattern of \ncollateralization, and diffuse arteriopathy. A fulminant course ensued and the \npatient did not survive the acute phase of ischemic disease.\nCONCLUSIONS: Moyamoya disease may rarely present in North American Hispanic \nmales, with advanced atypical clinical and imaging features involving the \nanterior corpus callosum and having a fulminant course.", "Moyamoya disease is a well-known cerebrovascular disorder of unknown \npathogenesis affecting terminal portion of internal carotid arteries and causing \nischemic attacks. Its familial occurrence suggests genetic background. We \nhypothesized that paternally imprinted gene might be associated with this \ndisorder. To identify the expressed sequence tags (ESTs) with monoallelic \nexpressions on chromosome 3, we used mouse A9 hybrid cells having human \nchromosome 3. Two ESTs showed only maternal expression in mouse A9 hybrid cells, \nand four showed non-expression in the lymphocytes derived from moyamoya \npatients. Although these ESTs are clustered on the same 150 kb region, we \nfinally failed to identify cDNA in this region.", "Moyamoya disease is a cerebrovascular disorder of unknown etiology. Its high \nincidence in East Asia and accumulation in family members suggest a genetic \nbackground. A high incidence of maternal inheritance implicates genomic \nimprinting in this disorder. Based on this hypothesis, we studied the \nassociation between moyamoya disease and IGF2R gene on chromosome 6, but found \nno evidence for such association between them. On the other hand, heterogeneous \nexpressions of IGF2R were confirmed in the lymphocytes. Some individuals showed \nmonoallelic expression and others showed biallelic expression.", "We present familial Moyamoya disease in two European children and emphasize the \nimportance of familial factors in the pathogenesis of this disease and its \nappearance not only in Asians but in the Western population as well. The first \npatient, a Greek female infant, also has coagulation disorders. Her mother, also \nsuffering from Moyamoya and other family members, have similar coagulation \ndisorders (Factor V Leiden, Methylene-tetrahydrofolic reductase and Factor II \n20210A mutations). The second patient, a Scottish boy, is unique in that \nfamilial Moyamoya affects five members of three consecutive generations of his \nmaternal family. Genetic analysis in the Greek family demonstrated no \nabnormality on chromosome 3p26, as in other cases. However, the mitochondrial \nDNA and Y chromosomal genotype showed that affected members had the same \nsequence of the Mitochondrial 3 portion of D-loop with Japanese patients. These \nfindings suggest that the pathogenesis of Moyamoya may vary across races and \nethnic groups.", "We reported an autopsy case of Down's syndrome with moyamoya syndrome. A \n30-year-old male with Down's syndrome suffered from a cerebral infarction and \ndied of brain herniation. Cerebral angiography showed vascular abnormalities \nthat were the same as moyamoya disease. Pathological findings revealed multiple \nstenosis of main trunk of the cerebral arteries. Pathologically, the stenosed \nvessels showed eccentric intimal thickness with cholesterin deposit, unlike \nmoyamoya disease. There are only two previous reports of autopsied cases of \nDown's syndrome with moyamoya syndrome. We postulate that a protein encoded on \nchromosome 21 may be related to the pathogenesis of Down's syndrome with \nmoyamoya syndrome.", "Genetic factors have been suggested to contribute to the etiology of moyamoya \ndisease. The authors have previously reported an association between moyamoya \ndisease and several alleles for human leukocyte antigens (HLA). To further \nspecify the genetic component of moyamoya disease, a linkage study of moyamoya \ndisease using markers on chromosome 6, where the HLA gene is located, was \nperformed. The 15 microsatellite markers of chromosome 6 were studied in 20 \naffected sibling pairs. From an identical-by-descent analysis of these markers, \nan allele with possible linkage to moyamoya disease was identified. Sharing of \nthe allele among affected members in 19 families was investigated, considering \nthe haplotype. The marker, D6S441, might be linked to moyamoya disease. \nConsidering the haplotype, the allele was shared among the affected members in \n16 (82%) of the 19 families, but not in two others. In one family, sharing of \nthe allele could not be determined because of low heterozygosity. Further \nstudies are necessary to clarify multiple genetic factors that are definitely \nlinked with moyamoya disease.", "OBJECTIVES: To identify whether any mutations of candidate genes including SHH, \nZIC2, SIX3, and TGIF exist in a Taiwanese family segregated with \nholoprosencephaly (HPE) and moyamoya disease.\nMETHODS: Genotypes of the candidate genes SHH, ZIC2, SIX3, and TGIF were \ndetermined in the family members who were available for analysis by sequencing. \nIn addition, genomic regions of another 50 unrelated Taiwanese (100 chromosomes) \nwere studied to verify whether the nucleotide changes we found were mutations or \npolymorphisms.\nRESULTS: A novel missense mutation 377T > C and two polymorphisms (420A > G and \n487C > T) in the TGIF gene were identified. No mutations in SHH, ZIC2 and SIX3 \nwere found. The mother of the three HPE fetuses was found to be afflicted with \nmoyamoya disease. A brief review of the mutations as well as polymorphisms \nreported in the TGIF gene up to 2005 is given.\nCONCLUSION: Molecular diagnosis can help genetic counseling in HPE, which is a \nheterogeneous disorder with its phenotypic and genotypic spectrum highly widened \nand variable. The possible association between TGIF mutation and moyamoya \ndisease noted in our study also appeared to be novel.", "A female, 2 years and 7 months of age, was admitted to the hospital with stupor \nand nystagmus following projectile vomiting. She had been prenatally diagnosed \nwith trisomy 12p with a familial pericentric inversion of chromosome 12 \noriginating from her mother. She manifested developmental delay and some \ndysmorphic features of the face and limbs compatible with the clinical features \nof trisomy 12p. Four-vessel cerebral angiography revealed severe stenosis and \nocclusion of the supraclinoid portion of the right and left internal carotid \narteries with numerous collateral vessels in the vicinity of the occlusion. \nThese features are consistent with moyamoya syndrome. This report presents the \nfirst case of moyamoya syndrome with trisomy 12p with a familial pericentric \ninversion of chromosome 12.", "We report a case of Prader-Willi syndrome (PWS) complicated with juvenile \nstroke. The patient is a 19-year-old man with right hemiplegia, who has had a \nhistory of non-insulin-dependent diabetes mellitus (NIDDM) for ten years. The \ndiagnosis of PWS was confirmed genetically by the method of fluorescence in situ \nhybridization which showed the deletion of chromosome 15. His brain MRI revealed \nabnormal signal intensities in the left basal ganglia and around the right \ntrigone of the lateral ventricle. Angiographic examination showed occlusions of \nbilateral proximal middle cerebral arteries with basal moyamoya vessels. The \nleft vertebral artery was also occluded at its origin. Only a few cases of PWS \ncomplicated with stroke have been reported before and, to date, there has been \nno case with arterial occlusion similar to our case. Though the cause of these \narterial occlusions is unknown, it may be related to arteriosclerosis following \nNIDDM.", "OBJECT: Moyamoya disease (MMD) is a rare cerebrovascular disorder involving \nstenosis of the major vessels of the circle of Willis and proximal portions of \nits principal branches. Despite concerted investigation, the pathophysiology of \nthe disorder has not been fully elucidated. Currently, the major proteins \nbelieved to play an active role in the pathogenesis include vascular endothelial \ngrowth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth \nfactor (HGF), transforming growth factor-β₁ (TGFβ₁), and granulocyte \ncolony-stimulating factor (G-CSF). In terms of the genetics, recent literature \nsuggests a low penetrance autosomal dominant or polygenic mode of transmission \ninvolving chromosomes 3, 6, 8, 12, and 17 for familial MMD. This review \nsummarizes the current knowledge on the histopathology, pathophysiology and \ngenetics of MMD.\nMETHODS: A PubMed/Medline systematic study of the literature was performed, from \nwhich 45 articles regarding MMD pathophysiology were identified and analyzed.\nCONCLUSIONS: Moyamoya disease is characterized by the intimal thickening and \nmedia attenuation of the proximal vessels of the circle of Willis as well as the \ndevelopment of an aberrant distal vascular network. The primary proteins that \nare currently implicated in the pathophysiology of MMD include VEGF, bFGF, HGF, \nTGFβ₁, and G-CSF. Furthermore, the current literature on familial MMD has \npointed to a low penetrance autosomal dominant or polygenic mode of \ntransmittance at loci on chromosomes 3, 6, 8, 12, and 17." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009072', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002875', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0005694', 'http://www.disease-ontology.org/api/metadata/DOID:13099', 'http://www.disease-ontology.org/api/metadata/DOID:0080014']
5313058de3eabad02100000e	[ 23096483, 21511940, 24156003, 8457417, 23969004, 16943469, 19547821, 19037900, 20624239, 19830065, 11154546, 18596536, 2533403, 19646556 ]	train	Abnormality in which vertebral region is important in the Bertolotti's syndrome?	factoid	Lumbosacral vertebral region is implicated in the Bertolotti's syndrome. Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. Patients often complain of intractable sciatica that arises from impingement of the nerve root extraforaminally by compression caused by the enlarged transverse process.	lumbosacral	[ "BACKGROUND AND INTRODUCTION: In 1991, a deceased human male was found frozen in \na glacier pool in the Italian Alps in north west Italy, and is now carefully \npreserved in the South Tyrol Museum of Archaeology, in Bolzano, Italy. The \nbodily tissues of the 5,300 year old male (colloquially referred to as the \nIceman or Ötzi) were well preserved despite damage related to freezing, and \nglacial movement. Associated articles of well-preserved clothing, tools, weapons \nand other devices were also present and have been studied in detail. Clinical \nexamination and imaging investigations have also shown that the Icemen had \nexperienced possible illnesses in his lifetime and had identifiable areas of \narthritis and musculoskeletal injury. This report includes some key observations \non the musculoskeletal state of Ötzi and reference to the involvement of tattoo \nmarkings. Some aspects about the aetiology of his abnormalities and inflammatory \narthritis are considered along with possible treatments that he might have \nemployed.\nMETHODS AND RESULTS: We (WFK and MK) undertook a clinical musculoskeletal \nexamination of the Iceman, details of which with available photographs and \nradiographic imaging pertaining to the musculoskeletal findings of the Iceman \nare reported here. The skin of the Iceman has numerous linear carbon tattoos, \nwhich are not of a decorative type. These have been presumed to possibly be \n\"medicinal\" tattoos administered for therapeutic reasons and may have been used \nin acupuncture-like treatment of pain. Spinal imaging identified areas of spinal \ndamage and our observations have provided clues as to possible sites of spinal \ninitiated pain and hence sites for administration of the \"medicinal\" tattoos. We \nobserved body areas of the Iceman, in which imaging demonstrated arthritis and \nother forms of long-term musculoskeletal damage, but which do not have adjacent \nor corresponding \"medicinal\" tattoos. We contend that the back and leg \n\"medicinal\" tattoos correspond directly to sites of chronic right knee and right \nankle pain, and left thoracolumbar pain. They also correspond to lower lumbar \nand sciatic referred radicular pain which may have a contributory cause related \nto the presence of a transitional lumbar 5 vertebra. Using recent published data \n(Keller et al. in Nature Commun 3:698, 2012. doi: 10.1038/ncomms1701 ) of the \ngenome structure of the Iceman, we suggest some potential causes of the \nosteoarthritis or inflammatory joint injury may relate to presence of coronary \nheart disease (CHD) and Lyme disease (Borrelia burgdorferi) infection. We \nspeculate on possible medical applications of natural products for \nself-medication.\nCONCLUSIONS: These observations highlight several diagnostic features of \nmusculoskeletal conditions in the Iceman with the possibility that tattoos may \nhave been used for diagnosis or location of his painful states. The origins of \nhis musculoskeletal conditions are unclear but there are indications that Lyme \ndisease and CHD may have been factors. The associations or use of natural \nproducts may give insights into their applications at the time of the life of \nthe Iceman.", "Patients with Bertolotti's syndrome have characteristic lumbosacral anomalies \nand often have severe sciatica. We describe a patient with this syndrome in whom \nstandard decompression of the affected nerve root failed, but endoscopic \nlumbosacral extraforaminal decompression relieved the symptoms. We suggest that \nthe intractable sciatica in this syndrome could arise from impingement of the \nnerve root extraforaminally by compression caused by the enlarged transverse \nprocess.", "BACKGROUND: Bertolotti's syndrome (BS), a form of lumbago in lumbosacral \ntransitional vertebrae, is an important cause of low back pain in young \npatients. The purpose of this study was to assess the etiology of low back pain \nand the efficacy of treatment offered to patients with BS.\nMETHODS: All patients of BS Castellvi type1a during a period of 6 months were \nenrolled in the study. The patients underwent interventional pain procedures for \ndiagnosis and pain relief. Response to the therapy was assessed based on VAS and \nODI scores. A 50% decrease in VAS score or a VAS score less than 3 would be \nconsidered adequate pain relief.\nRESULTS: All 20 patients diagnosed with BS during the 6-month observation period \nhad scoliosis. Common causes of back pain were the ipsilateral L5-S1 facet \njoint, neoarticulation, the SI joint, and disc degeneration. Responses to \nvarious interventions for pain relief were different and inconsistent from \npatient to patient. In particular, responses to interventions for neoarticular \npain were generally poor.\nCONCLUSIONS: Pain in patients with BS does not usually respond to interventional \npain treatment. A very dynamic treatment approach must be pursued while managing \nBS patients, and the treatment plan must be individualized at various stages in \norder to obtain satisfactory pain relief.", "We surgically treated 16 patients with Bertolotti's syndrome (chronic, \npersistent low back pain and radiographically diagnosed transitional lumbar \nvertebra). Eight had posterolateral fusion and another eight resection of the \ntransitional articulation. Thirteen patients had in addition to the chronic low \nback pain, suffered from repeated episodes or chronic sciatica. In six cases \nwith resection treatment, local injections were administered at the transitional \narticulation before deciding for resection of the transitional joint; each \npatient reported transient relief of pain, while this preoperative test did not \ncorrelate with successful outcome of treatment. Six patients had to be treated \nwith second operations. Ten of the 16 operatively treated patients showed \nimprovement of the low back pain, and this result was similar in the group \ntreated with fusion and in that treated with resection. Seven had no low back \npain at follow-up, and the improvement according to the Oswestry pain scale was \nsimilar in the two groups, and statistically significant. Eleven patients still \nhad persisting episodes of sciatica (versus 13 preoperatively). The average \ndisability according to the Oswestry total disability scale was 30%, \ncorresponding with moderate outcome, and both operatively treated groups did \nequally well. At follow-up the first disc above the fused segments was found to \nbe degenerated in seven out of eight cases, and in the group treated with \nresection the first disc above the transitional vertebra was degenerated in five \ncases.(ABSTRACT TRUNCATED AT 250 WORDS)", "Painful L5/S1 pseudoarthrosis has been previously managed with posterior \nexcision and/or lumbar fusion. To our knowledge, the anterior approach for L5/S1 \npseudoarthrectomy in the treatment of Bertolotti's syndrome has not been \ndescribed. We present two patients with severe symptomatic L5/S1 pseudoarthroses \nthat were successfully excised via an anterior retroperitoneal approach with 2 \nyear clinical and radiological follow-up. The literature regarding surgical \ntreatments for Bertolotti's syndrome is reviewed. The technique for an anterior \nretroperitoneal approach is described. This approach has been safe and effective \nin providing long term symptomatic relief to our two patients. Further studies \ncomparing the outcomes of anterior versus posterior pseudoarthrectomy will guide \nthe management of this condition.", "Bertolotti's syndrome is characterised by anomalous enlargement of the \ntransverse process(es) of the most caudal lumbar vertebra which may articulate \nor fuse with the sacrum or ilium and cause isolated L4/5 disc disease. We \nanalysed the elective MR scans of the lumbosacral spine of 769 consecutive \npatients with low back pain taken between July 2003 and November 2004. Of these \n568 showed disc degeneration. Bertolotti's syndrome was present in 35 patients \nwith a mean age of 32.7 years (15 to 60). This was a younger age than that of \npatients with multiple disc degeneration, single-level disease and isolated disc \ndegeneration at the L4/5 level (p </= 0.05). The overall incidence of \nBertolotti's syndrome in our study was 4.6% (35 of 769). It was present in 11.4% \n(20 patients) of the under-30 age group. Our findings suggest that Bertolotti's \nsyndrome must form part of a list of differential diagnoses in the investigation \nof low back pain in young people.", "OBJECTIVE: Bertolotti's syndrome is a spine disorder characterized by the \noccurrence of a congenital lumbar transverse mega-apophysis in a transitional \nvertebral body that usually articulates with the sacrum or the iliac bone. It \nhas been considered a possible cause of low back pain.\nMETHOD: We analyzed the cases of Bertolotti's syndrome that failed clinical \ntreatment and reviewed the literature concerning this subject.\nRESULTS: Five patients in our series had severe low back pain due to the \nneo-articulation and two of them were successfully submitted to surgical \nresection of the transverse mega-apophysis. Taking into account the clinical and \nsurgical experience acquired with these cases, we propose a \ndiagnostic-therapeutic algorithm.\nCONCLUSION: There is still no consensus about the most appropriate therapy for \nBertolotti's syndrome. In patients in whom the mega-apophysis itself may be the \nsource of back pain, surgical resection may be a safe and effective procedure.", "STUDY DESIGN: A case report and literature review is presented.\nOBJECTIVE: To review relevant data for the management of Bertolotti's syndrome \nand to determine whether the transverse process-ilium articulation may be a pain \ngenerator.\nBACKGROUND: Bertolotti's syndrome is associated with axial low back pain \nsecondary to arthritic changes; the pain generator in the disorder is unclear.\nMETHODS: We present a case report of symptomatic Bertolotti's syndrome managed \nwith intra-articular steroid injections.\nRESULTS: A patient with Bertolotti's syndrome had significant relief of axial \npain after steroid injection of the ilium-transverse process articulation.\nCONCLUSIONS: Steroid therapy may be a non-surgical alternative for the treatment \nof symptomatic Bertolotti's syndrome.", "OBJECTIVE: Describe the clinical presentation, diagnostic evaluation, and \nsuccessful treatment of a case of symptomatic unilateral lumbosacral junction \npseudarticulation using a novel radiofrequency nerve ablation technique.\nCASE: A 56-year-old female patient who had suffered with low back and right \nupper buttock pain for 16 years experienced incomplete relief with L4/5 facet \njoint radiofrequency ablation. She was found to have an elongated right L5 \ntransverse process that articulated with the sacral ala (Bertolotti's syndrome). \nFluoroscopically guided local anesthetic/corticosteroid injection into the \npseudarthrosis eliminated her residual right buttock pain for the duration of \nthe local anesthetic only. Complete pain relief was achieved by injecting local \nanesthetic circumferentially around the posterior pseudarthrosis articular \nmargin. Accordingly, bipolar radiofrequency strip thermal lesions were created \nat the same locations. Complete pain relief and full restoration of function was \nachieved for 16 months postprocedure.\nCONCLUSION: This case report describes a novel radiofrequency technique for \ntreating symptomatic lumbosacral junction pseudarticulation that warrants \nfurther evaluation.", "INTRODUCTION: Lumbosacral transitional vertebra is an anatomical variation of \nthe fifth lumbar vertebra in which an enlarged transverse process can form a \njoint or fusion with the sacrum or ilium. The association of that variant with \nlow back pain and the change in the biomechanical properties of the lumbar spine \nis called Bertolotti's syndrome.\nCASE PRESENTATION: We report a case of a 40-year-old male patient with chronic \nlow back pain extending to the left buttock, just above the ipsilateral \nsacroiliac joint. Radiographic investigation revealed an anomalous enlargement \nof the left transverse process of the fifth lumbar vertebra forming a \npseudarthrosis with the infrajacent ala of the sacrum.\nCONCLUSION: In young patients with back pain the possibility of Bertolotti's \nsyndrome should always be taken in account.", "STUDY DESIGN: Case report of surgically treated mechanical low back pain from \nthe facet joint contralateral to a unilateral anomalous lumbosacral articulation \n(Bertolotti's syndrome).\nOBJECTIVES: To describe the clinical presentation, diagnostic evaluation, and \nmanagement of facet-related low back pain in a 17-year-old cheerleader and its \nsuccessful surgical treatment with resection of a contralateral anomalous \narticulation.\nSUMMARY OF BACKGROUND DATA: Lumbosacral transitional vertebrae are common in the \ngeneral population. Bertolotti's syndrome is mechanical low back pain associated \nwith these transitional segments. Little is known about the pathophysiology and \nmechanics of these vertebral segments and their propensity to be pain \ngenerators. Treatment of this syndrome is controversial, and surgical \nintervention has been infrequently reported.\nMETHOD: A retrospective chart analysis and radiographic review were performed.\nRESULTS: Repeated fluoroscopically guided injections implicated a symptomatic \nL6-S1 facet joint contralateral to an anomalous lumbosacral articulation. \nEventually, a successful surgical outcome was achieved with resection of the \nanomalous articulation.\nCONCLUSION: Clinicians should consider the possibility that mechanical low back \npain may occur from a facet contralateral to a unilateral anomalous lumbosacral \narticulation, even in a young patient. Although reports of surgical treatment of \nBertolotti's syndrome are infrequent, resection of the anomalous articulation \nprovided excellent results in this patient, presumably because of reduced \nstresses on the symptomatic facet.", "OBJECTIVE: This article aims to provide more insight into the presentation, \ndiagnosis, and treatment of Bertolotti's syndrome, which is a rare spinal \ndisorder that is very difficult to recognize and diagnose correctly. The \nsyndrome was first described by Bertolotti in 1917 and affects approximately 4 \nto 8% of the population. It is characterized by an enlarged transverse process \nat the most caudal lumbar vertebra with a pseudoarticulation of the transverse \nprocess and the sacral ala. It tends to present with low back pain and may be \nconfused with facet and sacroiliac joint disease.\nMETHODS: In this case report, we describe a 40-year-old man who presented with \nlow back pain and was eventually diagnosed with Bertolotti's syndrome. The \ncorrect diagnosis was made based on imaging studies which included computed \ntomographic scans, plain x-rays, and magnetic resonance imaging scans. The \npatient experienced temporary relief when the abnormal pseudoarticulation was \ninjected with a cocktail consisting of lidocaine and steroids. In order to \nminimize the trauma associated with surgical treatment, a minimally invasive \napproach was chosen to resect the anomalous transverse process with the \naccompanying pseudoarticulation.\nRESULTS: The patient did well postoperatively and had 97% resolution of his pain \nat 6 months after surgery.\nCONCLUSION: As with conventional surgical approaches, a complete knowledge of \nanatomy is required for minimally invasive spine surgery. This case is an \nexample of the expanding utility of minimally invasive approaches in treating \nspinal disorders.", "Bertolotti's syndrome refers to the association of back pain with lumbosacral \ntransitional vertebrae. Such vertebrae were observed in 140 of 2,000 adults with \nback pain over a 4-year period of study. Each patient had radiographic \nevaluation of the lumbar spine by plain films as well as a sectional imaging \nmodality (magnetic resonance [MR] or computed tomography [CT]). The overall \nincidence of structural pathology (eg, spinal stenosis and disc protrusion) \ndetected by CT or MR was not apparently higher in patients with transitional \nvertebrae, but the distribution of these lesions was significantly different. \nDisc bulge or herniation, when it occurred, was nearly nine times more common at \nthe interspace immediately above the transitional vertebra than at any other \nlevel. Spinal stenosis and nerve root canal stenosis were more common at or near \nthe interspace above the transitional vertebra than at any other level. \nDegenerative change at the articulation between the transverse process of the \ntransitional vertebra and the pelvis was an uncommon occurrence; when seen there \nwas no significant correlation with the reported side of pain. It is postulated \nthat hypermobility and altered stresses become concentrated in the spine at the \nlevel immediately above a lumbar transitional vertebra. Accelerated disc and \nfacet joint degeneration at this level may then result.", "The availability of hybrid devices that combine the latest single-photon \nemission computed tomography (SPECT) imaging technology with multislice computed \ntomography (CT) scanning has allowed us to detect subtle, nonspecific \nabnormalities on bone scans and interpret them as specific focal areas of \npathology. Abnormalities in the spine can be separated into those caused by pars \nfractures, facet joint arthritis, or osteophyte formation on vertebral bodies. \nCompression fractures can be distinguished from severe degenerative disease, \nboth of which can cause intense activity across the spine on either planar or \nSPECT imaging. Localizing activity in patients who have had spinal fusion can \nprovide tremendous insight into the causes of therapeutic failures. Infections \nof the spine now can be diagnosed with gallium SPECT/CT, despite the fact that \ngallium has long been abandoned because of its failure to detect spine infection \non either planar or SPECT imaging. Small focal abnormalities in the feet and \nankles can be localized well enough to make specific orthopedic diagnoses on the \nbasis of their location. Moreover, when radiographic imaging provides equivocal \nor inadequate information, SPECT/CT can provide a road map for further \ndiagnostic studies and has been invaluable in planning surgery. Our ability to \nlocalize activity within a bone or at an articular surface has allowed us to \ndistinguish between fractures and joint disease. Increased activity associated \nwith congenital anomalies, such as tarsal coalition and Bertolotti's syndrome \nhave allowed us to understand the pathophysiology of these conditions, to \nconfirm them as the cause of the patient's symptoms, and to provide information \nthat is useful in determining appropriate clinical management. As our experience \nbroadens, SPECT/CT will undoubtedly become an important tool in the evaluation \nand management of a wider variety of orthopedic patients." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D013131', 'http://www.disease-ontology.org/api/metadata/DOID:225', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D013577']
5a981e66fcd1d6a10c00002f	[ 23519746, 26280340, 17137436, 28106792, 23145009, 16762931, 10682170, 18497723, 10863169, 26543426, 17125447, 19108808, 12137304, 15827427, 26871396, 11276389, 15940204, 12148078, 17469041 ]	train	According to guidelines, insulin resistance is one risk factor in the diagnosis of metabolic syndrome, name 3 more risk factors.	list	Metabolic syndrome (MetS) is generally defined as a cluster of metabolically related cardiovascular risk factors which are often associated with the condition of insulin resistance, elevated blood pressure, and abdominal obesity.	['obesity', 'hypertension', 'dyslipdemia']	[ "Obesity and overweight are nowadays very prevalent worldwide. They are known to \nbe linked with an increased risk of developing cardiovascular comorbidities and \nmortality. Abdominal obesity is frequently associated with a collection of \nmetabolic disorders that include elevated blood pressure, characteristic lipid \nabnormalities (low high-density lipoprotein cholesterol and high triglycerides) \nand increased fasting glucose, with an underlying situation of insulin \nresistance, which has been defined as metabolic syndrome, conferring a high \ncardiovascular risk profile to these subjects. A multidisciplinary approach is \nrequired, including lifestyle changes and pharmacological and surgical \napproaches. Intensive management of all the risk factors of the metabolic \nsyndrome is also needed to reduce body weight and waist circumference, lessen \ninsulin resistance and avoid the development of new-onset diabetes and \ncardiovascular disease associated with this entity. This article will review the \nrecently published literature and guideline updates on this topic, although it \nis not yet included in the highlights.", "Metabolic syndrome is a cluster of conditions that synergistically increase the \nrisk of cardiovascular disease, type 2 diabetes, and premature mortality. The \ncomponents are abdominal obesity, impaired glucose metabolism, dyslipidemia, and \nhypertension. Prediabetes, which is a combination of excess body fat and insulin \nresistance, is considered an underlying etiology of metabolic syndrome. \nPrediabetes manifests as impaired fasting glucose and/or impaired glucose \ntolerance. Impaired fasting glucose is defined as a fasting blood glucose level \nof 100 to 125 mg/dL; impaired glucose tolerance requires a blood glucose level \nof 140 to 199 mg/dL 2 hours after a 75-g oral intake of glucose. In patients \nwith prediabetes, the rate of progression to diabetes within 3 years can be \ndecreased by approximately 58% with lifestyle modifications. These include \nweight loss through exercise (30 minutes or more of moderate physical activity \non most, preferably all, days of the week) and dietary modifications. \nRecommended diets are high in fruits, vegetables, whole grains, and fish. \nConsumption of sweetened beverages, including diet soda, should be avoided. For \npatients who do not achieve goals with lifestyle modifications, metformin can be \nconsidered. Weight loss drugs and bariatric surgery are appropriate for select \npatients. Hypertension and dyslipidemia should be managed according to current \nguidelines.", "Metabolic syndrome (MS) refers to the clustering of cardiometabolic risk factors \n- including abdominal obesity, hyperglycaemia, dyslipidaemia and elevated blood \npressure - that are thought to be linked to insulin resistance. MS is associated \nwith increased risk of cardiovascular disease and type 2 diabetes. MS is common, \naffecting a quarter to a third of adults, and its prevalence is rising, in \nparallel with increasing obesity and population ageing. Operational definitions \nof MS have been proposed by the World Health Organization and the National \nCholesterol Education Program. Recently, the International Diabetes Federation \nproposed a global definition that emphasised the importance of central \nadiposity. In cardiovascular risk assessment, MS encapsulates the contribution \nof non-traditional risk factors and provides a clinically useful framework for \nearly identification of people at increased long-term risk. It should be used in \nconjunction with standard algorithms based on conventional risk factors, which \nbetter predict short-term risk. Management of MS should emphasise lifestyle \ninterventions (eg, physical activity, healthy diet and weight reduction) to \nreduce long-term risk of cardiovascular disease and diabetes. Those at increased \nshort-term risk should also have individual risk factors treated according to \nestablished guidelines.", "Metabolic syndrome (MetS) is generally defined as a cluster of metabolically \nrelated cardiovascular risk factors which are often associated with the \ncondition of insulin resistance, elevated blood pressure, and abdominal obesity. \nDuring the past decades, MetS has become a major public health issue worldwide \nin both adults and children. In this study, data from the China Health and \nNutrition Surveys (CHNS) was used to assess the prevalence of MetS based on both \nthe National Cholesterol Education Program Adult Treatment Panel III \n(NCEP-ATPIII) guidelines and the International Diabetes Federation (IDF) \ncriteria, and to evaluate its possible correlates. A total of 831 children aged \n7-18 years were included in this study, and 28 children were classified as \nhaving MetS as defined by the modified NCEP-ATPIII definition, which yielded an \noverall prevalence of 3.37%. Elevated blood pressure was the most frequent MetS \ncomponent. The results of logistic regression models revealed that increased \nbody mass index (BMI), hyperuricemia, and insulin resistance (IR) were all \nassociated with the presence of MetS. To conclude, our study revealed the \nprevalence of MetS in Chinese children at the national level. Further \nlarge-scale studies are still needed to identify better MetS criteria in the \ngeneral paediatric population in China.", "The waist circumference cut point for diagnosing the metabolic syndrome in \nsub-Saharan African subjects is based on that obtained from studies in European \npopulations. The aim of this study was to measure the prevalence of obesity and \nrelated metabolic disorders in an urban population of African females, a group \nat high risk for such diseases, and to determine the appropriate waist cut point \nfor diagnosing the metabolic syndrome. Anthropometry and fasting lipid, glucose \nand insulin levels were measured in a cohort of 1251 African females \nparticipating in the Birth to Twenty cohort study in Soweto, Johannesburg. The \nwaist circumference cut points for diagnosing metabolic syndrome (as defined \nusing the new harmonised guidelines), insulin resistance, dysglycaemia, \nhypertension and dyslipidaemia were obtained using receiver operator \ncharacteristic curve analysis. The prevalence of obesity, type 2 diabetes and \nmetabolic syndrome were 50.1%, 14.3% and 42.1%, respectively. The appropriate \nwaist cut point for diagnosing metabolic syndrome was found to be 91.5 cm and \nwas similar to the cuts points obtained for detecting increased risk of insulin \nresistance (89.0 cm), dysglycaemia (88.4 cm), hypertension (90.1 cm), hypo-high \ndensity lipoproteinaemia (87.6 cm) and hyper-low density lipoproteinaemia (90.5 \ncm). The present data demonstrates that urban, African females have a high \nprevalence of obesity and related disorders and the waist cut point currently \nrecommended for the diagnosis of the metabolic syndrome (80.0 cm) in this \npopulation should be increased to 91.5 cm. This latter finding demonstrates a \nclear ethnic difference in the relationship between abdominal adiposity and \nmetabolic disease risk. The similar waist cut points identified for the \ndetection of the individual components of the metabolic syndrome and related \ncardiovascular risk factors demonstrates that the risk for different metabolic \ndiseases increases at the same level of abdominal adiposity suggesting a common \naetiological pathway.", "\"The metabolic syndrome\" is the name for a clustering of risk factors for \ncardiovascular disease and type 2 diabetes that are of metabolic origin. These \nrisk factors consist of atherogenic dyslipidemia, elevated blood pressure, \nelevated plasma glucose, a prothrombotic state, and a proinflammatory state. \nThere are 2 major, interacting causes of the metabolic syndrome-obesity and \nendogenous metabolic susceptibility. The latter typically is manifested by \ninsulin resistance. The metabolic syndrome is accompanied by a 2-fold increase \nin the risk of cardiovascular disease and a 5-fold increase in the risk of type \n2 diabetes. A clinical diagnosis of the metabolic syndrome is useful because it \naffects therapeutic strategy in patients at higher risk. However, there are 2 \nviews about the best therapeutic strategy for patients with the metabolic \nsyndrome. One view holds that each of the metabolic risk factors should be \nsingled out and treated separately. The other view holds that greater emphasis \nshould be given to implementing therapies that will reduce all of the risk \nfactors simultaneously. The latter approach emphasizes lifestyle therapies \n(weight reduction and increased exercise), which target all of the risk factors. \nThis approach is also the foundation of other therapies for targeting multiple \nrisk factors together by striking at the underlying causes, as in the \ndevelopment of drugs to promote weight reduction and to reduce insulin \nresistance. Treating the underlying causes does not rule out the management of \nindividual risk factors, but it will add strength to the control of multiple \nrisk factors.", "Insulin resistance syndrome (IRS), also termed syndrome X, is a distinctive \nconstellation of risk factors for the development of type 2 diabetes mellitus \nand cardiovascular disease. The syndrome's hallmarks are glucose intolerance, \nhyperinsulinemia, a characteristic dyslipidemia (high triglycerides; low \nhigh-density lipoprotein cholesterol, and small, dense low-density lipoprotein \ncholesterol), obesity, upper-body fat distribution, hypertension, and increased \nprothrombotic and antifibrinolytic factors. Insulin resistance, caused by a \ncomplex of genetic and environmental influences, is now recognized not just as a \nmechanism contributing to hyperglycemia in type 2 diabetes, but also as an early \nmetabolic abnormality that precedes the development of overt diabetes. The \nclinical definition of insulin resistance is the impaired ability of insulin \n(either endogenous or exogenous) to lower blood glucose. In some \ninsulin-resistant individuals, insulin secretion will begin to deteriorate under \nchronic stress (glucose toxicity) and overt diabetes will result. If not, \nindividuals will remain hyperinsulinemic, with perhaps some degree of glucose \nintolerance, together with other hallmarks of the IRS. The statistical \ncorrelation between hypertension and impaired glucose tolerance is clear, \nalthough the mechanism is not yet fully understood. Epidemiologic evidence of \ninsulin resistance as an independent risk factor for atherosclerosis and \ncoronary heart disease (CHD) completed the evolving concept of IRS as the common \nsoil for the development of both diabetes and CHD. No single laboratory test \nexists for diagnosis of IRS. Rather, IRS remains a clinically evident syndrome \nthat can be suspected on the basis of physical and laboratory findings. This \nidentifies individual patients whom the clinician should screen for associated \ncomorbid conditions, aggressively control cardiovascular risk factors, and \ntailor drug therapy for optimal benefit. This article provides practical \nguidelines to achieve these goals and specific strategies to ameliorate \ncardiovascular and metabolic risk in the IRS.", "The metabolic syndrome is a constellation of risk factors including glucose \ndysregulation, central obesity, dyslipidemia, and hypertension. There are \nmultiple definitions that have been described by various health organizations. \nHowever, we do know that insulin resistance plays a major role as the underlying \ncause for the development and potentiation of the metabolic syndrome. At \npresent, it is unclear if the diagnosis of metabolic syndrome is greater than \nthe sum of its parts. However, the presence of more than one of the associated \nrisk factors should indicate that a patient is at increased risk for developing \ndiabetes, cardiovascular disease and death. Thus, the primary care physician \nshould aggressively treat the metabolic risk factors in their patients to \nprevent the onset and progression to more severe disease.", "Metabolic syndrome X is a multifaceted syndrome, which occurs frequently in the \ngeneral population. It is more common in men than in women. A large segment of \nthe adult population of industrialized countries develops the metabolic \nsyndrome, produced by genetic, hormonal and lifestyle factors such as obesity, \nphysical inactivity and certain nutrient excesses. This disease is characterized \nby the clustering of insulin resistance and hyperinsulinemia, and is often \nassociated with dyslipidemia (atherogenic plasma lipid profile), essential \nhypertension, abdominal (visceral) obesity, glucose intolerance or \nnoninsulin-dependent diabetes mellitus and an increased risk of cardiovascular \nevents. Abnormalities of blood coagulation (higher plasminogen activator \ninhibitor type 1 and fibrinogen levels), hyperuricemia and microalbuminuria have \nalso been found in metabolic syndrome X. This review summarizes the present \nknowledge of abnormalities in this syndrome. Each risk factor is reviewed, and \npotential criteria for diagnosis and therapeutic targets are discussed. Because \npatients with metabolic syndrome X accumulate cardiac risk factors, they should \nbe given special attention in terms of diagnosis and treatment.", "This article reviews the relationship between metabolic syndrome (MetS) and \nnephrolithiasis, as well as the clinical implications for patients with this \ndual diagnosis. MetS, estimated to affect 25% of adults in the United States, is \nassociated with a fivefold increase in the risk of developing diabetes, a \ndoubling of the risk of acquiring cardiovascular disease, and an increase in \noverall mortality. Defined as a syndrome, MetS is recognized clinically by \nnumerous constitutive traits, including abdominal obesity, hypertension, \ndyslipidemia (elevated triglycerides, low high-density lipoprotein cholesterol), \nand hyperglycemia. Urologic complications of MetS include a 30% higher risk of \nnephrolithiasis, with an increased percentage of uric acid nephrolithiasis in \nthe setting of hyperuricemia, hyperuricosuria, low urine pH, and low urinary \nvolume. Current American Urological Association and European Association of \nUrology guidelines suggest investigating the etiology of nephrolithiasis in \naffected individuals; however, there is no specific goal of treating MetS as \npart of the medical management. Weight loss and exercise, the main lifestyle \ntreatments of MetS, counter abdominal obesity and insulin resistance and reduce \nthe incidence of cardiovascular events and the development of diabetes. These \nrecommendations may offer a beneficial adjunctive treatment option for \nnephrolithiasis complicated by MetS. Although definitive therapeutic \nrecommendations must await further studies, it seems both reasonable and \njustifiable for the urologist, as part of a multidisciplinary team, to recommend \nthese important lifestyle changes to patients with both conditions. These \nrecommendations should accompany the currently accepted management of \nnephrolithiasis.", "Approximately 2500 Americans die from cardiovascular disease (CVD) each day. \nEach year, CVD claims more lives than the next four leading causes of death \ncombined. Direct and indirect costs of CVD are estimated to be Dollars 403.1 \nbillion in 2006. Despite advancements in conventional therapy, the residual risk \nof CVD continues to rise. One component of the cardiometabolic risk is metabolic \nsyndrome. Metabolic syndrome is a constellation of interrelated risk factors of \nmetabolic origin including abdominal obesity, atherogenic dyslipidemia, elevated \nblood pressure, elevated plasma glucose level, and prothrombotic and \nproinflammatory states that promote atherosclerotic CVD and increase the risk of \ntype 2 diabetes mellitus. Approximately 47 million residents of the United \nStates have metabolic syndrome. Abdominal obesity and insulin resistance appear \nto be its predominant underlying risk factors. Abdominal adiposity is considered \nhigh-risk fat, and it is associated with insulin resistance, hyperglycemia, \ndyslipidemia, hypertension, and prothrombotic and/or proinflammatory states. \nDespite notable advances in cardiovascular risk management, the prevalence of \ncardiovascular events and type 2 diabetes remains high. First-line therapy for \nindividuals with metabolic syndrome should be directed to the major CVD risk \nfactors, namely, elevated low-density lipoprotein cholesterol levels, \nhypertension, and diabetes, and it should emphasize lifestyle modification. \nUntil additional research better defines the most appropriate therapies, \nconventional cardiovascular risk factors, such as lipid levels, blood pressure, \nand diabetes, should be managed in individuals with metabolic syndrome according \nto nationally accepted clinical guidelines.", "Clinical investigations designed to determine risk profiles for the development \nof cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) are usually \nperformed in homogenous populations and often focus on body mass index (BMI), \nwaist circumference (WC), and fasting triglyceride (TG) levels. However, there \nare major ethnic differences in the relationship of these risk factors to \noutcomes. For example, the BMI risk threshold may be higher in blacks than in \nwhites and higher in women than in men. Furthermore, a WC that predicts an obese \nBMI in white women only predicts a BMI in the overweight category in black \nwomen. In addition, overweight black men have a greater risk of developing type \n2 DM than do overweight black women. Although TG levels are excellent predictors \nof insulin resistance in whites, they are not effective markers of insulin \nresistance in blacks. Among the criteria sets currently available to predict the \ndevelopment of CVD and type 2 DM, the most well known is the metabolic syndrome. \nThe metabolic syndrome has 5 criteria: central obesity, hypertriglyceridemia, \nlow high-density lipoprotein (HDL) levels, fasting hyperglycemia, and \nhypertension. To make the diagnosis of the metabolic syndrome, 3 of the 5 \nfactors must be present. For central obesity and low HDL, the metabolic syndrome \nguidelines are sex specific. Diagnostic guidelines should also take ethnic \ndifferences into account, particularly in the diagnosis of central obesity and \nhypertriglyceridemia.", "Metabolic Syndrome X is a clinical entity which comprises the following factors: \ndiabetes mellitus, arterial hypertension, high levels of triglyceride and/or low \nlevels of HDL cholesterol, central obesity and microalbuminuria (by WHO \ncriteria). The first goal of this study was to determine the frequency of the \nMetabolic Syndrome X (MSX) in patients with acute myocardial infarction compared \nwith the general population. The second goal of the study was to examine the \nfrequency of heart failure and reinfarction rate in the patients with myocardial \ninfarction, with and without MSX. Furthermore, the relationship between gender \nand MSX was analyzed. A total of 101 patients with acute myocardial infarction \ntook part in randomized trial (32 women and 69 men). MSX and all of its \ncomponents were diagnosed according to WHO criteria. To determine statistical \nsignificance of our results, we used chi2 test and t-test for independent \nsamples. From 101 patient 48 had MSX (47.52%), while in the general population \nincidence of MSX is 3-4%. The reinfarction and the heart failure rate were \nsignificantly higher in the group of patients with MSX (p = 0.0067 and p = \n0.0217, respectively). To conclude, the results of the present study confirm \nthat MSX is a high risk factor for myocardial infarction and its complications.", "Metabolic syndrome, defined as a cluster of obesity, hypertension, dyslipidemia, \nand insulin resistance/glucose intolerance, has been identified as a major risk \nfactor for coronary heart disease in women. Nurses should increase their \nawareness of metabolic syndrome to help identify and treat the current estimated \n47 million US residents who have metabolic syndrome.", "BACKGROUND: Metabolic syndrome (MetS) is a collection of clinical conditions, \nincluding central obesity, hypertension, glucose intolerance and dyslipidemia. \nThe long-term inflammatory and metabolic dysfunction associated with MetS may \ncontribute to osteoarthritic processes leading up to total joint arthroplasty \n(TJA). The purpose of this study was to investigate levels of metabolic \nbiomarkers and the prevalence of MetS in patients undergoing TJA.\nMETHODS: Under IRB approval, citrated plasma samples were collected from 41 \npatients undergoing total hip and knee arthroplasty (THA/TKA) preoperatively and \nday 1 postoperatively. Control group consisted of 25 healthy human plasma \nsamples (female and male, 18-35 years old) purchased from George King Biomedical \nInc. (Overland Park, KS, USA). Samples were profiled for c-peptide, ferritin, \nIL-6, insulin, resistin, TNF-α, IL-1a, leptin, and PAI-1 using metabolic \nbiochips purchased from RANDOX Co. (Antrim, Northern Ireland). NCEP/ATP III \nguidelines were used to evaluate which patients met MetS criteria.\nRESULTS: Levels of IL-6, resistin, TNF-a, IL-1a, leptin, and PAI-1 were \nsignificantly elevated in patients undergoing TJA compared to normal. C-peptide \nand insulin were both decreased in TJA compared to normal. No significance was \nfound when comparing TJA to normal for ferritin. TNFα was significantly lower in \nTJA+MetS compared to TJA-MetS, while other biomarkers showed no difference in \nTJA±MetS populations. Insulin & c-peptide both showed a significant decrease in \nTJA-MetS compared to normal, but levels in TJA+MetS patients were not \nsignificantly different from controls. Resistin showed significant increases in \nTJA+MetS vs. normal, but not in TJA-MetS vs. normal.\nCONCLUSIONS: Overall, the differing metabolic profile seen in patients \nundergoing TJA suggest ongoing metabolic dysfunction. Insulin and c-peptide \npatterns among the different test groups hint toward a complex and dysfunctional \nmetabolic process involved, with leptin and underlying insulin resistance \nplaying a role. Increased resistin in TJA+MetS, but not in TJA-MetS, compared to \nnormal, suggests that while elevated resistin levels may be associated with the \nosteoarthritic process, levels are further attenuated by MetS, which is highly \nprevalent in this population. Increased TNFα in TJA-MetS compared to TJA+MetS \nmay be an artifact of differing sample populations or a true complication of the \ncomplex pathophysiology and medical regimen seen in patients with both OA and \nMetS. The lack of difference seen in the remaining biomarkers suggest that \nhaving MetS as a comorbidity does not contribute to the elevated levels seen in \npatients undergoing TJA.", "The metabolic syndrome is a complex association of several risk factors \nincluding insulin resistance, dyslipidemia, and essential hypertension. Insulin \nresistance has been associated with sympathetic activation and endothelial \ndysfunction, which are the main mechanisms involved in the pathophysiology of \nhypertension and its related cardiovascular risk. According to the Sixth Report \nof the Joint National Committee, and guidelines of the World Health \nOrganization/International Society of Hypertension, the presence of multiple \nrisk markers suggests that both hypertension and risk factors should be \naggressively managed in order to obtain a better outcome. Primary prevention of \nobesity at different levels--individual, familial, and social-- starting early \nin childhood has proven to be cost effective, and will be mandatory to reduce \nthe world epidemic of obesity and its severe consequences.", "Metabolic syndrome is widely spread in population especially among subjects with \nrisk factors of atherosclerosis related diseases. Since 1988 criteria of \nmetabolic syndrome have undergone substantial transformation. Technical \ndifficulties related to detection of insulin resistance created obstacles to \napplication of the term \"metabolic syndrome\" in clinical practice. In 2001 \nexperts of National Cholesterol Education Program in USA suggested new set of \ncriteria. The presence of 3 or more of the following 5 components (abdominal \nobesity, hypertriglyceridemia, low level of high density lipoprotein \ncholesterol, hypertension and high fasting blood glucose) allows to diagnose \nmetabolic syndrome. These worldwide used criteria do not imply detection of \ninsulin resistance. Feasibility of this approach has been confirmed by analysis \nof correlation between presence of markers of insulin resistance and that of \nmetabolic syndrome according to novel criteria. This analysis has shown that \ncombination of 3 or more components is significantly associated with insulin \nresistance.", "Insulin resistance represents a common metabolic abnormality leading to \ncardiovascular disease, the major cause of morbidity and mortality in most parts \nof the world. Insulin resistance is also associated with an increased risk of \ntype 2 diabetes which is strongly associated with obesity. The insulin \nresistance of obese people and subjects with type 2 diabetes is characterised by \ndefects at many levels, affecting insulin receptor concentration, glucose \ntransport mechanisms and the activities of intracellular enzymes. Around 25% of \nwestern populations show some features of the insulin resistance syndrome (often \nreferred to as syndrome X or the metabolic syndrome) ie, a clustering of \nmetabolic, atheromatous risk factors, including hypertriglyceridaemia, \nhyperinsulinaemia, hyper-tension, hypercholesterinaemia and obesity. However, \nthe known metabolic cardiovascular risk factors associated with the insulin \nresistance syndrome do not sufficiently explain the excess vascular risk \nattributed to this syndrome. The observation, that increased plasma plasminogen \nactivator inhibitor 1 (PAI-1) levels were associated with insulin resistance and \natherothrombosis added for the first time a pathological basis for an \nassociation of the insulin resistance syndrome not only with metabolic, \natheromatous (atherosclerotic) risk but also with atherothrombotic risk. It is \nvery likely that not only PAI-1, but also other abnormalities in haemostatic \nvariables contribute to this excess vascular risk. Knowledge of how haemostatic \nvariables cluster with classical metabolic risk factors associated with the \ninsulin resistance syndrome could help to better understand the pathogenesis of \ncardiovascular diseases. Indeed, many coagulation and fibrinolytic proteins have \nbeen shown to be associated with features of the insulin resistance syndrome and \nthese associations suggest that some coagulation and fibrinolytic proteins have \na role in atherothrombotic disorders, principally through an association with \nother established metabolic (atheromatous) risk factors in the presence of \nunderlying insulin resistance. Interestingly, new therapeutic approaches in the \nprevention and treatment of insulin resistance do show some influence on \ncoagulation and fibrinolysis. The newest drugs are the thiazolidinediones, a \ntotally novel class of insulin sensitisers. They have the potential to offer \nimprovements both in glycaemic control and in cardiovascular events.", "The metabolic syndrome is a clustering of risk factors which predispose an \nindividual to cardiovascular morbidity and mortality. There is general consensus \nregarding the main components of the syndrome (glucose intolerance, obesity, \nraised blood pressure and dyslipidaemia [elevated triglycerides, low levels of \nhigh-density lipoprotein cholesterol]) but different definitions require \ndifferent cut points and have different mandatory inclusion criteria. Although \ninsulin resistance is considered a major pathological influence, only the World \nHealth Organization (WHO) and European Group for the study of Insulin Resistance \n(EGIR) definitions include it amongst the diagnostic criteria and only the \nInternational Diabetes Federation (IDF) definition has waist circumference as a \nmandatory component. The prevalence of metabolic syndrome within individual \ncohorts varies with the definition used. Within each definition, the prevalence \nof metabolic syndrome increases with age and varies with gender and ethnicity. \nThere is a lack of diagnostic concordance between different definitions. Only \nabout 30% of people could be given the diagnosis of metabolic syndrome using \nmost definitions, and about 3540% of people diagnosed with metabolic syndrome \nare only classified as such using one definition. There is currently debate \nregarding the validity of the term metabolic syndrome, but the presence of one \ncardiovascular risk factor should raise suspicion that additional risk factors \nmay also be present and encourage investigation. Individual risk factors should \nbe treated." ]	['https://meshb.nlm.nih.gov/record/ui?ui=D024821', 'https://meshb.nlm.nih.gov/record/ui?ui=D007333']
61f5914e882a024a1000000d	[ 27582220, 34554383, 33135381, 34366359, 34506904, 34827546, 34550687, 29067304, 29686315, 29181491, 34697913, 34585212, 34263875, 34324167, 34539340, 34234067, 34554982, 34535787, 34650610, 34741884, 33836798 ]	train	Aducanumab can be used for treatment of which disease?	factoid	Aducanumab is approved for treatment of Alzheimer's disease.	Alzheimer's disease	[ "Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) \nplaques and neurofibrillary tangles in the brain, accompanied by synaptic \ndysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to \ntrigger its clearance or mitigate its neurotoxicity has so far been \nunsuccessful. Here we report the generation of aducanumab, a human monoclonal \nantibody that selectively targets aggregated Aβ. In a transgenic mouse model of \nAD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce \nsoluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal \nor mild AD, one year of monthly intravenous infusions of aducanumab reduces \nbrain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing \nof clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini \nMental State Examination scores. The main safety and tolerability findings are \namyloid-related imaging abnormalities. These results justify further development \nof aducanumab for the treatment of AD. Should the slowing of clinical decline be \nconfirmed in ongoing phase 3 clinical trials, it would provide compelling \nsupport for the amyloid hypothesis.", "The pipeline for new treatments for Alzheimer's disease (AD) in the USA contains \nover 100 different agents, 80% of which can be categorized as disease-modifying \ntherapies. The regulatory approval of the disease-modifying agent aducanumab has \nbrought more attention to the complexity of the diagnosis, evaluation, and \ntreatment of AD and the difficult decisions payers and policy makers will face \nover the next few years as innovation continues in this space. The value of AD \ntreatment can vary widely according to the perspective of the analysis, sources \nof data, and methodological approach for the value assessment. This article \nfocuses on AD-specific data gaps and measurement challenges and provides \nguidance for evidence generation to facilitate better value assessments for \nfuture AD treatments.", "Aducanumab recently underwent two large phase III clinical trials that were \nstopped prematurely by the sponsor Biogen. One trial was trending positive while \nthe other showed no benefits from aducanumab. Post hoc analyses led the sponsor \nto assert that there was a sufficient efficacy signal to justify a new drug \napplication as a treatment for Alzheimer's disease. The sponsor claimed that \nsubsets of participants receiving sufficiently high doses of aducanumab \ndemonstrated benefits in both trials. In contrast, we identified alternative \naccounts for the apparent drug benefits in post hoc subgroups that are unrelated \nto dose effects. Biomarker data were consistent with target engagement, but no \nevidence was presented to correlate biomarker changes to cognitive benefits. Our \nanalysis supports the conduct of a third, phase III trial with high-dose \naducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction \nin Alzheimer's disease cannot be proven by clinical trials with divergent \noutcomes.", "Alzheimer's disease (AD) is the most common form of dementia with global burden \nprojected to triple by 2050. It incurs significant biopsychosocial burden \nworldwide with limited treatment options. Aducanumab is the first monoclonal \nantibody recently approved by the US-FDA for mild AD through the accelerated \napproval pathway. It is the first molecule to be approved for AD since 2003 and \ncarries with it a therapeutic promise for the future. As the definition of AD \nhas evolved from a pathological entity to a Clinico-biological construct over \nthe years, the amyloid-β (Aβ) pathway has been increasingly implicated in its \npathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in \nthe brain, which forms a surrogate marker for this pathway. The research \npopulace has, however, been globally divided by skepticism and hope regarding \nthis approval. Failure to meet clinical endpoints in the trials, alleged \ntransparency issues, cost-effectiveness, potential adverse effects, need for \nregular monitoring, and critique of 'amyloid cascade hypothesis' itself are the \nmain caveats concerning the antibody. With this controversy in background, this \npaper critically looks at antibody research in AD therapeutics, evidence, and \nevolution of Aducanumab as a drug and the potential clinical implications of its \nuse in future. While the efficacy of this monoclonal antibody in AD stands as a \ntest of time, based on the growing evidence it is vital to rethink and explore \nalternate pathways of pathogenesis (oxidative stress, neuroinflammation, \ncholesterol metabolism, vascular factors, etc.) as possible therapeutic targets \nthat may help elucidate the enigma of this complex yet progressive and \ndebilitating neurodegenerative disorder.", "The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still \ndominates the field, yet the clinical trial evidence does not robustly support \nit. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should \nbe elevated in the brain regions and at the disease stages where and when neuron \ndeath and synaptic protein loss begin and are the most severe, but we review \nprevious evidence to demonstrate that this is not consistently the case. To \nrescue the Aβ oligomer hypothesis from falsification, we propose the novel \nad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally \nproduce Aβ peptides even in healthily aging individuals, and hippocampal \noxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate \nand drive Aβ peptide aggregation into oligomers and spreading, neuron death, \nsynaptic dysfunction, and other aspects of AD neurodegeneration. We highlight \nadditional evidence consistent with the underwhelming efficacy of Aβ \noligomer-lowering agents, such as aducanumab, and of antioxidants, such as \nvitamin E, versus the so far isolated case report that DNase-I treatment for 2 \nmonths resulted in a severe AD patient's Mini-Mental State Exam score increasing \nfrom 3 to 18, reversing his diagnosis to moderate AD, according to the \nMini-Mental State Exam.", "Aducanumab, a human monoclonal antibody, was approved in June of 2021 as the \nfirst disease-modifying treatment for Alzheimer's disease by the United States \nFood and Drug Administration (U.S. FDA). A substantial proportion of patients \nwith Alzheimer's disease live in low- and middle-income countries (LMICs), and \nthe debilitating effects of this disease exerts burdens on patients and \ncaregivers in addition to the significant economic strains many nations bear. \nWhile the advantages of a disease-modifying therapy are clear in delaying the \nprogression of disease to improve patient outcomes, aducanumab's approval by the \nU.S. FDA was met with controversy for a plethora of reasons. This paper will \nprovide precursory insights into aducanumab's role, appropriateness, and \ncost-effectiveness in low- and middle-income countries. We extend some of the \ncontroversies associated with aducanumab, including the contradicting evidence \nfrom the two trials (EMERGE and ENGAGE) and the resources required to deliver \nthe treatment safely and effectively to patients, among other key \nconsiderations.", "The recent approval of aducanumab for Alzheimer's disease has heightened the \ninterest in therapies targeting the amyloid hypothesis. Our research has focused \non identification of novel compounds to improve amyloid processing by modulating \ngamma secretase activity, thereby addressing a significant biological deficit \nknown to plague the familial form of the disease. Herein, we describe the \ndesign, synthesis, and optimization of new gamma secretase modulators (GSMs) \nbased on previously reported oxadiazine 1. Potency improvements with a focus on \npredicted and measured properties afforded high-quality compounds further \ndifferentiated via robust Aβ42 reductions in both rodents and nonhuman primates. \nExtensive preclinical profiling, efficacy studies, and safety studies resulted \nin the nomination of FRM-024, \n(+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, \nas a GSM preclinical candidate for familial Alzheimer's disease.", "INTRODUCTION: Aducanumab (BIIB037), a human monoclonal antibody selective for \naggregated forms of amyloid beta, is being investigated as a disease-modifying \ntreatment for Alzheimer's disease (AD).\nMETHODS: This randomized, double-blind, placebo-controlled single ascending-dose \nstudy investigated the safety, tolerability, and pharmacokinetics (PK) of \naducanumab in patients with mild-to-moderate AD. Eligible patients were \nsequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) \nor placebo.\nRESULTS: The primary outcome was safety and tolerability. Doses ≤30 mg/kg were \ngenerally well tolerated with no severe or serious adverse events (SAEs). All \nthree patients who received 60 mg/kg aducanumab developed SAEs of symptomatic \namyloid-related imaging abnormalities, which completely resolved by weeks 8-15. \nAducanumab Cmax, AUC0-last, and AUCinf increased in a dose-proportional manner.\nDISCUSSION: In this single-dose study, aducanumab demonstrated an acceptable \nsafety and tolerability profile and linear PK at doses ≤30 mg/kg \n(clinicaltrials.govNCT01397539).", "Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 \nclinical trials for the treatment of Alzheimer's disease. Biochemical and \nstructural analyses show that aducanumab binds a linear epitope formed by amino \nacids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and \noligomeric or fibrillar aggregates based on weak monovalent affinity, fast \nbinding kinetics and strong avidity for epitope-rich aggregates. Direct \ncomparative studies with analogs of gantenerumab, bapineuzumab and solanezumab \ndemonstrate clear differentiation in the binding properties of these antibodies. \nThe crystal structure of the Fab fragment of aducanumab bound to its epitope \npeptide reveals that aducanumab binds to the N terminus of Aβ in an extended \nconformation, distinct from those seen in structures with other antibodies that \ntarget this immunodominant epitope. Aducanumab recognizes a compact epitope that \nsits in a shallow pocket on the antibody surface. In silico analyses suggest \nthat aducanumab interacts weakly with the Aβ monomer and may accommodate a \nvariety of peptide conformations, further supporting its selectivity for Aβ \naggregates. Our studies provide a structural rationale for the low affinity of \naducanumab for non-pathogenic monomers and its greater selectivity for \naggregated forms than is seen for other Aβ-targeting antibodies.", "The amyloid hypothesis has been the dominant framework for Alzheimer's disease \n(AD) research, including the development of anti-AD therapies. However, none of \nthe phase III clinical trials conducted to date that targeted amyloid β (Aβ) \nproduction, aggregation, or clearance demonstrated a statistically significant \ntreatment effect in patients with AD. This includes the approach of using \nmonoclonal antibodies that recognize various Aβ epitopes and display different \nbinding selectivity. While some monoclonal antibodies have failed in phase III \ntrials, several are still in development. Aducanumab (BIIB037) is a human \nantibody that selectively targets aggregated forms of Aβ, including soluble \noligomers and insoluble fibrils. In PRIME (NCT01677572), an ongoing phase Ib \ntrial (N=196 patients dosed), aducanumab was shown to reduce Aβ plaques and slow \ndecline in clinical measures in patients with prodromal or mild AD, with \nacceptable safety and tolerability. The main safety finding was amyloid-related \nimaging abnormalities (ARIA), a side effect associated with removal of Aβ, which \nwas dose-dependent and occurred more often in ApoE ε4 carriers than \nnon-carriers. ENGAGE (NCT02477800) and EMERGE (NCT02484547), the ongoing phase \nIII trials of aducanumab in early AD, have been designed based on the outcomes \nof PRIME and on lessons from past clinical trials in patients with AD. Those \nstudy design features include patient selection with confirmed Aβ pathology, \nensuring sufficient target engagement, and conducting clinical trials in \npatients at earlier symptomatic stages of AD.", "Aducanumab is a human immunoglobulin G1 anti-amyloid beta (Aβ) antibody \ncurrently being evaluated for potential treatment of patients with early \nAlzheimer's disease. This paper describes the relationship between the \npopulation pharmacokinetics (PopPKs) and pharmacokinetics-pharmacodynamics \n(PKs-PDs) of aducanumab using data from phase I to III clinical studies, with \nstandard uptake value ratio (SUVR) used as a PD marker. Across clinical studies, \naducanumab was administered intravenously either as a single dose ranging from \n0.3 to 60 mg/kg or as multiple doses of 1, 3, 6, or 10 mg/kg every 4 weeks. A \ntitration regimen with maintenance doses of 3, 6, or 10 mg/kg was also \nevaluated. Aducanumab PK was characterized with a two-compartment model with \nfirst-order elimination. No nonlinearities in PKs were observed. The PopPK-PD \nmodel was developed using a sequential estimation approach. The time course of \namyloid plaques, as expressed by composite SUVR measured using positron emission \ntomography, was described using an indirect response model with drug effect \nstimulating the elimination of SUVR. None of the identified covariates on PK and \nthe PopPK-PD model were clinically relevant. The PopPK-PD model showed that \nmagnitude, duration, and consistency of dosing are important factors determining \nthe degree of Aβ removal. The intrinsic pharmacology of aducanumab remained \nconsistent across studies.", "Conflict of interest statement: JC has provided consultation to Acadia, \nAlkahest, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, \nCerevel, Cortexyme, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, \nJanssen, Jazz, Karuna, LSP, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, \nRoche, Signant Health, Sunovion, Suven, United Neuroscience, and Unlearn AI \npharmaceutical and assessment companies. Dr. Cummings owns the copyright of the \nNeuropsychiatric Inventory. Dr Cummings has the following research support: \nNIGMS P20GM109025; NINDS U01NS093334; NIA R01AG053798; NIA P20AG068053; NIA \nR35AG71476. LGA has provided consultation to Eli Lilly, Biogen, and Two Labs. \nLGA receives the following research support: NIA U01 AG057195, NIA R01 AG057739, \nNIA P30 AG010133, Alzheimer Association LEADS GENETICS 19-639372, Roche \nDiagnostics RD005665, AVID Pharmaceuticals, Life Molecular Imaging. LGA has \nreceived honoraria for participating in independent data safety monitoring \nboards and providing educational CME lectures and programs. LGA has stock in \nCassava Sciences. AA has received honoraria for consulting; participating in \nindependent data safety monitoring boards; providing educational lectures, \nprograms, and materials; or serving on advisory boards for AbbVie, Acadia, \nAllergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, \nHarvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, \nRoche/Genentech, Novo Nordisk, Sunovion, and Suven. PA has received research \nfunding from NIA, FNIH, the Alzheimer’s Association, Janssen, Lilly and Eisai, \nand personal fees from Biogen, Merck, Roche, Abbvie, ImmunoBrain Checkpoint, \nRainbow Medical and Shionogi. SS was a site PI and co-chair of the investigator \nsteering committee for the ENGAGE trial and he receives research support and \nconsultancy fees from Lilly, Biogen, Avid, Eisai, Genentech, and Roche. MW has \nserved on Advisory Boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., \nMerck Sharp and Dohme Corp., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, \nNational Institute on Aging (NIA), Brain Health Registry and ADNI. He serves on \nEditorial Boards for Alzheimer’s and Dementia, TMRI and MRI. He has provided \nconsulting and/or acted as a speaker to Cerecin/Accera, Inc., BioClinica, \nNestle/Nestec, Roche, Genentech, NIH, The Buck Institute for Research on Aging, \nFUJIFILM-Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, \nUniversity of Southern California (USC), Cytox, and Japanese Organization for \nMedical Device Development, Inc. (JOMDD) and T3D Therapeutics. He holds stock \noptions with Alzheon, Inc., Alzeca, and Anven.", "On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab, \na monoclonal amyloid targeting β-amyloid, for the treatment for Alzheimer's \ndisease (AD). This decision was achieved through the Accelerated Approval \nPathway and was essentially motivated by the evidence that aducanumab reduces \nbrain amyloid plaques. This news is causing a heated debate in the scientific \ncommunity. On the one hand, aducanumab is the first drug to be approved for the \ntreatment of the disease since 2003 and is the first drug to act on the alleged \npathophysiological mechanisms of AD. At the same time, the evidence of clinical \nbenefit coming from two phase 3 clinical trials is contradictory and still \ninconclusive. The aim of the present editorial is to provide some points to \nconsider that can help understand the peculiarities and implications of this \napproval and feed the scientific debate underway.", "Aducanumab (aducanumab-avwa; Aduhelm™) is a human, immunoglobulin gamma 1 (IgG1) \nmonoclonal antibody directed against aggregated soluble and insoluble forms of \namyloid β. It has been co-developed by Biogen and Eisai under license from \nNeurimmune for the treatment of Alzheimer's disease. In June 2021, aducanumab \nreceived its first approval in the USA for the treatment of Alzheimer's disease. \nAccording to the US FDA prescribing information, treatment should be initiated \nin patients with mild cognitive impairment or mild dementia stage of disease, \nthe population in which treatment was initiated in clinical trials. There are no \nsafety or effectiveness data on initiating treatment at earlier or later stages \nof the disease than were studied. Aducanumab is under regulatory review in Japan \nand in Europe. Its long-term safety and tolerability is being evaluated in a \nmultinational phase 3b clinical study in patients with early Alzheimer's disease \n(mild cognitive impairment and mild Alzheimer's disease). This article \nsummarizes the milestones in the development of aducanumab leading to this first \napproval for Alzheimer's disease.", "Alzheimer's disease and Lewy body diseases are the most common causes of \nneurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are \ntwo key proteins involved in the pathogenesis of these neurodegenerative \ndiseases. Immunotherapy aims to reduce the harmful effects of protein \naccumulation by neutralising toxic species and facilitating their removal. The \nresults of the first immunisation trial against Aβ led to a small percentage of \nmeningoencephalitis cases which revolutionised vaccine design, causing a shift \nin the field of immunotherapy from active to passive immunisation. While the \nvast majority of immunotherapies have been developed for Aβ and tested in \nAlzheimer's disease, the field has progressed to targeting other proteins \nincluding αSyn. Despite showing some remarkable results in animal models, \nimmunotherapies have largely failed final stages of clinical trials to date, \nwith the exception of Aducanumab recently licenced in the US by the FDA. \nNeuropathological findings translate quite effectively from animal models to \nhuman trials, however, cognitive and functional outcome measures do not. The \napparent lack of translation of experimental studies to clinical trials suggests \nthat we are not obtaining a full representation of the effects of \nimmunotherapies from animal studies. Here we provide a background understanding \nto the key concepts and challenges involved in therapeutic design. This review \nfurther provides a comprehensive comparison between experimental and clinical \nstudies in Aβ and αSyn immunotherapy and aims to determine the possible reasons \nfor the disconnection in their outcomes.", "Alzheimer's disease (AD) is an irreversible brain disorder associated with \nsevere progressive dementia and is characterized by deposits of amyloid plaques \nin the brain. Over the past 20 years, the mortality of strokes and heart disease \nhas decreased, but deaths from AD have increased. The four drugs used clinically \nto treat AD can only relieve symptoms but cannot slow the progression of the \ndisease. Aducanumab, a human monoclonal antibody that preferentially binds to \naggregated amyloid-β to reduce the number of amyloid plaques and slow disease \nprogression, was approved to treat AD by the US Food and Drug Administration on \nJune 7, 2021. It is the first disease-modifying therapy for AD, but there is \nconsiderable controversy regarding the drug's approval. Aducanumab offers hope \nfor millions of patients.", "Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since \n2003, has received accelerated approval from the Food and Drug Administration \n(FDA).This drug's approval has been highly contentious in the medical and \nscientific community owing to contradictory study findings and the FDA's \nadvisory panel not recommending its approval.", "On 7 June 2021, aducanumab was granted accelerated approval for the treatment of \nAlzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects \nconsidered reasonably likely to confer clinical benefit. This decision makes \naducanumab the first new drug to be approved for the treatment of AD since 2003 \nand the first drug to ever be approved for modification of the course of AD. \nMany have questioned how scientific evidence, expert advice and the best \ninterests of patients and families were considered in the approval decision. In \nthis article, we argue that prior to approval, the FDA and Biogen's shared \ninterpretation of clinical trial data - that high-dose aducanumab was \nsubstantially clinically effective - avoided conventional scientific scrutiny, \nwas prominently advanced by patient representative groups who had been major \nrecipients of Biogen funds, and raised concerns that safeguards were \ninsufficient to mitigate regulatory capture within the FDA. Here, we reflect on \nevents leading to the FDA's decision on 7 June 2021 and consider whether any \nlessons can be learned for the field.", "Conflict of interest statement: Disclosure and potential conflicts of interest: \nRRT has none. BF reports grants and other from Biogen during the conduct of the \nstudy and grants from Lilly, Eisai, NIH, Rogers Family Foundation and Spier \nFamily Foundation and other from Acadia Pharmaceuticals, outside the submitted \nwork. MA reports consulting for Biogen, Otsuka and Eli Lilly. The International \nCommittee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests \nform for the authors is available for download at: \nhttps://www.drugsincontext.com/wp-content/uploads/2021/09/dic.2021-7-3-COI.pdf", "Based on the reduction of amyloid β plaques, US FDA has recently approved \nAducanumab as a disease modifying treatment for Alzheimer's disease (AD). With \nhigh pricing and the potential risks likely with this treatment, certainty of AD \ndiagnosis becomes crucial. The current pilot study evaluated plasma levels of \nneurofilament L, an axonal injury marker and amyloid β42, a major component of \namyloid plaques for discriminating AD from non-AD dementia (NAD). Results with \nSimoa assays indicate that a combination of neurofilament L and amyloid β42 can \nbe considered as a screening tool in identifying eligible subjects for AD \ntreatment/ clinical trials.", "BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced \namyloid pathology in Alzheimer's disease (AD) trials; however, it is \ncontroversial whether it also improved cognition, which has been suggested would \nrequire a sufficiently high cumulative dose of the antibody in the brain. \nTherapeutic ultrasound, in contrast, has only begun to be investigated in human \nAD clinical trials. We have previously shown that scanning ultrasound in \ncombination with intravenously injected microbubbles (SUS), which temporarily \nand safely opens the blood-brain barrier (BBB), removes amyloid and restores \ncognition in APP23 mice. However, there has been no direct testing of how the \neffects of SUS compare to immunotherapy or whether a combination therapy is more \neffective.\nMETHODS: In a study comprising four treatment arms, we tested the efficacy of an \nAducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, \nin APP23 mice (aged 13-22 months), using sham as a control. The active place \navoidance (APA) test was used to test spatial memory, and histology and ELISA \nwere used to measure amyloid. Brain antibody levels were also determined.\nRESULTS: We found that both Adu and SUS reduced the total plaque area in the \nhippocampus with no additive effect observed with the combination treatment \n(SUS + Adu). Whereas in the cortex where there was a trend towards reducing the \ntotal plaque area from either Adu or SUS, only the combination treatment yielded \na statistically significant decrease in total plaque area compared to sham. Only \nthe SUS and SUS + Adu groups included animals that had their plaque load reduced \nto below 1% from above 10%. There was a robust improvement in spatial memory for \nthe SUS + Adu group only, and in this group the level of Adu, when measured \n3 days post-treatment, was 5-fold higher compared to those mice that received \nAdu on its own. Together, these findings suggest that SUS should be considered \nas a treatment option for AD. Alternatively, a combination trial using \nAducanumab together with ultrasound to increase brain levels of the antibody may \nbe warranted." ]	nan
53189656b166e2b80600001c	[ 9600226, 12536227, 19272424, 9759660, 10967182, 16691119, 11005264, 12722831, 15854770, 10867800, 22370907, 10822429, 11207422, 10787032 ]	train	Against which protein is the antibody used for immonostaining of Lewy bodies raised?	factoid	alpha-Synuclein is a presynaptic protein, which was identified as a specific component of Lewy bodies (LB) and Lewy neurites. Therefore, immunostaining for detecting the presence of Lewy bodies is carried out using antibodies against alpha-synuclein.	alpha-Synuclein	[ "A mutation in the alpha-synuclein gene has recently been linked to some cases of \nfamilial Parkinson's disease (PD). We characterized the expression of this \npresynaptic protein in the midbrain, striatum, and temporal cortex of control, \nPD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate \npericellular immunostaining. PD brain demonstrated alpha-synuclein \nimmunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare \nneuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases \ndemonstrated these findings as well as alpha-synuclein immunoreactivity in \ncortical Lewy bodies and CA2-3 neurites. These results suggest that, even in \nsporadic cases, there is an early and direct role for alpha-synuclein in the \npathogenesis of PD and the neuropathologically related disorder DLB.", "Diffuse Lewy body disease (DLBD) is characterized by the presence of Lewy bodies \n(LB) in the neurons and neurites of cortical, subcortical, and brain stem \nstructures. Recently, alpha-synuclein (alphaS) has been found to be a central \nconstituent of LB. In DLBD, abnormal accumulation of alphaS has been reported in \nboth neurons and glia, but studies on glial lesions in DLBD have been limited. \nWe examined in detail the constituents and distribution of glial lesions in \neight patients with DLBD and report the pathogenesis of the glial lesions. \nalphaS-positive neuronal cytoplasmic inclusions (NI), neuropil threads (NT), and \ncoiled bodies (CB) showed similar immunostaining profiles. Without pretreatment, \nNI, NT, and CB were detected by all antibodies against alphaS. The \nimmunostaining profile of star-like astrocytes (SLA) was quite different from \nthose of NI, NT, and CB. A few SLA were stained by an antibody against the \nnon-Abeta component portion of alphaS without pretreatment, but formic acid \npretreatment dramatically enhanced SLA immunoreactivity. SLA and CB were found \nin all eight brains with DLBD. SLA were scarce in the brain stem, but there were \nhundreds of SLA per visual field at x100 magnification in the temporal cortex of \nmost cases, while CB were found diffusely in both the cerebral cortex and brain \nstem, similar to NI. This suggests that the pathogenesis of SLA is different \nfrom those of NI and CB.", "Parkinson's disease and dementia with Lewy bodies are very frequent neurological \ndisorders of the elderly. Mutations in the alpha-synuclein (alphaSYN) gene cause \nParkinson's disease, often associated with dementia. Neuropathologically these \ndiseases are characterized by the presence of Lewy bodies and Lewy neurites, \nintraneuronal inclusions mostly composed of alphaSYN protein fibrils. Moreover, \nalphaSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in \nneuropathological lesions. Using our (Thy1)-[A30P]alphaSYN transgenic mouse \nmodel that develops age-dependent impairment in fear conditioning behavior, we \ninvestigated PSer129 immunostaining in the brain. We found distinct staining \npatterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 \nimmunoreactivity increased with age in hippocampal and cortical areas as well as \nthe lateral/basolateral amygdalar nuclei and was present also in young, \npre-symptomatic mice, but not wild-type controls. The tendency of PSer129 \nimmunostaining to accumulate in the nucleus was confirmed in cell culture. \n(Thy1)-[A30P]alphaSYN transgenic mice further developed age-dependent, specific \nneuritic/terminal alphaSYN pathology in the medial parts of the central \namygdalar nucleus and one of its projection areas, the lateral hypothalamus. \nInterestingly, this type of PSer129 neuropathology was thioflavine S negative, \nunlike the Lewy-like neuropathology present in the brain stem of \n(Thy1)-[A30P]alphaSYN mice. Thus, alphaSYN becomes phosphorylated in distinct \nparts of the brain in this alpha-synucleinopathy mouse model, showing \nage-dependent increases of nuclear PSer129 in cortical brain areas and the \nformation of neuritic/terminal PSer129 neuropathology with variable amyloid \nquality within the fear conditioning circuitry and the brain stem.", "The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) \n(also known as alpha-synuclein) is a presynaptic terminal molecule that \nabnormally accumulates in the plaques of Alzheimer's disease (AD) and in the \nLewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and \nParkinson's disease. To better understand the distribution of \nNACP/alpha-synuclein and its fragments in the LB-bearing neurons and neurites, \nas well as to clarify the patterns of NACP/alpha-synuclein compartmentalization, \nwe studied NACP/alpha-synuclein immunoreactivity using antibodies against the \nC-terminal, N-terminal, and NAC regions after Proteinase K and formic acid \ntreatment in the cortex of patients with LBs. Furthermore, studies of the \nsubcellular localization of NACP/alpha-synuclein within LB-bearing neurons were \nperformed by immunogold electron microscopy. These studies showed that the \nN-terminal antibody immunolabeled the LBs and dystrophic neurites with great \nintensity and, to a lesser extent, the synapses. In contrast, the C-terminal \nantibody strongly labeled the synapses and, to a lesser extent, the LBs and \ndystrophic neurites. Whereas Proteinase K treatment enhanced \nNACP/alpha-synuclein immunoreactivity with the C-terminal antibody, it \ndiminished the N-terminal NACP/alpha-synuclein immunoreactivity. Furthermore, \nformic acid enhanced LB and dystrophic neurite labeling with both the C- and \nN-terminal antibodies. In addition, whereas without pretreatment only slight \nanti-NAC immunoreactivity was found in the LBs, formic acid pretreatment \nrevealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. \nUltrastructural analysis revealed that NACP/alpha-synuclein immunoreactivity was \ndiffusely distributed within the amorphous electrodense material in the LBs and \nas small clusters in the filaments of LBs and neurites. These results support \nthe view that aggregated NACP/alpha-synuclein might play an important role in \nthe pathogenesis of disorders associated with LBs.", "Hallervorden-Spatz syndrome (HSS) is a rare autosomal recessive disorder \nclinically characterized by extrapyramidal signs and progressive dementia. In a \ntypical case, the clinical symptoms become apparent during late childhood, and \nusually the course is protracted over a decade or more. We recently had an \nopportunity to study the brains of two cases of HSS with a clinical course of \nover 30 years. Case 1 was a 44-year-old female and case 2 was a 37-year-old \nmale. Grossly, the brains showed severe fronto-temporal lobar atrophy with \nabundant spheroids and mild iron deposits in the globus pallidus, associated \nwith features of motor neuron disease. In addition, there was diffuse sponginess \nin the atrophic cortex as well as widespread Alzheimer's neurofibrillary tangles \n(NFTs) and Lewy bodies (LBs) in the cortical and subcortical regions, including \nthe spinal cord. Ultrastructurally, NFTs were composed of paired helical \nfilaments, and LBs of central dense cores with radiating fibrils. Discrete \nimmunostaining was demonstrated in NFTs and neuropil threads with various \nantibodies against phosphorylated tau, and in LBs with antibody against \nalpha-synuclein. In addition, diffuse, overlapping immunoreactivity of \nalpha-synuclein and phosphorylated tau was seen within the cytoplasm of many \nneurons. However, when LBs and NFTs coexisted within the same neurons, they were \nclearly segregated. The findings of our present cases as well as those reported \nin the literature may indicate that simultaneous and extensive occurrence of \nabnormal phosphorylation of tau and accumulation of alpha-synuclein may \nconstitute cardinal pathological features of HSS with protracted clinical \ncourse.", "Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy \ncharacterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies \n(LBs) are detected in approximately 10% of PSP cases, but there is little \ninformation on the relationship of LBs to tau pathology. We determined the \nfrequency of LBs in a large series of autopsy-confirmed cases of PSP and studied \nthe density and distribution of LBs, including Parkinson disease stage, in cases \nwith LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including \nassessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for \nalpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple \nsystem atrophy in addition to PSP and was excluded from further study along with \n2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were \ncompared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, \nBraak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile \nplaques were not different among PSP, LBD, and PSP/LBD, but disease duration was \nlonger in LBD. The Parkinson disease stage was similar, but the density of LBs \nin most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In \ncontrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP \nand LBD. Double immunostaining demonstrated alpha-synuclein and tau in different \nneurons with few exceptions. The findings suggest that LBs in PSP are similar in \ndistribution to those in LBD and independent of tau pathology. The greater \ndensity of LBs in LBD compared with PSP/LBD may be the result of longer disease \nduration in LBD, whereas greater neuronal loss in the substantia nigra in \nPSP/LBD may be the result of vulnerability of this brain region to both disease \nprocesses.", "Although alpha-synuclein (alpha-syn) has been implicated as a major component of \nthe abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple \nsystem atrophy (MSA), it is uncertain if GCIs are homogenous and contain \nfull-length alpha-syn. Since this has implications for hypotheses about the \npathogenesis of GCIs, we used a novel panel of antibodies to defined regions \nthroughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in \nMSA brains. Although the immunostaining profile of GCIs with these antibodies \nwas similar for all MSA brains, there were significant differences in the \nimmunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, \ncarboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire \npanel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with \nLBs brain with similar intensity. While the distribution of alpha-syn labeled \nGCIs paralleled that previously reported using silver stains, antibodies to \ncarboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of \nGCIs in the MSA hippocampal formation. Finally, Western blots demonstrated \ndetergent insoluble monomeric and high-molecular weight alpha-syn species in GCI \nrich MSA cerebellar white matter. Collectively, these data indicate that \nalpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may \nresult from cell type specific conformational or post-translational permutations \nin alpha-syn.", "The major protein constituent of Lewy bodies (LBs), the pathological hallmark of \nParkinson disease and dementia with Lewy bodies, is considered to be \nalpha-synuclein, but other proteins, in particular the microtubule-associated \nprotein tau, have been implicated in the pathogenesis of LBs. Tau is the major \nstructural component of neurofibrillary tangles (NFTs). Both direct \nimmunochemical studies of partially purified LBs and indirect \nimmunohistochemical studies have suggested that LBs may contain tau, but most of \nthese studies were based upon a single tau antibody, and immunologic \ncross-reactivity was not completely excluded. To gain insight into the relation \nbetween tau and alpha-synuclein in LBs, double immunostaining was performed in \nLewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel \nof monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, \nCP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. \nTau-immunoreactive LBs were present in the medulla in 80% of the cases, \nirrespective of Braak stage. All tau antibodies recognized at least some LBs, \narguing against nonspecific antibody cross-reactivity. In most lesions the tau \nimmunostaining was present at the periphery of the LB. The phospho-tau antibody, \nTG3, detected more LBs than any of the other tau antibodies. The proportion of \nLBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such \nas those in the locus ceruleus and basal nucleus of Meynert, and least in \nneurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the \nmedulla. The present results suggest that tau may coaggregate with \nalpha-synuclein in LBs, especially in neuronal populations vulnerable to both \nNFTs and LBs.", "We immunohistochemically investigated the degeneration processes of the \nnigro-striatal and nigro-amygdaloid pathways and the relationship between the \nloss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia \nnigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of \ntyrosine hydroxylase (TH)-positive neurons in the substantia nigra and \nTH-positive axonal terminals in the putamen decreased with a specific pattern. \nThe substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that \nwere almost evenly distributed, while the putamen exhibited diffuse or granular \nalpha-synuclein-immunostaining. Most of the granular stains were positive for \nanti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were \nnegative. These findings suggest that the axonal terminals in the putamen \nundergo abnormal alpha-synuclein accumulation, but may not always originate from \nLB-bearing neurons in the substantia nigra. The central amygdaloid nucleus \ncontained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive \ndystrophic axonal terminals, the degree of which was greater for cases with \ngranular staining in the putamen, and which was proportional to the number of \nalpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal \nterminals in the central amygdaloid nucleus may have originated from LB-bearing \nneurons in the substantia nigra. The results of the present study indicate that \nthe nigro-striatal and nigro-amygdaloid pathways undergo different degeneration \nprocesses in DLB, and suggest that the degeneration of the nigro-amygdaloid \npathway more strongly reflects LB formation in dopaminergic neurons of the \nsubstantia nigra than that of the nigro-striatal pathway. In addition, they \nindicate that there is no direct relationship between the loss of dopaminergic \nneurons and LB formation in the substantia nigra.", "The identification of the alpha-synuclein gene on chromosome 4q as a locus for \nfamilial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy \nbodies has heralded a new era in the study of Parkinson's disease. We have \nidentified a large family with Lewy body parkinsonism linked to a novel locus on \nchromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here \nwe report the clinical and neuropathological findings in an individual from this \nfamily and describe unusual high molecular weight alpha-synuclein-immunoreactive \nproteins in brain homogenates from brain regions with the most marked \nneuropathology. Distinctive histopathology was revealed with alpha-synuclein \nimmunostaining, including pleomorphic Lewy bodies, synuclein-positive glial \ninclusions and widespread, severe neuritic dystrophy. We also discuss the \nrelationship of this familial disorder to a Lewy body disease clinical spectrum, \nranging from Parkinson's disease to dementia with psychosis.", "α-Synuclein is the major protein associated with Lewy body dementia, Parkinson's \ndisease and multiple system atrophy. Since α-synuclein is present in the brain \nin physiological conditions as a presynaptic protein, it is crucial to \ncharacterize disease-associated modifications to develop an in vivo biomarker. \nWith the aim to develop antibodies showing high specificity and sensitivity for \ndisease-associated α-synuclein, synthetic peptides containing different amino \nacid sequences were used for immunization of mice. After generation of \nα-synuclein aggregates, ELISA and immunoblotting were used to test the \nspecificity of antibodies. Tissue microarray sections originating from different \nhuman α-synucleinopathies were used to compare immunostaining with other, \ncommercially available antibodies. Immunization of mice with the peptide \nTKEGVVHGVATVAE (amino acid 44-57 of α-synuclein) resulted in the generation of a \nmonoclonal antibody (5G4), which was able to bind aggregated α-synuclein \npreparation in sandwich ELISA or coated on magnetic beads. 5G4 proved to be \nsuperior to other antibodies in comparative immunohistochemical studies by \nrevealing more widespread and distinct α-synuclein pathology. Immunoblotting of \nhuman brain tissue revealed an additional band seen in dementia with Lewy \nbodies, whereas the band representing monomeric α-synuclein was very weak or \nlacking. In summary, the 5G4 antibody is most promising for re-evaluation of \narchival material and may offer new perspective for the development of in vivo \ndiagnostic assays for detecting disease-associated α-synuclein in body fluids.", "BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or \nPD, usually occurring later in the protracted course of the illness. The primary \nsite of neuropathologic change in PD is the substantia nigra, but the \nneuropathologic and molecular basis of dementia in PD is less clear. Although \nAlzheimer's pathology has been a frequent finding, recent advances in \nimmunostaining of alpha-synuclein have suggested the possible importance of \ncortical Lewy bodies (CLBs) in the brains of demented patients with PD.\nMETHODS: The brains of 22 demented and 20 nondemented patients with a clinical \nand neuropathologic diagnosis of PD were evaluated with standard neuropathologic \ntechniques. In addition, CLBs and dystrophic neurites were identified \nimmunohistochemically with antibodies specific for alpha-synuclein and \nubiquitin; plaques and tangles were identified by staining with thioflavine S. \nAssociations between dementia status and pathologic markers were tested with \nlogistic regression.\nRESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and \nspecific (90%) neuropathologic markers of dementia in PD and slightly more \nsensitive than ubiquitin-positive CLBs. They are better indicators of dementia \nthan neurofibrillary tangles, amyloid plaques, or dystrophic neurites.\nCONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are \na more sensitive and specific correlate of dementia than the presence of \nAlzheimer's pathology, which was present in a minority of the cases in this \nseries.", "It is increasingly clear that the normal protein alpha-synuclein is in some \nmanner closely associated with presynaptic components of select neuronal types \nwithin the adult human central nervous system (CNS) and, in addition, that in \nits pathologically altered state alpha-synuclein aggregates selectively in the \nform of filamentous inclusion bodies during certain progressive \nneurodegenerative disorders, such as familial and sporadic Parkinson's disease. \nBy having the antibody AFshp raised specifically to alpha-synuclein to label \nParkinson disease-specific Lewy bodies and Lewy neurites as well as synaptic \nboutons containing the unaltered protein, an initial attempt is made to map the \noverall distribution pattern and describe the staining behavior of the \nimmunoreactive punctae in select regions of the prosencephalon. Neocortical \nimmunolabeling is most prominent in the prodigious, but incompletely myelinated, \nassociation fields and faintest in the heavily myelinated primary motor and \nprimary sensory fields, with the premotor and first order sensory association \nareas occupying an intermediate position. Of the thalamic grays evaluated, those \ncontaining powerfully myelinated fiber tracts (e.g. centrum medianum, habenular \ncomplex) show the weakest immunolabeling, whereas, less sturdily myelinated \nstructures are highly immunoreactive. The fact that the immunostaining spectrum \nfor normal alpha-synuclein is so broad, together with the fact that some \nthalamic sites actually are immunonegative leads to the following conclusions \n(1) alpha-synuclein, although present in the synaptic boutons of many nerve \ncells in the adult human CNS, is by no means ubiquitous there, and (2) neuronal \ntypes lacking the normal protein cannot generate the Parkinson's \ndisease-specific filamentous pathology.", "alpha-Synuclein is a presynaptic protein recently identified as a specific \ncomponent of Lewy bodies (LB) and Lewy neurites. The aim of this study was to \nassess the morphology and distribution of alpha-synuclein immunoreactivity in \ncases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin \nimmunostaining. We examined substantia nigra, paralimbic regions (entorhinal \ncortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and \noccipital association cortices) with double alpha-synuclein and ubiquitin \nimmunostaining in 25 cases meeting neuropathological criteria for DLB. \nalpha-Synuclein immunostaining was more specific than ubiquitin immunostaining \nin that it differentiated LB from globose tangles. It was also slightly more \nsensitive, staining 4-5% more intracytoplasmic structures, especially diffuse \nalpha-synuclein deposits that were ubiquitin negative. In addition to LB, \nalpha-synuclein staining showed filiform and globose neurites in the substantia \nnigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of \nalpha-synuclein staining was seen in substantia nigra: from diffuse \"cloud-like\" \ninclusions to aggregated intracytoplasmic inclusions with variable ubiquitin \nstaining to classic LB. We hypothesize that these represent different stages in \nLB formation." ]	['http://www.uniprot.org/uniprot/SYUA_SERCA', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000906', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D010300', 'http://www.disease-ontology.org/api/metadata/DOID:12217', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D051844', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D020961', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016631', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0003823']
515a9d86d24251bc050000a7	[ 18288611, 15822917, 16335978, 19327347, 21906361, 15952730, 18412540, 23300121 ]	train	Albumin depletion is a common first step for proteomic analysis of CSF fluid. What is the advantage and disadvantage of this procedure?	summary	Depletion of the high abundant protein Albumin from CSF samples is improving the detection of lower abundant proteins but may also lead to the potential loss of non-target proteins.	Depletion of the high abundant protein Albumin from CSF samples is improving the detection of lower abundant proteins but may also lead to the potential loss of non-target proteins.	[ "Glycoproteins in cerebrospinal fluid (CSF) are altered in Alzheimer's Disease \n(AD) patients compared to control individuals. We have utilized albumin \ndepletion prior to 2D gel electrophoresis to enhance glycoprotein concentration \nfor image analysis as well as structural glycoprotein determination without \nglycan release using mass spectrometry (MS). The benefits of a direct \nglycoprotein analysis approach include minimal sample manipulation and retention \nof structural details. A quantitative comparison of gel-separated glycoprotein \nisoforms from twelve AD patients and twelve control subjects was performed with \nglycoprotein-specific and total protein stains. We have also compared glycoforms \nin pooled CSF obtained from AD patients and control subjects with mass \nspectrometry. One isoform of alpha1-antitrypsin showed decreased glycosylation \nin AD patients while another glycosylated isoform of an unassigned protein was \nup-regulated. Protein expression levels of alpha1-antitrypsin were decreased, \nwhile the protein levels of apolipoprotein E and clusterin were increased in AD. \nNo specific glycoform could be specifically assigned to AD.", "Today, proteomics is an exciting approach to discover potential biomarkers of \ndifferent disorders. One challenge with proteomics experiments is the wide \nconcentration range of proteins in various tissues and body fluids. The most \nabundant component in human body fluids, human serum albumin (HSA), is present \nat concentrations corresponding to approximately 50% of the total protein \ncontent in, e.g., plasma and cerebrospinal fluid (CSF). If this component could \nbe selectively removed, then the chances of observing lower-abundance component \nof clinical interest would be greatly improved. There are today several \napproaches of varying specificity available for depletion. In this study, the \nproperties of two commercially available kits, for the removal of HSA and HSA \nand immunoglobulin G (IgG), respectively, were compared, and the benefits of \nusing depletion steps prior to on-line LC-FTICR MS were evaluated. Both methods \nwere applied on plasma and CSF. To our knowledge, these are the first results \nreported for CSF. Also, the combination with electrospray LC-FTICR MS is novel. \nThe proportion of depleted HSA and IgG was estimated using global labeling \nmarkers for peptide quantification. Both depletion-methods provided a \nsignificant reduction of HSA, and the identification of lower abundant \ncomponents was clearly facilitated. A higher proportion of HSA was removed using \nthe affinity-based removal kit, and consequently more proteins could be \nidentified using this approach.", "Glycoproteins in cerebrospinal fluid are found to be altered in Alzheimer \npatients compared to healthy control individuals. We have utilized \nmicro-solution isoelectric focusing and affinity chromatography, prior to gel \nelectrophoresis to enable site-specific structural determination of the N-linked \nglycans in apolipoprotein J with the use of FT-ICR MS. The albumin depletion \nmethod is the most suitable as prefractionation method of CSF prior to 2-DE for \nstructural determination of glycoproteins in the study of neurodegenerative \ndisorders.", "OBJECTIVES: Two different depletion strategies for removing albumin from human \ncerebrospinal fluid (CSF), Microcon Centrifugal Filter vs. Montage Albumin \nDeplete kit, were evaluated for improving protein profiling pattern and \nreproducibility in SELDI analysis.\nDESIGN AND METHODS: Pooled CSF was divided into 20 aliquots and these aliquots \nwere subjected to SELDI analysis either after albumin depletion or without \npreprocessing. Protein profiles were obtained by using CM10, Q10 and IMAC chips.\nRESULTS: Both strategies resulted in reliable albumin depletion (<6.2 mg/L, \nfilter; 8.1 mg/L, depletion kit). Investigated methods of albumin depletion \nshowed no significant differences in coefficients of variation (CVs) of peak \nintensities compared to unprocessed CSF on almost all chip types. Peak \nintensities were significantly higher after albumin depletion compared to CSF \nwithout preprocessing on Q10 and on CM10 chips. Nevertheless, the two strategies \nof albumin depletion led to a decrease in the number of detected peaks on all \nchip types compared to unprocessed CSF, but several additional peaks, not \ndetected in unprocessed CSF, occurred.\nCONCLUSIONS: This study demonstrates that reduction of sample complexity by \nalbumin depletion of CSF can be performed without CV impairment. However, the \nsignificance of this strategy needs to be evaluated separately for each \nindividual biomarker discovery study.", "BACKGROUND: In cerebrospinal fluid (CSF), which is a rich source of biomarkers \nfor neurological diseases, identification of biomarkers requires methods that \nallow reproducible detection of low abundance proteins. It is therefore crucial \nto decrease dynamic range and improve assessment of protein abundance.\nRESULTS: We applied LC-MS/MS to compare the performance of two CSF enrichment \ntechniques that immunodeplete either albumin alone (IgYHSA) or 14 high-abundance \nproteins (IgY14). In order to estimate dynamic range of proteins identified, we \nmeasured protein abundance with APEX spectral counting method.Both \nimmunodepletion methods improved the number of low-abundance proteins detected \n(3-fold for IgYHSA, 4-fold for IgY14). The 10 most abundant proteins following \nimmunodepletion accounted for 41% (IgY14) and 46% (IgYHSA) of CSF protein \ncontent, whereas they accounted for 64% in non-depleted samples, thus \ndemonstrating significant enrichment of low-abundance proteins. Defined \nproteomics experiment metrics showed overall good reproducibility of the two \nimmunodepletion methods and MS analysis. Moreover, offline peptide fractionation \nin IgYHSA sample allowed a 4-fold increase of proteins identified (520 vs. 131 \nwithout fractionation), without hindering reproducibility.\nCONCLUSIONS: The novelty of this study was to show the advantages and drawbacks \nof these methods side-to-side. Taking into account the improved detection and \npotential loss of non-target proteins following extensive immunodepletion, it is \nconcluded that both depletion methods combined with spectral counting may be of \ninterest before further fractionation, when searching for CSF biomarkers. \nAccording to the reliable identification and quantitation obtained with APEX \nalgorithm, it may be considered as a cheap and quick alternative to study sample \nproteomic content.", "A proper sample preparation, in particular, abundant protein removal is crucial \nin the characterization of low-abundance proteins including those harboring \npost-translational modifications. In human cerebrospinal fluid (CSF), \napproximately 80% of proteins originate from serum, and removal of major \nproteins is necessary to study brain-derived proteins that are present at low \nconcentrations for successful biomarker and therapeutic target discoveries for \nneurological disorders. In this study, phospho- and glycoprotein specific \nfluorescent stains and mass spectrometry were used to map proteins from CSF on \ntwo-dimensional gel electropherograms after immunoaffinity based protein \nremoval. Two protein removal methods were evaluated: batch mode with avian IgY \nantibody microbeads using spin filters and HPLC multiple affinity removal \ncolumn. Six abundant proteins were removed from CSF: human serum albumin (HSA), \ntransferrin, IgG, IgA, IgM, and fibrinogen with batch mode, and HSA, \ntransferrin, IgG, IgA, antitrypsin, and haptoglobin with column chromatography. \n2D gels were compared after staining for phospho-, glyco- and total proteins. \nThe column format removed the major proteins more effectively and approximately \n50% more spots were visualized when compared to the 2D gel of CSF without \nprotein depletion. After protein depletion, selected phospho- and glycoprotein \nspots were identified using mass spectrometry in addition to some of the spots \nthat were not visualized previously in nondepleted CSF. Fifty proteins were \nidentified from 66 spots, and among them, 12 proteins (24%) have not been \nannotated in previously published 2D gels.", "Various approaches for removal of high-abundance components in body fluids are \ncurrently available. While most methods are constructed for plasma depletion, \nthere is a need for body-fluid-specific strategies. The aim of the present study \nwas to design an affinity matrix suitable for the depletion of high-abundance \nproteins in CSF (cerebrospinal fluid). Hence, molecules with specific affinity \ntowards proteins present at high concentration in CSF were desired. Affibody \nmolecules are specific binders of small size that have shown high stability \nunder various conditions and are therefore good candidates for such a matrix. \nThe protein composition in CSF resembles that in plasma. However, 20% of the \nproteins are brain-derived and are therefore present in higher proportions in \nCSF than in plasma, whereas larger plasma-derived proteins are less abundant in \nCSF. Therefore five high-abundance CSF proteins were chosen for the design of a \nCSF-specific depletion setup. Affibody molecules with specificity towards HSA \n(human serum albumin), IgG, transferrin and transthyretin were combined in an \naffinity column. In addition, polyclonal antibodies against cystatin C were \ncoupled to chromatographic beads and packed in a separate column. Highly \nreproducible and efficient removal of the five target proteins was observed. The \nproportion of depleted proteins were estimated to be 99, 95, 74, 92 and 83% for \nHSA, IgG, transferrin, transthyretin and cystatin C respectively. SDS/PAGE \nanalysis was used for monitoring and identifying proteins in native CSF, \ndepleted CSF samples and the captured fractions. Moreover, shotgun proteomics \nwas used for protein identification in native as well as depleted CSF and the \nachieved data were compared. Enhanced identification of lower-abundance \ncomponents was observed in the depleted fraction, in terms of more detected \npeptides per protein.", "Analysis of serum and plasma proteomes is a common approach for biomarker \ndiscovery, and the removal of high-abundant proteins, such as albumin and \nimmunoglobins, is usually the first step in the analysis. However, albumin binds \npeptides and proteins, which raises concerns as to how the removal of albumin \ncould impact the outcome of the biomarker study while ignoring the possibility \nthat this could be a biomarker subproteome itself. The first goal of this study \nwas to test a new commercially available affinity capture reagent from Protea \nBiosciences and to compare the efficiency and reproducibility to four other \ncommercially available albumin depletion methods. The second goal of this study \nwas to determine if there is a highly efficient albumin depletion/isolation \nsystem that minimizes sample handling and would be suitable for large numbers of \nsamples. Two of the methods tested (Sigma and ProteaPrep) showed an albumin \ndepletion efficiency of 97% or greater for both serum and cerebrospinal fluid \n(CSF). Isolated serum and CSF albuminomes from ProteaPrep spin columns were \nanalyzed directly by LC-MS/MS, identifying 128 serum (45 not previously \nreported) and 94 CSF albuminome proteins (17 unique to the CSF albuminome). \nSerum albuminome was also isolated using Vivapure anti-HSA columns for \ncomparison, identifying 105 proteins, 81 of which overlapped with the ProteaPrep \nmethod." ]	['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D005441', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000418', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=0033326']
56c1f00cef6e39474100003e	[ 22113345, 20336066, 24157957, 22244809, 24016490, 22514701, 21114416, 21251281, 26093872, 24682069, 25407798, 19515415, 20837369 ]	train	Aleglitazar is agonist of which receptor?	factoid	Aleglitazar is a balanced peroxisome proliferator-activated receptor-α/γ agonist.	peroxisome proliferator-activated receptor-α/γ	[ "Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ \nagonist in clinical development, designed to offer a balanced activation of \nPPAR-α and PPAR-γ. A phase 2 trial has demonstrated improvements in dyslipidemia \nand glycemic control and reduction of cardiovascular risk markers in patients \nwith type 2 diabetes mellitus treated with aleglitazar. This study evaluated \nwhether supratherapeutic doses of aleglitazar affect cardiac repolarization, as \ndetected by changes in the QT interval.Healthy subjects were randomized to \nreceive single oral doses of placebo, 300 μg aleglitazar, 3000 μg aleglitazar, \nand 400 mg moxifloxacin, in 1 of 4 sequences. Triplicate 12-lead \nelectrocardiogram measurements were recorded predose and regularly (0.75-72 \nhours) after each treatment. The primary outcome was measurement of QT interval \nusing a study-specific correction factor for heart rate.Administration of \naleglitazar (300 μg and 3000 μg) did not cause any significant QT prolongation \nand after aleglitazar treatment any mean increases from placebo were <5 msec, at \nall time points. There was a trend for aleglitazar to cause a small \ndose-dependent decrease in QT interval using a study-specific correction factor \nfor heart rate. The incidence of adverse events was similar with aleglitazar \n(18%-20%) and placebo (26%).Single supratherapeutic doses of aleglitazar are not \nassociated with prolongation of the QT interval corrected for heart rate.", "This multicenter, randomized, double-blind, placebo-controlled, ascending-dose \nstudy investigated the pharmacokinetics, pharmacodynamic effects, safety, and \ntolerability of aleglitazar, a novel peroxisome proliferator-activated receptor \nalpha/gamma (PPARalpha/gamma) dual agonist. After a 3-week washout period, 71 \npatients with type 2 diabetes received either a single oral dose of aleglitazar \n(20, 50, 100, 300, 600, or 900 microg) or placebo, followed by once-daily dosing \nfor 6 weeks. Few adverse events were reported, with no apparent relationship \nbetween the rate of incidence or severity of the adverse events and the dose of \naleglitazar administered. Aleglitazar exposure increased in a dose-proportional \nmanner both after a single dose and at steady state, with no accumulation. \nAleglitazar produced dose-dependent improvements in levels of fasting and \npostprandial glucose, insulin resistance, and lipid parameters. Dose-dependent \ndecreases from baseline in creatinine clearance exceeded 10% at doses >300 \nmicrog. The PPARalpha- and PPARgamma-related effects occurred over similar dose \nranges, indicating that aleglitazar is a balanced agonist of the two receptor \nsubtypes.", ": Aleglitazar acts through balanced activation of peroxisome \nproliferator-activated receptors α and γ; warfarin is a commonly prescribed \nanticoagulant. Given the extent of cardiovascular disease in patients with type \n2 diabetes, cotreatment with aleglitazar and warfarin is likely in this \npopulation. This open-label, randomized, 2-period, crossover study in 12 healthy \nmale subjects investigated the potential for drug-drug interactions between \nwarfarin and aleglitazar (final data drawn from 11 white subjects). The primary \nobjective was to investigate the effect of aleglitazar on the pharmacokinetic \nproperties of S-warfarin and on the pharmacodynamics of the racemic mixture; the \nsecondary objectives included the effect of aleglitazar on R-warfarin \npharmacokinetics and of racemic warfarin on aleglitazar pharmacokinetics. \nSubjects were randomized to single-dose warfarin on day 1 or aleglitazar once \ndaily (12 days) plus single-dose warfarin on day 6 followed by a 14-day washout \nperiod, then crossover. Coadministration of aleglitazar reduced S- and \nR-warfarin exposure (AUC0-∞) by 18% and 13%, respectively, but did not change \nits pharmacodynamic effects (prothrombin time and factor VII activity). After \nwarfarin dosing, aleglitazar trough concentrations remained within the same \nrange. These findings indicate that coadministration of aleglitazar and warfarin \nis unlikely to affect the efficacy or safety of either agent.", "BACKGROUND: Aleglitazar is a dual peroxisome proliferator-activated receptor \n(PPAR)-α/γ agonist with a balanced activity (similar half-maximal effective \nconcentrations) toward PPAR-α and -γ that is in clinical development for the \ntreatment of patients who have experienced an acute coronary syndrome and have \ntype 2 diabetes mellitus.\nOBJECTIVE: This study aimed to characterize the metabolic profile and the routes \nand rates of elimination of aleglitazar and its major metabolites in humans.\nMETHODS: In this Phase I, nonrandomized, open-label, single-center, single-dose \nstudy, 6 healthy male subjects each received a single oral dose of 300 μg \n[(14)C]-labeled aleglitazar. Total urine and feces were collected for up to 15 \ndays. Venous blood samples were collected to determine the plasma concentrations \nof aleglitazar and its metabolites and for radioactivity counting.\nRESULTS: The median age (range) and mean (SD) body mass index of subjects were \n48 (41-60) years and 24.8 (3.0) kg/m(2), respectively. Recovery of total \nradioactivity, as a percentage of the dose administered, was high (93 [3]%). \nAleglitazar was predominantly eliminated in feces (mean, 66% [range, 55%-74%]), \nwith only 28% (range, 22%-36%) of the radioactivity recovered in urine. Only a \nmean (SD) of 1.8 (0.8)% of aleglitazar was eliminated unchanged as parent \ncompound in feces and only 0.3 (0.4)% was eliminated in urine. Almost all \nexcreted drug-related material could be attributed to its 2 main metabolites, M1 \n(21%) and M6 (38%). Treatment with aleglitazar was well tolerated, and no \nserious adverse events were reported.\nCONCLUSIONS: In healthy volunteers, aleglitazar was excreted mainly in the form \nof inactive metabolites, mostly M1 and M6, with only a small proportion \neliminated unchanged.", "BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) regulate \ntranscription of genes involved in glucose uptake, lipid metabolism, and \ninflammation. Aleglitazar is a potent dual PPAR agonist with insulin-sensitizing \nand glucose-lowering actions and favorable effects on lipid profiles and \nbiomarkers of cardiovascular risk. The AleCardio trial examines whether the \naddition of aleglitazar to standard medical therapy reduces the risk of \ncardiovascular morbidity and mortality in patients with type 2 diabetes mellitus \nand recent acute coronary syndrome.\nSTUDY DESIGN: AleCardio is a phase 3, multicenter, randomized, double-blind, \nplacebo-controlled trial. A total of 7,228 patients were randomized to \naleglitazar 150 μg or placebo daily in addition to standard medical therapy. The \nprimary efficacy end point is time to the first event of cardiovascular death, \nmyocardial infarction, or stroke. Principal safety end points are \nhospitalization due to heart failure and changes in renal function. Treatment \nwill continue until 7,000 patients are followed up for at least 2.5 years and \n950 primary end point events are adjudicated.\nCONCLUSIONS: AleCardio will establish whether the PPAR-α/γ agonist aleglitazar \nimproves cardiovascular outcomes in patients with diabetes and high-risk \ncoronary disease.", "AIMS: To compare the molecular and biologic signatures of a balanced dual \nperoxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with \ntesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; \nPPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes.\nMETHODS AND RESULTS: Gene expression microarray profiles were obtained from \nprimary human hepatocytes treated with EC(50)-aligned low, medium and high \nconcentrations of the three treatments. A systems biology approach, Causal \nNetwork Modeling, was used to model the data to infer upstream molecular \nmechanisms that may explain the observed changes in gene expression. \nAleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional \nsignatures, despite comparable core PPAR signaling. Although all treatments \ninferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to \nhave greater effects on high- and low-density lipoprotein cholesterol levels \nthan tesaglitazar and Pio/Feno, due to a greater number of gene expression \nchanges in pathways related to high-density and low-density lipoprotein \nmetabolism. Distinct transcriptional and biologic signatures were also inferred \nfor stress responses, which appeared to be less affected by aleglitazar than the \ncomparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a \nkey component of the stress response pathway, while aleglitazar had no \nsignificant effect. All treatments were inferred to decrease proliferative \nsignaling.\nCONCLUSIONS: Aleglitazar induces transcriptional signatures related to lipid \nparameters and stress responses that are unique from other dual PPAR-α/γ \ntreatments. This may underlie observed favorable changes in lipid profiles in \nanimal and clinical studies with aleglitazar and suggests a differentiated gene \nprofile compared with other dual PPAR-α/γ agonist treatments.", "BACKGROUND: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of \nfibrates and the insulin-sensitizing benefits of thiazolidinediones.\nOBJECTIVE: To investigate the pharmacokinetic effects of co-administration of \natorvastatin or rosuvastatin with aleglitazar.\nRESEARCH DESIGN AND METHODS: In a two-cohort, open-label, randomised, \nthree-period crossover study, 44 healthy subjects received once-daily oral doses \nof aleglitazar 300 μg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and \naleglitazar co-administered with each statin for 7 days. Plasma concentrations \nof each drug were measured and pharmacokinetic parameters determined on day 7 in \neach period.\nMAIN OUTCOME MEASURES: Peak observed plasma concentration (C(max)) and total \nexposures (AUC(0 - 24)) of aleglitazar, atorvastatin and rosuvastatin.\nRESULTS: C(max) and AUC(0 - 24) to aleglitazar were similar, whether \nadministered alone or in combination with a statin. Total exposure to either \nstatin was unaffected by co-administration with aleglitazar. C(max) treatment \nratios for both statins exceeded the conventional no-effect boundary (1.25) when \nadministered with aleglitazar.\nCONCLUSIONS: Co-administration of aleglitazar with a statin does not alter the \npharmacokinetic profile of either drug.", "BACKGROUND: Glycemic control and management of dyslipidemia to reduce \ncardiovascular risk are major therapeutic goals in individuals with type 2 \ndiabetes mellitus (T2DM). This study was performed to evaluate the effects of \naleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ \n(PPARα/γ) agonist, on both lipid and glycemic parameters in obese, \nhypertriglyceridemic, insulin-resistant rhesus monkeys.\nMETHODS: A 135-day efficacy study was performed in six rhesus monkeys. After a \n28-day baseline assessment (vehicle only), monkeys received oral aleglitazar \n0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma \nlevels of markers of glycemic and lipid regulation were measured at baseline, at \nthe end of the dosing period, and at the end of the washout period.\nRESULTS: Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced \ntriglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when \nnormalized for baseline levels) and increased high-density lipoprotein \ncholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, \naleglitazar reduced low-density lipoprotein cholesterol levels (41%) and \nincreased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also \nimproved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by \n5.9% from baseline values with aleglitazar at this dose (P = 0.043).\nCONCLUSIONS: Aleglitazar, a dual PPARα/γ agonist, has beneficial effects on both \nlipid and glucose parameters and may have a therapeutic role in modifying \ncardiovascular risk factors and improving glycemic control in patients with \nT2DM.", "BACKGROUND: Insulin-resistant states, including type 2 diabetes (T2D) and \nprediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar \nis a dual peroxisome proliferator-activated receptor α/γ agonist with favorable \ninsulin-sensitizing and glucose-lowering actions, favorable effects on blood \nlipids, and an acceptable safety profile in short-time studies. Therefore, it \nwas hypothesized that aleglitazar would reduce CV morbidity and mortality in \npatients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin \n≥5.7% to <6.5%) with previous CV complications.\nSTUDY DESIGN: ALEPREVENT was a phase III, multicenter, randomized, double-blind, \ntrial comparing aleglitazar 150 μg or placebo daily in patients with T2D or \nprediabetes with established, stable CV disease. The intended sample size was \n19,000 with a primary efficacy measure of major adverse CV events. However, the \ntrial was halted prematurely after 1,999 patients had been randomized because of \nfutility and an unfavorable benefit risk ratio in another CV outcomes trial \nevaluating aleglitazar.\nRESULTS: At study termination after 58 ± 38 days of treatment, data had been \ncollected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the \nbrief duration of treatment, aleglitazar induced favorable changes in \nglycosylated hemoglobin and blood lipids, similar for participants with T2D or \nprediabetes. However, compared with placebo, aleglitazar increased the incidence \nof hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012).\nCONCLUSIONS: Even within a short duration of exposure, aleglitazar was \nassociated with excess adverse events, corroborating the findings of a larger \nand longer trial in T2D. Coupled with the previous failure of several other \nperoxisome proliferator-activated receptor α/γ activators, this class now holds \nlittle promise for CV therapeutics.", "Collaborators: Vico ML, Conde DG, Botta CE, Gelersztein E, Ramos H, Prado AD, \nPiombo A, Piredda A, Lorente C, Canella JP, Guzman P, Avaca H, Maffei LE, Vita \nNA, Gorosito V, Cosman C, Caccavo A, Piskorz D, Jure HO, Fernandez RA, Toledo \nSS, Nul D, Marino JC, Estrada JL, Sztejfman L, Amerena J, Arnolda L, Yadav R, \nGarrahy P, Lo S, Brieger D, Nelson G, Arstall M, Worthley M, Colquhoun D, Wilson \nS, Dang TH, Prasan A, Kilian J, Collins N, Oqueli E, Carroll P, De Lima E Silva \nF, Dutra O, Franken M, Tumelero R, Pimentel P, Herdy A, Paiva MS, Frack CR, \nRossi F, Maia L, Forti A, Saraiva JF, Bodanese L, Oliveira J, Rossi P, Gross J, \nFeitosa A, Wainstein M, Silva R, Silva D, Botelho R, Manenti E, de Arruda JA, \nFortes JA, Ardito W, Dos Santos Filho R, Precoma DB, Saad J, Jatene JA, Hissa M, \nJunior A, Borges J, Sampaio C, Reis G, Issa A, Leaes PE, Kaiser SE, Savard D, \nTardif JC, Sanaratne M, Syan G, Kouz S, Kornder J, Diaz A, Bourgeois R, \nSchampaert E, Lonn E, Nigro F, Degrace M, Mazza G, Robichaud P, Title L, Rupka \nD, Baril JF, Hatheway RJ, Roy A, Lavoie JP, Leung R, Tremblay G, Pouliot J, Hill \nL, Labonte R, Lavi S, Bergin P, Pesant Y, Phaneuf DC, Nogareda G, Smith S, Huynh \nT, Rolfe A, Conway J, Bertrand O, Chehayeb R, Pandey S, Petrella R, Lepage S, \nNawaz S, Johri A, Abramson B, Fay D, Searles G, Chouinard G, Luterman M, Zadra \nR, Welsh R, Vizel S, Leduc C, Nault P, Beaudry P, Bakbak A, Shabani F, \nBerlingieri J, Yang X, Zhao R, Peng J, Hu H, Luo M, Ke Y, Yuan Z, Zhang Y, Lv X, \nMa C, Ma G, Chen J, Li X, Li Z, Yan X, Gan X, Chen J, Zhao S, Chen Y, Li H, Li \nL, Huimin L, Guo Y, Hu T, Fang W, Wang X, Yang K, Bao X, Fu G, Li H, Yan J, Wang \nD, He B, Zhang F, Han Y, Liu J, Wei M, Ma H, Wu S, Li W, Shi H, Monhart Z, Solar \nM, Belohlavek J, Ferkl R, Kral R, Hutyra M, Novak M, Kettner J, Podpera I, Malik \nJ, May O, Gohr T, Clemmensen P, Lomholdt J, Verges M, Agraou B, Montalescot G, \nProbst V, Galinier M, Roudaut R, Tropeano AI, Ovize M, Elhadad S, Belhassane A, \nDhoudain F, Schiele F, Danchin N, Dutoiu T, Caussin C, Cottin Y, Münzel T, \nVoeller H, Neumann FJ, Edel K, Kamke W, vom Dahl J, Ali T, Schächinger V, Natour \nM, Kadel C, Löw A, Hamm C, Düngen HD, Eckert S, Hoffmann U, von Hodenberg E, \nWerner N, Laufs U, Voehringer HF, Reinecke H, Mügge A, Fleck E, Reuter H, Hensen \nJ, Bergmann M, Tschoepe C, Kuehne U, Proskynitopoulos N, Michalko P, Kelm M, \nEdes I, Koranyi L, Papp A, Vertes A, Horvath I, Lupkovics G, Deak L, Benczur B, \nSziliczei-Nemeth E, Hodi G, Csapo K, Dudas M, Somogyi A, Czuriga I, Nagy L, \nParikh K, Sethi BK, Sahay RK, Premchand R, Bhattacharya A, Hiremath J, Ghosh S, \nJawahirani A, Sharma K, Gadkari M, Dash A, Dani S, Kumar S, Khanna P, Deshpande \nN, Kumar H, Arneja J, Setthuraman S, Chowdhury S, Kumble Y, Jali M, Yerra S, \nGandhi P, Mehrotra S, Bantwal G, Basavanagowdappa H, Kannampilly J, Pathanakayil \nR, Malpani G, Prasad G, Sarna M, Kapoor D, Adhikari P, Hardas S, Byrapaneni R, \nSuvarna T, Barton J, McAdam B, MacNeill BD, Maher VM, Sugrue D, Crean PA, \nGrassia V, Morocutti G, Tortorella G, Cosentino F, Bramucci E, Filardi PP, \nMafrici A, Salvioni A, Ansani L, Pancaldi L, De Servi S, Cavallini C, Zanini R, \nMusumeci G, Roncon L, Moon KW, Shin ES, Kim HY, Jeong JO, Cha TJ, Kim DK, Jeon \nHK, Lim do S, Yoon JH, Park KS, Kang WC, Jeong MH, Lee NH, Kim SH, Park WJ, Hur \nSH, Park CG, Kim HS, Park JS, Tahk SJ, Lee SY, Chae JK, Kim SW, Kim SJ, Jeon DW, \nHyon MS, Hong TJ, Ong TK, Ahmad WA, Ismail O, Ng KH, Mohamed M, Yahya M, Ali RM, \nGhapar AK, Cervantes J, Gambe MA, Castillo AG, Riojas C, Benavides M, Llamas G, \nPons JL, Rosas EL, Ramos G, De Los Rios M, Violante R, Mendoza E, Ruiz LN, \nLechuga A, Alva JC, Cedeño R, Hernandez J, Cantu RQ, Fernandez LE, Velasco R, \nLopez AG, Cardona E, Chavez J, Alpizar M, Arechavaleta R, Micher D, Bayram E, \nSánchez RR, Herrera CH, Guerrero HG, Isunza JR, Sanchez H, Munoz L, Garza MG, \nMalpica EM, Hof AV, Herrman JP, Jukema JW, Bronzwaer P, Ten Holt W, ten Berg J, \nDe Winter R, Basart D, de Graaf J, Gerdes VE, Bokern M, Troughton R, Fisher N, \nWong S, Tang EW, Nirmalaraj KB, O'Meeghan T, Nowak J, Kusnierz B, Pieniazek P, \nDrozdz D, Zarebinski M, Ponikowski P, Kosmider M, Musial W, Zabowka M, \nHamankiewicz M, Derlaga B, Piepiorka M, Kuc K, Janion M, Kuzniar J, Wierzykowski \nT, Serafin R, Kochman J, Pijanowski Z, Jaworska K, Szpajer M, Miekus P, Cwetsch \nA, Ochala A, Konieczny M, Hoffmann A, Kowalski J, Walczewska J, \nKrzeminska-Pakula M, Buszman P, Bryniarski L, Ogorek M, Dluzniewski M, Buszman \nP, Sciborski R, Miarka J, Hiczkiewicz J, Kleinrok A, Wysokinski A, Janiak B, \nSzczuka K, Lesiak M, Dryja T, Rynkiewicz A, Szwed H, Gorski J, Olszewski M, \nBuszman P, Benedek IS, Popa AR, Militaru C, Morosanu M, Constantinescu S, \nTivadar S, Popescu A, Radoi M, Fruntelata AG, Veresiu IA, Dragulescu SI, Eryshev \nS, Baranova E, Yakovlev A, Gordeev I, Gorelov A, Lopez MG, Pinto X, Coronado JB, \nMuñoz CP, Acuna JG, Soriano FR, Navarro MJ, Sanz RR, Basilio EG, Cortada JB, Ros \nJA, Macaya CM, Juanatey CG, Torrent AJ, Recena JB, Botas J, Fernandez PA, \nAlegret J, Moll XG, Sanz E, Blázquez JC, Soldevila JG, Murga N, Bellido D, Plaza \nI, Mellbin L, Boberg G, Mooe T, Tyden P, Linder R, Luostarinen R, Axelkvist M, \nPettersson T, Boman K, Jidbratt H, Lindgren M, Johanson P, Wongvipaporn C, \nKuanprasert S, Srimahachota S, Siriwattana K, Ngamjanyaporn P, Tresukosol D, \nPromlikitchai P, Chotnoparatpat P, Taweesangsuksakul P, Thongsri T, Wongtheptian \nW, Sansanayudh N, Hutayanon P, Laksomya T, Sritara P, Price D, Aggarwal R, \nPurcell I, Davies C, Malik I, Violaris A, Game F, Harvey J, Robertson D, Kadr H, \nTrouton TG, Kaprielian R, Dutka D, Hildick-Smith D, Butler R, MacRury S, \nMillward BA, Purvis J, Reckless J, Ajjan R, Bruce D, Cox D, Malik I, Kooner J, \nMuir S, Hutchinson S, Gupta D, Weinstein D, Bieniarz M, Traina M, Lieber I, \nMohart J, Prodafikas J, Laurion D, Oberoi M, Carlson E, Schmedtje J, Mayfield R, \nChandler G, Modi K, Budoff M, Zelman R, Dalton R, Lee K, Gordon P, Ayenew W, \nMathis C, Busch R, Schuchard T, Raisinghani A, Shepherd AM, Jaffrani N, Lee PV, \nChandrashekhar Y, Mohammed A, Weisz G, Almassi H, Krantzler J, Quadrel M, Martin \nS, Brener S, Harris B, Eaton C, Nalluri C, Schwartz G, Gogia H, Colfer H, \nDoherty J, Dang N, Blonder R, Jacobson S, Rogers W Jr, Levin E, Isa G, Chandna \nH, Singh J, Forgosh L, Melucci M, Chilton R, El Hafi S, Way B, Lambert C, Korban \nE, Auerbach E, Hickey K, McKenzie M, Tandon N, Mahal S, Heitner S, O'Halloran D, \nLoh IK, Harris J, Gelormini J, Clavijo L, Klapholz M, Studeny M, Goswami R, \nNorris R, Busui RP, Cox SL, Tak T, Anan T, Taghizadeh T, Pompili V, Camp A, \nKhera A, Shah A, Frey A, Zakhary B, Humiston D, Griffin D, Herrington D, Perloff \nD, Kereiakes D, Christofides E, Dippel E, Fung G, Marais H, Dotani I, Fidelholtz \nJ, Hermiller J, Naidu J, Gilbert J, El-Shahawy M, Mandviwala M, Rastogi P, \nBreaux P, Norwood P, Staab P, Fish R, Sanchez R, Gupta V, Herzog W, Rabinowitz \nA, Samal A, Kabour A, Lee D, Carlos E, Kosinski E, Portnay E, Rivera E, Madu IJ, \nWelker J, Fialkow J, Londono J, Martinez L, Pirwitz M, Ariani M, Saklayen M, \nVijay N, Feldman R, Rosenson R, Steinhubl S, Srinivasan V, Nair V, Shalev Y, \nBouchard A, Adolphe A, Miller A, Ahmad A, Omar B, Masri B, Iteld B, Gifford C, \nScott C, Maislos F, Longo J, Rider J, Silverstein J, Miller M, Nanna M, Khan M, \nSchneider R, Bashir R, Evans R, Fierer R, Teniola S, Welka S, Singh V, Randall \nW, Rowe W, Salacata A, Bazzi A, Steinberg A, Mooss A, Tang A, Kahn B, Chandler \nB, Bayron C, Schmalfuss C, Hirsch C, Thompson C, Thompson C, Singal D, Lo E, \nSpivack E, Gopalakrishnan G, Lowe J, Talano J, Albu J, McClure J, McGettigan J, \nHemphill J, Vora K, Solano Mdel P, Shoukfeh M, Best P, Thompson P, Borromeo S \n3rd, Barringer T, Hilton T, Knickelbine T, Palmer W.", "BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, \nwhich substantially increases the risk of cardiovascular disease mortality. This \nPhase IIb safety study (AleNephro) in patients with stage 3 chronic kidney \ndisease and type 2 diabetes, evaluated the renal effects of aleglitazar, a \nbalanced peroxisome proliferator-activated receptor-α/γ agonist.\nMETHODS: Patients were randomized to 52 weeks' double-blind treatment with \naleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an \n8-week off-treatment period. The primary endpoint was non-inferiority for the \ndifference between aleglitazar and pioglitazone in percentage change in \nestimated glomerular filtration rate from baseline to end of follow-up. \nSecondary endpoints included change from baseline in estimated glomerular \nfiltration rate and lipid profiles at end of treatment.\nRESULTS: Mean estimated glomerular filtration rate change from baseline to end \nof follow-up was -2.7% (95% confidence interval: -7.7, 2.4) with aleglitazar \nversus -3.4% (95% confidence interval: -8.5, 1.7) with pioglitazone, \nestablishing non-inferiority (0.77%; 95% confidence interval: -4.5, 6.0). \nAleglitazar was associated with a 15% decrease in estimated glomerular \nfiltration rate versus 5.4% with pioglitazone at end of treatment, which \nplateaued to 8 weeks and was not progressive. Superior improvements in \nhigh-density lipoprotein cholesterol, low-density lipoprotein cholesterol and \ntriglycerides, with similar effects on glycosylated hemoglobin were observed \nwith aleglitazar versus pioglitazone. No major safety concerns were identified.\nCONCLUSIONS: The primary endpoint in AleNephro was met, indicating that in stage \n3 chronic kidney disease patients with type 2 diabetes, the decrease in \nestimated glomerular filtration rate after 52 weeks' treatment with aleglitazar \nfollowed by 8 weeks off-treatment was reversible and comparable (non-inferior) \nto pioglitazone.\nTRIAL REGISTRATION: NCT01043029 January 5, 2010.", "BACKGROUND: Despite previous reports of potential adverse cardiovascular effects \nof peroxisome proliferator-activated receptor (PPAR) agonists, the promise for \nPPAR agonists to positively affect risk of cardiovascular disease in patients \nwith type 2 diabetes is of continued interest. The SYNCHRONY study aimed to \nestablish the glucose-lowering and lipid-modifying effects, and safety profile, \nof the dual PPAR-alpha and PPAR-gamma agonist aleglitazar.\nMETHODS: In this double-blind study, patients with type 2 diabetes (either \ndrug-naive or pre-treated with </=two oral agents) were enrolled from 47 sites \nin seven countries. After a single-blind, 4-5-week placebo run-in period, 332 \npatients were randomised double-blind (via an interactive voice-response system) \nto 16 weeks' treatment with aleglitazar at once-daily doses of 50 mug, 150 mug, \n300 mug, or 600 mug, or matching placebo (n=55 in each group), or to open-label \npioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy \nendpoint was the change in glycosylated haemoglobin (HbA(1c)) concentration from \nbaseline to the end of treatment. Patients who received at least one dose of \nstudy drug and had at least one evaluable post-baseline HbA(1c) measurement were \nincluded in the efficacy analysis. This study is registered with \nClinicalTrials.gov, number NCT00388518.\nFINDINGS: The efficacy analysis excluded six patients (n=0 in pioglitazone \ngroup; n=1 in each of placebo, 50 mug, 150 mug, and 600 mug aleglitazar groups; \nand n=2 in 300 mug aleglitazar group). Aleglitazar significantly reduced \nbaseline HbA(1c) versus placebo in a dose-dependent manner, from -0.36% (95% CI \n0.00 to -0.70, p=0.048) with 50 mug to -1.35% (-0.99 to -1.70, p<0.0001) with \n600 mug. The trend of changes over time suggests that the maximum effect of \naleglitazar on HbA(1c) concentration was not yet reached after 16 weeks of \ntreatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent \nmanner. However, at aleglitazar doses less than 300 mug, no patients had \ncongestive heart failure, frequency of oedema was similar to placebo (one case \nat 50 mug, two at 150 mug, and three with placebo) and less than with \npioglitazone (four cases), and bodyweight gain was less than with pioglitazone \n(0.52 kg at 150 mug vs 1.06 kg).\nINTERPRETATION: The favourable balance in the safety and efficacy profile of \naleglitazar represents encouraging short-term clinical data for this agent and \nprovides good evidence to enter phase III investigation.\nFUNDING: F Hoffmann-La Roche AG (Switzerland).", "BACKGROUND: Aleglitazar is a new, balanced dual peroxisome \nproliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and \nglycemic benefits and minimize PPAR-related adverse effects.\nMETHODS: SESTA R was a 26-week, randomized, double-blind, multicenter study \ncomparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) \nwith pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients \nwith type 2 diabetes and normal to mildly impaired renal function (estimated GFR \n[eGFR] 60 to 120 ml/min/1.73 m(2)).\nRESULTS: In 118 patients with evaluable GFR measurements, baseline mean (± SD) \nmGFR was 97.6 ± 17.5 ml/min/1.73 m(2) in the aleglitazar group and \n101.9±21.6ml/min/1.73m(2) in the pioglitazone group. Mean percent change from \nbaseline mGFR was -16.9% (90% confidence interval -22.0 to -11.5) with \naleglitazar and -4.6% (-10.15 to 1.35) with pioglitazone, a mean treatment \ndifference of -13.0% (-19.0 to -6.5). The 17% decrease from baseline in mGFR was \nconsistent with the 19% decrease in eGFR Modification of Diet in Renal Disease \n(MDRD) observed with aleglitazar, which reached a plateau after 4weeks, with no \nfurther progression until treatment discontinuation. Following aleglitazar \nwithdrawal, eGFR values returned to pretreatment levels within the 4-8-week \nfollow-up, which suggests reversible hemodynamic changes in renal function.\nCONCLUSIONS: Despite the increased incidence of expected, dose-dependent PPAR \nclass side effects (e.g., peripheral edema, weight gain, and congestive heart \nfailure) limiting further development of this supratherapeutic dosage of \naleglitazar (600 μg/day), these data, together with the data from the \ndose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new \ntreatment for cardiovascular risk reduction in post-acute coronary syndrome \npatients at the therapeutic 150 μg daily dose." ]	nan
5540b9800083d1bf0e000002	[ 3517024, 9115173, 9356261, 14747656, 21215336, 21527722, 11502188, 1634521, 10652315, 15522301, 14761982 ]	train	Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?	factoid	Alpha and beta spectrin subunits form antiparallel spectrin heterodimers by lateral association.	antiparallel	[ "Spectrin, the major component of the erythroid membrane skeleton, is a long, \nasymmetrical rodlike protein that interacts with several other proteins to form \na two-dimensional membrane skeleton. Progress in several laboratories over the \npast few years including substantial partial peptide and nucleotide sequence \ndetermination has greatly enhanced our knowledge of the structural properties of \nthis large molecule (heterodimer = 465,000 daltons). The alpha and beta subunits \nare homologous with approximately 30% identity. They are aligned in an \nantiparallel side-to-side orientation with the amino- and carboxy-termini near \nopposite physical ends of the molecule. The predominant structural feature \nelucidated from sequencing this large molecule is the nearly universal \noccurrence in both subunits of a single type of repetitive structure. The \nperiodicity of this homologous structure is exactly 106 amino acid residues. As \nmany as 36 homologous, but nonidentical, repeats exist and comprise more than \n90% of the mass of the heterodimer. Each of these repetitive units is folded \ninto a triple-stranded structure that is highly helical. Peptide maps, antibody \ncrossreactivity, peptide sequence analysis, and more recently nucleic acid \nsequences have defined several major properties of the erythroid molecule and \nrelated proteins in other tissues. Tissue-specific spectrins have the same \n106-residue repetitive structure and show sequence homology to erythroid \nspectrin.", "The actin-cross-linking protein spectrin is a prominent component of the \nmembrane cytoskeleton. Spectrin is a tetramer of two antiparallel \nalphabeta-dimers which share a unique and ancient gene structure. The \nalpha-spectrin and beta-spectrin genes are composed primarily of tandemly \nrepeated 106-amino-acid segments, each of which forms a triple alpha-helical \ncoiled coil. Both the genes and the repeats themselves are homologous. The two \ngenes are thought to be the result of a gene duplication event, and each gene is \nthe product of duplications of the 106-amino-acid repeats. In this work we \ncompare the process of molecular evolution across the repeated segments of the \nalpha- and beta-spectrin genes. We find that the alpha-spectrin segments have, \nfor the most part, evolved in a homogeneous fashion, while considerable \nheterogeneity is found among beta-spectrin segments. Several segments with \nunique known functions are found to have evolved differently than the others. On \nthe basis of heterogeneity of the evolutionary process, we suggest that at least \none repeat has a unique function that has yet to be documented. We also present \nnew statistical methods for comparing the evolutionary process between different \nregions of DNA sequences.", "Cytoskeletal proteins belonging to the spectrin family have an elongated \nstructure composed of repetitive units. The three-dimensional solution structure \nof the 16th repeat from chicken brain alpha-spectrin (R16) has been determined \nby NMR spectroscopy and distance geometry-simulated annealing calculations. We \nused a total of 1035 distance restraints, which included 719 NOE-based values \nobtained by applying the ambiguous restraints for iterative assignment (ARIA) \nmethod. In addition, we performed a direct refinement against 1H-chemical \nshifts. The final ensemble of 20 structures shows an average RMSD of 1.52 A from \nthe mean for the backbone atoms, excluding loops and N and C termini. R16 is \nmade up of three antiparallel alpha-helices separated by two loops, and folds \ninto a left-handed coiled-coil. The basic unit of spectrin is an antiparallel \nheterodimer composed of two homologous chains, beta and alpha. These assemble a \ntetramer via a mechanism that relies on the completion of a single repeat by \nassociation of the partial repeats located at the C terminus of the beta-chain \n(two helices) and at the N terminus of the alpha-chain (one helix). This \ntetramer is the assemblage able to cross-link actin filaments. Model building by \nhomology of the \"tetramerization\" repeat from human erythrocyte spectrin \nilluminates the possible role of point mutations which cause hemolytic anemias.", "The large size of spectrin, the flexible protein promoting reversible \ndeformation of red cells, has been an obstacle to elucidating the molecular \nmechanism of its function. By studying cloned fragments of the repeating unit \ndomain, we have found a correspondence between positions of selected spectrin \nrepeats in a tetramer with their stabilities of folding. Six fragments \nconsisting of two spectrin repeats were selected for study primarily on the \nbasis of the predicted secondary structures of their linker regions. Fragments \nwith a putatively helical linker were more stable to urea- and heat-induced \nunfolding than those with a putatively nonhelical linker. Two of the less stably \nfolded fragments, human erythroid alpha-spectrin repeats 13 and 14 \n(HEalpha13,14) and human erythroid beta-spectrin repeats 8 and 9 (HEbeta8,9), \nare located opposite each other on antiparallel spectrin dimers. At least \npartial unfolding of these repeats under physiological conditions indicates that \nthey may serve as a hinge. Also less stably folded, the fragment of human \nerythroid alpha-spectrin repeats 4 and 5 (HEalpha4,5) lies opposite the site of \ninteraction between the partial repeats at the C- and N-terminal ends of beta- \nand alpha-spectrin, respectively, on the opposing dimer. More stably folded \nfragments, human erythroid alpha-spectrin repeats 1 and 2 (HEalpha1,2) and human \nerythroid alpha-spectrin repeats 2 and 3 (HEalpha2,3), lie nearly opposite each \nother on antiparallel spectrin dimers of a tetramer. These clusterings along the \nspectrin tetramer of repeats with similar stabilities of folding may have \nrelevance for spectrin function, particularly for its well known flexibility.", "Spectrins comprise α- and β-subunits made up predominantly of a series of \nhomologous repeating units of about 106 amino acids; the α- and β-chains form \nantiparallel dimers by lateral association, and tetramers through head-to-head \ncontacts between the dimers. Here we consider the first of these interactions. \n(1) We confirm earlier observations, showing that the first two paired repeats \n(βIR1 with αIR21, and βIR2 with αRI20) at one end of the erythroid spectrin \n(αIβI) dimer are necessary and sufficient to unite the chains; (2) we resolve a \nconflict in published reports by showing that the strength of the interaction is \nconsiderably increased on adding the adjoining pair of repeats (βIR3-αIR19); (3) \nin brain (αIIβII) spectrin the first two pairs of repeats are similarly \nessential and sufficient for heterodimer formation; (4) this interaction is \n~60-fold stronger than that in the erythroid counterpart, but no enhancement can \nbe detected on addition of three further pairs of repeats; (5) formation of a \ntight αIβI dimer probably depends on structural coupling of the first two \nrepeats in each chain; (6) an analysis of the sequences of the strongly \ninteracting repeats, βIR1, βIIR1, αIR21 and αIIR20 and repeats in α-actinin, \nwhich also interact very strongly in forming an antiparallel dimer, affords a \npossible explanation for the different properties of the two spectrin isoforms \nin respect of the stability of the inter-chain interactions, and also suggests \nthe evolutionary path by which the erythroid and non-erythroid sequences \ndiverged.", "Questions of if and when protein structures change within cells pervade biology \nand include questions of how the cytoskeleton sustains stresses on \ncells--particularly in mutant versus normal cells. Cysteine shotgun labeling \nwith fluorophores is analyzed here with mass spectrometry of the spectrin-actin \nmembrane skeleton in sheared red blood cell ghosts from normal and diseased \nmice. Sheared samples are compared to static samples at 37 °C in terms of cell \nmembrane intensity in fluorescence microscopy, separated protein fluorescence, \nand tryptic peptide modification in liquid chromatography-tandem mass \nspectrometry (LC-MS/MS). Spectrin labeling proves to be the most sensitive to \nshear, whereas binding partners ankyrin and actin exhibit shear thresholds in \nlabeling and both the ankyrin-binding membrane protein band 3 and the \nspectrin-actin stabilizer 4.1R show minimal differential labeling. Cells from \n4.1R-null mice differ significantly from normal in the shear-dependent labeling \nof spectrin, ankyrin, and band 3: Decreased labeling of spectrin reveals less \nstress on the mutant network as spectrin dissociates from actin. Mapping the \nstress-dependent labeling kinetics of α- and β-spectrin by LC-MS/MS identifies \nCys in these antiparallel chains that are either force-enhanced or \nforce-independent in labeling, with structural analyses indicating the \nforce-enhanced sites are sequestered either in spectrin's triple-helical domains \nor in interactions with actin or ankyrin. Shear-sensitive sites identified \ncomprehensively here in both spectrin and ankyrin appear consistent with stress \nrelief through forced unfolding followed by cytoskeletal disruption.", "Human erythrocyte spectrin is an antiparallel heterodimer comprised of a 280 kDa \nalpha subunit and a 246 kDa beta subunit which further associates into tetramers \nin the red cell membrane cytoskeleton. Lateral association of the flexible \nrodlike monomers involves a multiple-step process that is initiated by a high \naffinity association near the actin-binding end of the molecule (dimer \nnucleation site). In this study, recombinant alpha and beta proteins comprising \ntwo or four \"spectrin type\" motifs with and without adjacent, terminal \nnonhomologous domains were evaluated for their relative contributions to dimer \ninitiation, and the thermodynamic properties of these heterodimer complexes were \nmeasured. Sedimentation equilibrium studies showed that in the absence of the \nheterologous subunit, individual recombinant proteins formed weak homodimers \n(K(d) > 0.3 mM). When 2-motif (alpha20-21 and beta1-2) and 4-motif (alpha18-21 \nand beta1-4) recombinants lacking the terminal nonhomologous domains were paired \nwith the complementary protein, high affinity heterodimers were formed in \nsedimentation equilibrium analysis. Both the alpha20-21/beta1-2 complex and the \nalpha20-21EF/betaABD1-2 complex showed stoichiometric binding with similar \nbinding affinities (K(d) approximately 10 nM) using isothermal titration \ncalorimetry. The alpha20-21/beta1-2 complex showed an enthalpy of -10 kcal/mol, \nwhile the alpha20-21EF/betaABD1-2 complex showed an enthalpy of -13 kcal/mol. \nPull-down assays using alpha spectrin GST fusion proteins showed strong \nassociations between all heterodimer complexes in physiological buffer, but all \nheterodimer complexes were destabilized by the presence of Triton X-100 and \nother detergents. Complexes lacking the nonhomologous domains were destabilized \nto a greater extent than complexes that included the nonhomologous domains. The \ndetergent effect appears to be responsible for the apparent essential role of \nthe nonhomologous domains in prior reports. Taken together, our results indicate \nthat the terminal nonhomologous domains do not contribute to dimer initiation \nnor are they required for formation of high affinity spectrin heterodimers in \nphysiological buffers.", "The antiparallel side-to-side association of spectrin alpha and beta monomers is \na two-step process which occurs in seconds even at 0 degrees C and at low \nconcentrations. Assembly involves initial contact of complementary nucleation \nsites on each subunit, which are located near the actin binding end of the long, \nflexible heterodimer rod. The minimum nucleation sites are comprised of \napproximately four contiguous 106-residue homologous segments or repeats. Three \nrepeats in the nucleation site contain an 8-residue insertion and have the \nhighest homology to the four spectrin-like repeats in alpha-actinin. The \nadjacent actin binding domain on the beta subunit and the adjacent EF hand \nmotifs on the alpha subunit are not required for heterodimer assembly. The \nnucleation sites probably have a specific lock and key structure which defines \nthe unique side-to-side pairing of the many homologous segments in both \nsubunits. Assembly of spectrin heterodimers is probably most analogous to a \nzipper. After initial nucleation site binding, the remainder of the subunits \nquickly associate along their full lengths to reconstitute a normal dimer by \nsupercoiling around each other to form a rope-like, flexible rod. Assembly is \nterminated if either polypeptide is interrupted by a protease cleavage. \nHeterozygotic mutations involving either nucleation site are predicted to affect \nallele incorporation into the mature membrane skeleton.", "The spectrin heterodimer is formed by the antiparallel lateral association of an \nalpha and a beta subunit, each of which comprises largely a series of homologous \ntriple-helical motifs. Initiation of dimer assembly involves strong binding \nbetween complementary motifs near the actin-binding end of the dimer. In this \nstudy, the mechanism of lateral spectrin association at this dimer nucleation \nsite was investigated using the analytical ultracentrifuge to analyze \nheterodimers formed from recombinant peptides containing two or four homologous \nmotifs from each subunit (alpha20-21/beta1-2; alpha18-21/beta1-4). Both the \ntwo-motif and four-motif dimer associations were weakened substantially with \nincreasing salt concentration, indicating that electrostatic interactions are \nimportant for the dimer initiation process. Modeling of the electrostatic \npotential on the surface of the alpha20 and beta2 motifs showed that the side of \nthe motifs comprising the A and B helices is the most favorable for association, \nwith an area of positive electrostatic potential on the AB face of the beta2 \nmotif opposite negative potential on the AB face of the alpha20 motif and vise \nversa. Protease protection analysis of the alpha20-21/beta1-2 dimer showed that \nmultiple trypsin and proteinase K sites in the A helices of the beta2 and \nalpha21 motifs become buried upon dimer formation. Together, these data support \na model where complementary long range electrostatic interactions on the AB \nfaces of the triple-helical motifs in the dimer nucleation site initiate the \ncorrect pairing of motifs, i.e. alpha21-beta1 and alpha20-beta2. After initial \ndocking of these complementary triple-helical motifs, this association is \nprobably stabilized by subsequent formation of stronger hydrophobic interactions \nin a complex involving the A helices of both subunits and possibly most of the \nAB faces. The beta subunit A helix in particular appears to be buried in the \ndimer interface.", "Previous X-ray crystal structures have shown that linkers of five amino acid \nresidues connecting pairs of chicken brain alpha-spectrin and human erythroid \nbeta-spectrin repeats can undergo bending without losing their alpha-helical \nstructure. To test whether bending at one linker can influence bending at an \nadjacent linker, the structures of two and three repeat fragments of chicken \nbrain alpha-spectrin have been determined by X-ray crystallography. The \nstructure of the three-repeat fragment clearly shows that bending at one linker \ncan occur independently of bending at an adjacent linker. This observation \nincreases the possible trajectories of modeled chains of spectrin repeats. \nFurthermore, the three-repeat molecule crystallized as an antiparallel dimer \nwith a significantly smaller buried interfacial area than that of alpha-actinin, \na spectrin-related molecule, but large enough and of a type indicating \nbiological specificity. Comparison of the structures of the spectrin and \nalpha-actinin dimers supports weak association of the former, which could not be \ndetected by analytical ultracentrifugation, versus strong association of the \nlatter, which has been observed by others. To correlate features of the \nstructure with solution properties and to test a previous model of stable \nspectrin and dystrophin repeats, the number of inter-helical interactions in \neach repeat of several spectrin structures were counted and compared to their \nthermal stabilities. Inter-helical interactions, but not all interactions, \nincreased in parallel with measured thermal stabilities of each repeat and in \nagreement with the thermal stabilities of two and three repeats and also partial \nrepeats of spectrin.", "Protein extensibility appears to be based broadly on conformational changes that \ncan in principle be modulated by protein-protein interactions. Spectrin family \nproteins, with their extensible three-helix folds, enable evaluation of \ndimerization effects at the single molecule level by atomic force microscopy. \nAlthough some spectrin family members function physiologically only as \nhomodimers (e.g. alpha-actinin) or are strictly monomers (e.g. dystrophin), \nalpha- and beta-spectrins are stable as monomeric forms but occur \nphysiologically as alpha,beta-heterodimers bound laterally lengthwise. For short \nconstructs of alpha- and beta-spectrin, either as monomers or as \nalpha,beta-dimers, sawtooth patterns in atomic force microscopy-forced extension \nshow that unfolding stochastically extends repeats approximately 4-5-fold \ngreater in length than native conformations. For both dimers and monomers, \ndistributions of unfolding lengths appear bimodal; major unfolding peaks reflect \nsingle repeats, and minor unfolding peaks at twice the length reflect tandem \nrepeats. Cooperative unfolding thus propagates through helical linkers between \nserial repeats (1, 2). With lateral heterodimers, however, the force \ndistribution is broad and shifted to higher forces. The associated chains in a \ndimer can stay together and unfold simultaneously in addition to unfolding \nindependently. Weak lateral interactions do not inhibit unfolding, but strong \nlateral interactions facilitate simultaneous unfolding analogous to serial \nrepeat coupling within spectrin family proteins." ]	['http://www.biosemantics.org/jochem#4249968', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0008091']
5c98ac7fecadf2e73f00002b	[ 29398602, 30217516 ]	train	Anaplasma phagocytophilum is an obligate gram-negative, intracellular bacterium, yes or no	yesno	Anaplasma phagocytophilum is an obligate gram-negative, intracellular bacterium and causes anaplasmosis	yes	[ "The genus Anaplasma belonging to the Anaplasmataceae family (order \nRickettsiales) comprises obligate intracellular Gram-negative bacteria of \nveterinary and public health importance. Six species and five types of strains \ngenetically related are currently assigned to the genus Anaplasma including \nAnaplasma marginale, A. centrale, A. bovis, A. phagocytophilum, A. ovis and A. \nplatys as classified species, and \"A. capra\", A. odocolei sp. nov., A. \nphagocytophilum-like 1 (Anaplasma sp.-Japan), A. phagocytophilum-like 2 \n(Anaplasma sp.-China) and A. platys-like (also named Candidatus Anaplasma \ncamelii) as unclassified strains. Most of these Anaplasma species and strains \nhave been molecularly identified in several animal and/or tick species in the \nnorth of Africa. The aim of this review is to summarize the current knowledge \nabout molecular epidemiology, associated risk factors and genetic diversity of \nAnaplasma species and related strains infecting animals and/or their \nincriminated tick vectors in North Africa. All these data should be considered \nwhen establishing of common management and control programs for anaplasmosis \ninfecting humans and different animal species in North African countries.", "Human granulocytic anaplasmosis (HGA), an increasingly recognized febrile \ntick-borne illness, is caused by a gram-negative obligate intracellular \nbacterium Anaplasma phagocytophilum. Because of nonspecific clinical \nmanifestations, diagnosis of HGA highly depends on laboratory tests. \nIdentification of immunoreactive proteins is prerequisite for development of \nspecific and sensitive immunoassays for HGA. In this study, we identified novel \nimmunoreactive proteins of A. phagocytophilum. Previous studies indicated that \nsecreted proteins of A. phagocytophilum and other bacteria can be immunoreactive \nantigens. Here we in silico screened A. phagocytophilum genome for encoding \nproteins which bear features of type IV secretion system substrates. Among \nseventy seven predicted proteins, fourteen proteins were determined for \nantigenicity and nine proteins were showed to be immunoreactive antigens. In \naddition, an APH1384 peptide harboring a B cell epitope predicted by \nbioinformatics was found specifically reacting with anti-A. phagocytophilum \nsera. Hereby, we identified novel immunoreactive proteins and delineated a \nspecific epitope of A. phagocytophilum, which might be employed for HGA \ndiagnosis." ]	nan
5880b073c872c95565000003	[ 26449414, 27575436, 27895055, 26686866, 25516695, 27082776, 26069913, 26627486, 27697443, 27789605, 20007090, 26872887, 25431993, 25494843, 27659071, 27913536, 27147456, 25387210, 26559317, 25816811, 26519420 ]	train	Andexanet Alfa is an antidote of which clotting factor inhibitors?	factoid	Andexanet alfa is a specific reversal agent for Factor Xa inhibitors.	Factor Xa or Xa	[ "Although there is controversy about the absolute need for a reversal agent for \nthe new direct oral anticoagulants (DOACs), the absence of such an agent is a \nbarrier to more widespread use of these agents. For the management of major \nlife-threatening bleeding with the DOACs, most authorities recommend the use of \nfour factor prothrombin complex concentrates, although the evidence to support \ntheir use in terms of improving outcomes is meager. At the present time, there \nare three antidotes in development and poised to enter the market. Idarucizumab \nis a drug-specific antidote targeted to reverse the direct thrombin inhibitor, \ndabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the \noral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. \nCiraparantag is a universal antidote targeted to reverse the direct thrombin and \nfactor Xa inhibitors as well as the indirect inhibitor, enoxaparin.", "Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting \nanticoagulants, are frequently used to prevent stroke and systemic embolism in \npatients with atrial fibrillation and to prevent and treat venous \nthromboembolism. These drugs reduce the risk of clotting at the expense of \nincreasing the risk of bleeding, and currently they have no specific reversal \nagent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in \na late-phase clinical trial in bleeding patients, and ciraparantag, a small \nmolecule that appears to reverse many anticoagulants including the FXa \ninhibitors, is in development. This review summarizes the published data to date \non both drugs, which have the potential to change the management approach to \npatients with FXa inhibitor-associated major hemorrhage.", "PURPOSE: The available clinical data on target-specific oral anticoagulant \n(TSOAC) reversal agents that are currently in development or have been approved \nby the Food and Drug Administration (FDA) are reviewed.\nSUMMARY: The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, \nand apixaban has presented benefits and new challenges. One of the main \nchallenges associated with the use of TSOACs is the lack of suitable \nagent-specific reversal agents. Several treatment options for the management of \nlife-threatening bleeding events associated with TSOAC use, such as fresh frozen \nplasma, prothrombin complex concentrates, and recombinant coagulation factor \nVIIa, have been used, with inconsistent results. Currently, two potential \nreversal agents for oral direct factor Xa inhibitors (andexanet alfa and \nciraparantag) are at various stages of clinical development. Idarucizumab, a \nreversal agent for the oral direct thrombin inhibitor dabigatran, was approved \nby FDA in October 2015. Idarucizumab and andexanet alfa have been reported to \nproduce anticoagulation reversal effects within minutes of administration. \nCiraparantag was demonstrated to decrease whole blood clotting time to within \n10% of baseline values in 10 minutes or less, with a return to baseline \nhemostasis in 10-30 minutes. TSOAC reversal agents have been generally well \ntolerated in clinical trials.\nCONCLUSION: Idarucizumab and other TSOAC reversal agents, such as andexanet alfa \nand ciraparantag, present the potential for consistent and effective treatment \nand management options when life-threatening or uncontrolled TSOAC-associated \nbleeding occurs or when emergency surgery is warranted in patients using TSOACs.", "Andexanet alfa is a specific reversal agent for Factor Xa inhibitors. The \nmolecule is a recombinant protein analog of factor Xa that binds to Factor Xa \ninhibitors and antithrombin:LMWH complex but does not trigger prothrombotic \nactivity. In ex vivo, animal, and volunteer human studies, andexanet alfa (AnXa) \nwas able to dose-dependently reverse Factor Xa inhibition and restore thrombin \ngeneration for the duration of drug administration. Further trials are underway \nto examine its safety and efficacy in the population of patients experiencing \nFXa inhibitor-related bleeding.", "Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and \napixaban-have been approved by the FDA to reduce the risk of stroke and systemic \nembolism in patients with nonvalvular atrial fibrillation; however, no agents \nare currently approved to reverse the anticoagulant effects of these TSOACs in \ncases of active bleeding. This review discusses the benefits and risks of these \nTSOACs from a clinician's perspective, with a focus on the interruption of \ntreatment for either elective or emergent surgery, monitoring, and reversal of \nanticoagulation. Available coagulation assays are not ideal for monitoring the \neffects of TSOACs and do not provide reliable quantitative measurement of their \nanticoagulant effects. When necessary, activated partial thromboplastin time \n(aPTT) may provide qualitative information on dabigatran, and prothrombin time \n(PT) may provide qualitative assessment of the presence of the factor Xa \ninhibitors, rivaroxaban and apixaban. Current recommendations for reversal of \nTSOACs are based largely on limited and sometimes conflicting data from in vitro \nor in vivo animal models, and clinical experience with these recommendations is \nalso limited. Methods that have been investigated for effectiveness for reversal \nof the pharmacodynamic effects of the TSOACs include dialysis, activated \ncharcoal, prothrombin complex concentrate (PCC), and recombinant activated \nfactor VII. It is important to note that even within a class of anticoagulant \ndrugs, compounds respond differently to reversal agents; therefore, \nrecommendations for one agent should not be extrapolated to another, even if \nthey are from the same therapeutic class. New antidotes are being explored, \nincluding a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential \nuniversal factor Xa inhibitor reversal agent; and a synthetic small molecule \n(PER977) that may be effective for the reversal of factor Xa inhibitors and \ndirect thrombin inhibitors. Given the short half-lives of TSOACs, watchful \nwaiting, rather than reversal, may be the best approach in some circumstances.", "The Vitamin K antagonist warfarin was the only oral anticoagulant available for \ndecades for the treatment of thrombosis and prevention of thromboembolism until \nDirect Oral Anticoagulants (DOACs); a group of new oral anticoagulants got \napproved in the last few years. Direct thrombin inhibitor: dabigatran and factor \nXa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the \ncoagulation cascade. DOACs have many advantages over warfarin. However, the \nbiggest drawback of DOACs has been the lack of specific antidotes to reverse the \nanticoagulant effect in emergency situations. Activated charcoal, hemodialysis, \nand activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific \nagents used in a DOAC associated bleeding but with limited success. \nIdarucizumab, the first novel antidote against direct thrombin inhibitor \ndabigatran was approved by US FDA in October 2015. It comprehensively reversed \ndabigatran-induced anticoagulation in a phase I study. A phase III trial on \nIdarucizumab also complete reversal of anticoagulant effect of dabigatran. \nAndexanet alfa (PRT064445), a specific reversal agent against factor Xa \ninhibitors, showed a complete reversal of anticoagulant activity of apixaban and \nrivaroxaban within minutes after administration without adverse effects in two \nrecently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. \nIt is currently being studied in ANNEXA-4, a phase IV study. Aripazine \n(PER-977), the third reversal agent, has shown promising activity against \ndabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and \nLMWH. This review article summarizes pharmacological characteristics of these \nnovel antidotes, coagulation's tests affected, available clinical and \npreclinical data, and the need for phase III and IV studies.", "The number of patients taking new oral anticoagulants is rising, so is the \nnumber of serious bleeding events. In severe bleeding, the decision to start a \nprocoagulant therapy is difficult to take. With Idarucizumab and Andexanet Alfa, \nspecific antidotes have been developed against both, direct thrombin inhibitors \nas well as direct Factor Xa inhibitors. In the endoscopic treatment of severe \ngastrointestinal bleeding, alternative treatment options are available with \nHemospray™, Endoclot™ and new hemostasis clips. Especially in the recurrent \nulcer bleeding, the newly developed clips can achieve hemostasis and prevent an \noperational procedure.", "Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our \ntherapeutic armamentarium. They are at least as effective as warfarin in the \nthromboprophylaxis of non-valvular atrial fibrillation and management of \nthromboembolic disease, with a more favorable safety profile. Their predictable \npharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the \nneed for anticoagulation monitoring. A major concern regarding NOACs is the lack \nof a readily available antidote to reverse their anticoagulation effect in case \nof life-threatening bleeding or need for emergent surgery. In this review, we \nsummarize preclinical and clinical data on (a) hemostatic agents used to reverse \nNOACs, and (b) novel, target-specific NOACs reversal agents under development. \nThe prothrombin complex concentrates, activated prothrombin complex concentrates \nand recombinant activated factor VII are hemostatic agents that have been \nassessed in reversing NOACs. Preclinical studies with hemostatic agents report \nvariable results and there is only limited clinical data available to date. \nIdarucizumab and andexanet alfa are NOAC-specific reversal agents designed to \nreverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a \nuniversal anticoagulation reversal agent. Preclinical studies show promising \nresults and these agents are already in different stages of clinical \ndevelopment. Phase I and II clinical trials demonstrate efficacy in reversing \nNOACs without major side effects. Until these agents become commercially \navailable, management of patients receiving NOACs who present with major \nbleeding or require emergent surgery should focus on (a) immediate \ndiscontinuation of NOACs, (b) supportive measures or postponing surgery for \n12-24 h after the last NOAC dose, and/or", "Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting \nanticoagulants, are frequently used to prevent stroke and systemic embolism in \npatients with atrial fibrillation and to prevent and treat venous \nthromboembolism. These drugs reduce the risk of clotting at the expense of \nincreasing the risk of bleeding, and currently they have no specific reversal \nagent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in \na late-phase clinical trial in bleeding patients, and ciraparantag, a small \nmolecule that appears to reverse many anticoagulants including the FXa \ninhibitors, is in development. This review summarizes the published data to date \non both drugs, which have the potential to change the management approach to \npatients with FXa inhibitoreassociated major hemorrhage.", "Bleeding is the most common complication of all anticoagulants. Any bleeding \npatient on an anticoagulant should be risk-stratified based on hemodynamic \ninstability, source of bleeding, and degree of blood loss. Although minor bleed \nmay be managed with discontinuation of anticoagulant, major bleed may require \ntransfusion of blood products and use of specific antidote. The residual effects \nof each anticoagulant may be monitored with distinct coagulation assay. \nIntravenous or oral vitamin K can reverse the effect of warfarin within 24 to 48 \nhours and is indicated for any bleeding, international normalized ratio of >10 \nor 4.5 to 10 in patients with other risk factors for bleeding. Fresh frozen \nplasma or prothrombin complex concentrate (PCC) may be necessary in major \nbleeding related to warfarin. Protamine sulfate reverses the effect of \nunfractionated heparin completely and of low-molecular-weight heparin (LMWH) \npartially. Idarucizumab has recently been approved in United States for \ndabigatran reversal, whereas andexanet alfa is expected to get approved in the \nnear future for reversal of oral factor Xa inhibitors. The PCC may reverse the \neffect of rivaroxaban to some extent, but no data are available regarding \nreversal of apixaban and edoxaban. Aripazine has shown promising results to \nreverse the effects of LMWH, fondaparinux, and direct oral anticoagulants but is \nstill in the developmental phase.", "1. ", "The vitamin K antagonists (VKAs) have been the standard (and only) oral \nanticoagulants used for the long-term treatment or prevention of venous \nthromboembolism or stroke in patients with atrial fibrillation. The coagulopathy \ninduced by VKAs can be reversed with vitamin K, and in urgent situations, the \nvitamin K-dependent coagulation factors can be replaced by transfusion. In the \nlast decade, a new class of oral anticoagulants has been developed, direct oral \nanticoagulants that bind to a specific coagulation factor and neutralize it. \nThese compounds were shown to be effective and safe compared with the VKAs and \nwere licensed for specific indications, but without a specific reversal agent. \nThe absence of a reversal agent is a barrier to more widespread use of these \nagents. Currently, for the management of major life-threatening bleeding with \nthe direct oral anticoagulants, most authorities recommend the use of four \nfactor prothrombin complex concentrates. There are now three reversal agents in \ndevelopment and poised to enter the market. Idarucizumab is a specific antidote \ntargeted to reverse the direct thrombin inhibitor, dabigatran, which was \nrecently approved for use in the USA. Andexanet alfa is an antidote targeted to \nreverse the oral direct factor Xa inhibitors as well as the indirect inhibitor \nenoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin \nand factor Xa inhibitors as well as the indirect inhibitor enoxaparin.", "Thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban and \nedoxaban form a new class of non-vitamin K antagonist oral anticoagulants and \nhave been extensively studied in patients with venous thromboembolism and atrial \nfibrillation. They offer anticoagulation that is as effective and at least as \nsafe compared to warfarin without the need for routine laboratory monitoring; \nhowever, no reversal strategies are currently validated in case of a non-vitamin \nK antagonist oral anticoagulant-associated bleed. In emergency situations, \nlaboratory drug measurement and well-defined management for non-vitamin K \nantagonist oral anticoagulant-induced hemorrhage may improve clinical outcome. \nIn this review, the merits and limitations of the routine coagulation tests and \nsome of the more specific laboratory assays are compared. Furthermore, \nprohemostatic measures are reviewed and the recommended strategies in case of \nbleeding are summarized. Specific reversal agents are currently under \ndevelopment (idarucizumab for dabigatran, andexanet alfa for Xa inhibitors, and \nPER977 for both Xa- and thrombin inhibitors), which will facilitate clinical \nmanagement of severe bleeding and emergency surgery.", "In the last decade, several direct oral anticoagulants (DOAC; dabigatran, \nrivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or \ntreatment of thromboembolism without having specific antidotes available for \ntheir reversal. Current management of bleeding associated to DOAC includes the \nremoval of all antithrombotic medications and supportive care. Non-specific \nprocoagulant agents (prothrombin complex concentrates and activated factor VIIa) \nhave been used in case of serious bleeding. Currently, some specific antidotes \nfor the DOAC are under development. Idarucizumab (BI 655075; Boehringer \nIngelheim) is a fragment of an antibody (Fab), which is a specific antidote to \nthe oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, \nPRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically \ninactive factor Xa, which binds and reverses the anticoagulant action of the \nfactor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine \n(PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) \nthat reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous \nfondaparinux and LMWH in vivo. These antidotes could provide an alternative for \nmanagement of life-threatening bleeding events occurring with the \nabove-mentioned anticoagulants. In addition, the specific antidote anivamersen \n(RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to \nreverse the anticoagulant effect of the parenteral factor IXa inhibitor \npegnivacogin, which is also in development. This anticoagulant-antidote pair may \nprovide an alternative in situations in which a fast onset and offset of \nanticoagulation is needed, like in patients undergoing cardiac surgery with \nextracorporeal circulation, as an alternative to the heparin/protamine pair. \nThis patent review includes a description of the pharmacological characteristics \nof the novel specific antidotes, the available results from completed \nnon-clinical and clinical studies and the description of ongoing clinical trials \nwith the new compounds.", "BACKGROUND: Four nonvitamin K antagonist oral anticoagulants (NOACs) are \napproved for the prevention of stroke in patients with nonvalvular atrial \nfibrillation and for the treatment of venous thromboembolism. These include the \ndirect thrombin inhibitor dabigatran and the direct factor Xa inhibitors \nrivaroxaban, apixaban, and edoxaban. Bleeding is a complication for all \nanticoagulants and concerns regarding bleeding risk and the suitability of \neffective reversal strategies may be a barrier to their prescription. Despite \nthe reduced risk of bleeding compared with vitamin K antagonists, questions \npersist regarding the management of bleeding related to NOAC use.\nMAIN TEXT: To date, although a number of assays are responsive to NOACs, no \nsingle routine laboratory test has been identified to accurately measure the \nclinical anticoagulation state of patients on NOACs or established as a reliable \npredictor of bleeding risk. In addition, the establishment of a reliable human \nbleeding model to test novel inhibitors of the coagulation cascade has proved \nchallenging. Although routine monitoring of anticoagulant levels is not \nnecessary in patients taking NOACs, anticoagulant reversal and a means of \nmeasuring reversal may be required for patients who present with bleeding or \nrequire urgent surgery. Prothrombin complex concentrates are pooled plasma \nproducts containing varying amounts of inactive vitamin K-dependent clotting \nfactors in addition to vitamin K-dependent proteins and can replenish factors in \nthe intrinsic and extrinsic coagulation cascade, reversing an anticoagulant \neffect. Only one agent, idarucizumab, has been approved for rapid reversal of \ndabigatran-induced anticoagulation and one more agent, andexanet alfa, has been \nsubmitted for approval to reverse the anticoagulatory effects of direct and \nindirect factor Xa inhibitors.\nCONCLUSIONS: This review discusses the laboratory tests available for assessing \nanticoagulation, human models of bleeding, and the use of current \nstrategies-including prothrombin complex concentrates for reversal of \nanticoagulation by NOACs-to manage bleeding in patients.", "Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared \nwith other oral anticoagulants and have ancillary benefits, including overall \nbetter safety profiles, lack of the need for routine monitoring, rapid onset of \naction, and ease of administration. Reversal of these agents may be indicated in \ncertain situations such as severe bleeding and for perioperative management. \nDOAC-associated bleeding should be risk stratified: patients with moderate or \nsevere bleeding should have the DOAC discontinued and reversal strategies should \nbe considered. Laboratory testing has limited utility in the acute management of \nbleeding; thrombin time and activated partial thromboplastin time may be useful \nfor excluding clinically relevant levels of dabigatran. Prothrombin time is \npotentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays \nare optimal for determining clinically relevant levels of factor Xa inhibitors. \nBecause specific reversal agents are not widely available, supportive care and \ninterventions for local hemostasis remain the cornerstones of therapy in the \npatient with DOAC-associated bleeding. Nonspecific reversal agents should be \nconsidered only in the event of severe bleeding because their efficacy is \nunknown, and they are associated with risk of thrombosis. Recent results from \nphase 3/4 studies demonstrate efficacy for an antidote to dabigatran \n(idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) \nand an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and \ninactive form of factor Xa that binds inhibitors). A universal reversal agent \n(ciraparantag) for many anticoagulants, including the DOACs, shows promise in \nresults from phase 1 and 2 studies.", "PURPOSE: The properties of three oral anticoagulant-specific reversal agents are \nreviewed, and guidance is presented to assist pharmacists in planning for the \nagents' introduction to the market.\nSUMMARY: Idarucizumab, which received Food and Drug Administration approval in \nOctober 2015, is a humanized monoclonal antibody fragment that immediately \nneutralizes the anticoagulant effect of dabigatran, as evidenced by reduced \nunbound dabigatran concentrations and normalized coagulation tests. Preliminary \nPhase III trial results demonstrated a median maximum reversal of 100%, a median \ntime to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis \nin 92% of patients requiring anticoagulation reversal before an urgent \nprocedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and \nindirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet \nalfa reduced anti-FXa activity by more than 90%, reduced the concentration of \nunbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is \na reversal agent under development for reversal of anticoagulation with direct \nand indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its \neffect through hydrogen bonding. Concerns for thromboembolic events directly \nrelated to administration of idarucizumab, andexanet alfa, or ciraparantag have \nnot arisen. Pharmacists need to begin preparing for the introduction of these \nspecific reversal agents through protocol development and provider education; in \naddition, pharmacy departments need to plan for procurement and storage. The \nspecific reversal agents should be incorporated into antithrombotic stewardship \nor other clinical pharmacy programs for surveillance.\nCONCLUSION: As agents that provide rapid reversal of direct oral anticoagulant \nactivity become available, advance planning will help hospitals to optimize \ntheir use.", "The new oral anticoagulants have many advantages over vitamin K antagonists, but \nthey are still associated with a troublesome incidence of major bleeding. \nAdditionally, the absence of a reversal agent for the new oral anticoagulants is \na barrier to their more widespread use. Currently, there are 3 potential \nreversal agents in development: idarucizumab is a humanized murine monoclonal \nantibody fragment directed specifically at dabigatran; andexanet alfa is a \nrecombinant modified decoy factor Xa that binds to factor Xa inhibitors; and \nPER977 is a small molecule that binds to factor Xa and IIa inhibitors and to \nheparin-based anticoagulants through charge interaction. These agents have \nundergone phase I clinical testing, appear to be well tolerated in healthy \nvolunteers, and are effective in neutralizing their respective targets. All 3 \nare currently undergoing or entering into a phase II or III clinical study. This \narticle reviews the available data for idarucizumab, andexanet alfa, and PER977.", "BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, \nbut there are no specific agents for the reversal of the effects of these drugs. \nAndexanet is designed to reverse the anticoagulant effects of factor Xa \ninhibitors.\nMETHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 \nmg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized \nplacebo-controlled study was conducted to evaluate andexanet administered as a \nbolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean \npercent change in anti-factor Xa activity, which is a measure of factor Xa \ninhibition by the anticoagulant.\nRESULTS: Among the apixaban-treated participants, anti-factor Xa activity was \nreduced by 94% among those who received an andexanet bolus (24 participants), as \ncompared with 21% among those who received placebo (9 participants) (P<0.001), \nand unbound apixaban concentration was reduced by 9.3 ng per milliliter versus \n1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% \nversus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the \nrivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% \namong those who received an andexanet bolus (27 participants), as compared with \n18% among those who received placebo (14 participants) (P<0.001), and unbound \nrivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng \nper milliliter (P<0.001); thrombin generation was fully restored in 96% versus \n7% of the participants (P<0.001). These effects were sustained when andexanet \nwas administered as a bolus plus an infusion. In a subgroup of participants, \ntransient increases in levels of d-dimer and prothrombin fragments 1 and 2 were \nobserved, which resolved within 24 to 72 hours. No serious adverse or thrombotic \nevents were reported.\nCONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and \nrivaroxaban in older healthy participants within minutes after administration \nand for the duration of infusion, without evidence of clinical toxic effects. \n(Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R \nClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).", "In recent years, non-vitamin K oral anticoagulants (NOACs) have emerged as an \nalternative to warfarin for the prevention and treatment of thrombo-embolic \ndisease. Large randomized trials have demonstrated that these agents, which act \nby directly targeting thrombin (dabigatran) and factor Xa (rivaroxaban, \napixaban, and edoxaban), are at least as effective as warfarin, with lower rates \nof bleeding and fewer interactions with food and drugs. In addition, NOACs have \na more predictable anticoagulant effect, allowing a fixed dose regimen and \nobviating the need for routine anticoagulation monitoring. Since the \nintroduction of NOACs, one of the major concerns for clinicians has been the \nlack of specific agents to reverse their anticoagulant effect in case of \nlife-threatening haemorrhagic complications or emergency surgery, which have \nlimited their use in patients deemed at a higher risk of bleeding. New specific \nantidotes (e.g. idarucizumab, andexanet alfa, and ciraparantag) show promising \ndata, and may soon become available for clinical use. In this article, we review \nthe pharmacology of these agents, the incidence and outcomes of haemorrhagic \ncomplications, the available strategies for anticoagulation reversal, and the \nmore recent advances for the development of specific antidotes.", "The non-vitamin K antagonist oral anticoagulants (NOACs) are used for \nthromboembolic prophylaxis of patients with atrial fibrillation and in the \ntreatment as well as secondary prophylaxis of patients with venous \nthromboembolism. Even though NOACs have a better safety profile than vitamin K \nantagonists (VKAs), there will still be bleeding complications on NOAC \ntreatment. In some cases, stopping the NOAC and non-drug-related management such \nas manual compression and interventional endoscopy will be sufficient to stop \nthe bleeding. In more serious bleeding events and before acute surgery, \ncoagulation factor concentrates or NOAC-specific antidotes could be used. \nCoagulation factor concentrates can be used in patients with haemophilia and to \nreverse the effect of VKAs but, in NOAC-treated patients, results are \ninconsistent and these agents could potentially have pro-thrombotic effects. \nSpecific antidotes for NOACs are expected to be on the market soon. Phase III \nclinical trials with a humanized antibody fragment directed against dabigatran \n(idarucizumab) and recombinant, modified factor Xa (andexanet alfa) are ongoing. \nA molecule (aripazine) with broad activity against various anticoagulants \nincluding NOACs is currently undergoing phase II trials. For use of these \nspecific antidotes, it is desirable that measurements for coagulation activity \nwith a short response delay are widely available for the different NOACs and \nfurther research in this field is needed. Furthermore, guidelines for antidote \nuse, including general measures for the treatment of NOAC-related bleeding, \nshould be available." ]	['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000925', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000931', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D019774']
58e3d9ab3e8b6dc87c000002	[ 2564739, 1985457, 26713299, 2309781, 1714232 ]	train	Angelman syndrome is associated with deletion of a part of Chromosome 15 but if the deletion occurs in the paternally inherited chromosome 15, what is the disease?	factoid	Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13.	Prader-Willi syndrome	[ "Many Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients have a \ncytogenetic deletion of 15q11q13. While AS and PWS share a similar cytogenetic \nanomaly, they have very different clinical phenotypes. DNAs from 4 AS patients \nwere examined using 5 chromosome 15q11q13-specific cloned DNA segments. With the \npresent level of resolution, the molecular deletions between AS and those \npreviously reported for PWS did not appear to differ. However, in contrast to \nthe paternal inheritance of the deleted chromosome 15 observed in the majority \nof PWS patients, maternal inheritance of the deleted chromosome 15 was \ndemonstrated in the AS patients by restriction fragment length polymorphisms \n(RFLPs).", "Genetic imprinting has been implicated in the etiology of two clinically \ndistinct but cytogenetically indistinguishable disorders--Angelman syndrome (AS) \nand Prader-Willi syndrome (PWS). This hypothesis is derived from two lines of \nevidence. First, while the molecular extents of de novo cytogenetic deletions of \nchromosome 15q11q13 in AS and PWS patients are the same, the deletions originate \nfrom different parental chromosomes. In AS, the deletion occurs in the \nmaternally inherited chromosome 15, while in PWS the deletion is found in the \npaternally inherited chromosome 15. The second line of evidence comes from the \ndeletion of an abnormal parental contribution of 15q11q13 in PWS patients \nwithout a cytogenetic and molecular deletion. These patients have two maternal \ncopies and no paternal copy of 15q11q13 (maternal uniparental disomy) instead of \none copy from each parent. By qualitative hybridization with chromosome 15q11q13 \nspecific DNA markers, we have now examined DNA samples from 10 AS patients (at \nleast seven of which are familial cases) with no cytogenetic or molecular \ndeletion of chromosome 15q11q13. Inheritance of one maternal copy and one \npaternal copy of 15q11q13 was observed in each family, suggesting that paternal \nuniparental disomy of 15q11q13 is not responsible for expression of the AS \nphenotype in these patients.", "BACKGROUND: Prader-Willi syndrome (PWS) results from a deletion of the paternal \ngenes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which \nwhen left unmanaged, leads to an excessive ingestion of food. To date there is \ninadequate pharmacological treatment or supplementation for modification of the \nPWS hyperphagia and/or the associated behaviors. Therefore, the best practice is \nfamilial supervision and restriction of diet and environment.\nAIM: We aimed to determine if the natural supplement of Caralluma fimbriata \nextract (CFE) could attenuate hyperphagia or the associated appetite behaviors \nin children and adolescents with PWS over the 4-week pilot trial period.\nMATERIALS AND METHODS: We conducted a placebo-controlled, double-blind, \nrandomized crossover trial over a 10-week period to investigate the effects of \nCFE on hunger control, in a cohort of children and adolescents with confirmed \nPWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). \nParticipants from Australia and New Zealand ingested CFE or a placebo of \nmaltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the \ncrossover to the other treatment. Weekly comparisons in appetite behavior, \nseverity, and drive were recorded by parents, as scaled time-point measures on a \nhyperphagia questionnaire validated for PWS.\nRESULTS: CFE administration was found to induce a significant accumulative \neasing of hyperphagia (P = 0.05), with decreases evident in one-third of the \nparticipants. Furthermore due to CFE supplementation, a significant decrease (P \n≤ 0.05) was recorded in the category of behavior and a decrease in hyperphagia \n(n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended \nadult dose). There were no reported adverse effects at any dose.\nCONCLUSION: We demonstrate that an extract of the Indian cactus succulent \nCaralluma fimbriata eases hyperphagic appetite behavior within a cohort of \nchildren and adolescents (n = 15) with PWS without notable adverse effects. The \noutcomes of this study will have a potential positive impact on PWS management.", "Six persons with the classical Angelman syndrome (AS) phenotype and de novo \ndeletions of chromosome 15q11-q13 were studied to determine the parental origin \nof the chromosome deletion. Four of the 6 patients had informative cytogenetic \nstudies and all demonstrated maternal inheritance of the deletion. These \nfindings, together with other reported cases of the origin of the chromosome 15 \ndeletion in AS, suggest that deletion of the maternally contributed chromosome \nleads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) \nin which a similar deletion of the paternally contributed chromosome 15 is \nobserved. In deletion cases, a parental gamete effect such as genomic imprinting \nmay be the best model to explain why apparently identical 15q11-q13 deletions \nmay develop the different phenotypes of AS or PWS.", "Deletions of the proximal long arm of chromosome 15 (bands 15q11q13) are found \nin the majority of patients with two distinct genetic disorders, Angelman \nsyndrome (AS) and Prader-Willi syndrome (PWS). The deleted regions in the two \nsyndromes, defined cytogenetically and by using cloned DNA probes, are similar. \nHowever, deletions in AS occur on the maternally inherited chromosome 15, and \ndeletions in PWS occur on the paternally derived chromosome 15. This observation \nhas led to the suggestion that one or more genes in this region show \ndifferential expression dependent on parental origin (genetic imprinting). No \ngenes of known function have previously been mapped to this region. We show here \nthat the gene encoding the GABAA (gamma-aminobutyric acid) receptor beta 3 \nsubunit maps to the AS/PWS region. Deletion of this gene (GABRB3) was found in \nAS and PWS patients with interstitial cytogenetic deletions. Evidence of beta 3 \ngene deletion was also found in an AS patient with an unbalanced 13;15 \ntranslocation but not in a PWS patient with an unbalanced 9;15 translocation. \nThe localization of this receptor gene to the AS/PWS region suggests a possible \nrole of the inhibitory neurotransmitter GABA in the pathogenesis of one or both \nof these syndromes." ]	['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002872', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D025063', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D011218', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002901', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D017353']
5d387c20a1e1595105000010	[ 27869828 ]	train	Approximately how many genes are contained in the X chromosome's non-pseudoautosomal region (non-PAR)?	factoid	The total number of genes contained in the X chromosome's non- pseudoautosomal region (PAR) is 783.	7	[ "There is a striking and unexplained male predominance across many cancer types. \nA subset of X-chromosome genes can escape X-inactivation, which would protect \nfemales from complete functional loss by a single mutation. To identify putative \n'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic \nalterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 \nnon-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, \nKDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males \n(based on a false discovery rate < 0.1), in comparison to zero of 18,055 \nautosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in \ngenes that escape X-inactivation were observed in combined analysis across many \ncancers and in several individual tumor types, suggesting a generalized \nphenomenon. We conclude that biallelic expression of EXITS genes in females \nexplains a portion of the reduced cancer incidence in females as compared to \nmales across a variety of tumor types." ]	nan
534e364e288f4dae47000001	[ 19557188, 16640774, 18682829, 8290959, 17478517, 18449558 ]	train	Approximately how many recombination hotspots have been found in the yeast genome?	factoid	In the fission yeast genome DSBs are located within 194 prominent peaks separated on average by 65-kbp intervals of DNA that are largely free of DSBs.	2	[ "Deleterious mutations inevitably emerge in any evolutionary process and are \nspeculated to decisively influence the structure of the genome. Meiosis, which \nis thought to play a major role in handling mutations on the population level, \nrecombines chromosomes via non-randomly distributed hot spots for meiotic \nrecombination. In many genomes, various types of genetic elements are \ndistributed in patterns that are currently not well understood. In particular, \nimportant (essential) genes are arranged in clusters, which often cannot be \nexplained by a functional relationship of the involved genes. Here we show by \ncomputer simulation that essential gene (EG) clustering provides a fitness \nbenefit in handling deleterious mutations in sexual populations with variable \nlevels of inbreeding and outbreeding. We find that recessive lethal mutations \nenforce a selective pressure towards clustered genome architectures. Our \nsimulations correctly predict (i) the evolution of non-random distributions of \nmeiotic crossovers, (ii) the genome-wide anti-correlation of meiotic crossovers \nand EG clustering, (iii) the evolution of EG enrichment in pericentromeric \nregions and (iv) the associated absence of meiotic crossovers (cold \ncentromeres). Our results furthermore predict optimal crossover rates for yeast \nchromosomes, which match the experimentally determined rates. Using a \nSaccharomyces cerevisiae conditional mutator strain, we show that haploid lethal \nphenotypes result predominantly from mutation of single loci and generally do \nnot impair mating, which leads to an accumulation of mutational load following \nmeiosis and mating. We hypothesize that purging of deleterious mutations in \nessential genes constitutes an important factor driving meiotic crossover. \nTherefore, the increased robustness of populations to deleterious mutations, \nwhich arises from clustered genome architectures, may provide a significant \nselective force shaping crossover distribution. Our analysis reveals a new \naspect of the evolution of genome architectures that complements insights about \nmolecular constraints, such as the interference of pericentromeric crossovers \nwith chromosome segregation.", "BACKGROUND: Meiotic double-strand breaks occur at relatively high frequencies in \nsome genomic regions (hotspots) and relatively low frequencies in others \n(coldspots). Hotspots and coldspots are receiving increasing attention in \nresearch into the mechanism of meiotic recombination. However, predicting \nhotspots and coldspots from DNA sequence information is still a challenging \ntask.\nRESULTS: We present a novel method for classification of hot and cold ORFs \nlocated in hotspots and coldspots respectively in Saccharomyces cerevisiae, \nusing support vector machine (SVM), which relies on codon composition \ndifferences. This method has achieved a high classification accuracy of 85.0%. \nSince codon composition is a fusion of codon usage bias and amino acid \ncomposition signals, the ability of these two kinds of sequence attributes to \ndiscriminate hot ORFs from cold ORFs was also investigated separately. Our \nresults indicate that neither codon usage bias nor amino acid composition taken \nseparately performed as well as codon composition. Moreover, our SVM based \nmethod was applied to the full genome: We predicted the hot/cold ORFs from the \nyeast genome by using cutoffs of recombination rate. We found that the \nperformance of our method for predicting cold ORFs is not as good as that for \npredicting hot ORFs. Besides, we also observed a considerable correlation \nbetween meiotic recombination rate and amino acid composition of certain \nresidues, which probably reflects the structural and functional dissimilarity \nbetween the hot and cold groups.\nCONCLUSION: We have introduced a SVM-based novel method to discriminate hot ORFs \nfrom cold ones. Applying codon composition as sequence attributes, we have \nachieved a high classification accuracy, which suggests that codon composition \nhas strong potential to be used as sequence attributes in the prediction of hot \nand cold ORFs.", "BACKGROUND: Polyadenylated, mRNA-like transcripts with no coding potential are \nabundant in eukaryotes, but the functions of these long non-coding RNAs (ncRNAs) \nare enigmatic. In meiosis, Rec12 (Spo11) catalyzes the formation of dsDNA breaks \n(DSBs) that initiate homologous recombination. Most meiotic recombination is \npositioned at hotspots, but knowledge of the mechanisms is nebulous. In the \nfission yeast genome DSBs are located within 194 prominent peaks separated on \naverage by 65-kbp intervals of DNA that are largely free of DSBs.\nMETHODOLOGY/PRINCIPAL FINDINGS: We compared the genome-wide distribution of DSB \npeaks to that of polyadenylated ncRNA molecules of the prl class. DSB peaks map \nto ncRNA loci that may be situated within ORFs, near the boundaries of ORFs and \nintergenic regions, or most often within intergenic regions. Unconditional \nstatistical tests revealed that this colocalization is non-random and robust \n(P<or=5.5 x 10(-8)). Furthermore, we tested and rejected the hypothesis that the \nncRNA loci and DSB peaks localize preferentially, but independently, to a third \nentity on the chromosomes.\nCONCLUSIONS/SIGNIFICANCE: Meiotic DSB hotspots are directed to loci that express \npolyadenylated ncRNAs. This reveals an unexpected, possibly unitary mechanism \nfor what directs meiotic recombination to hotspots. It also reveals a likely \nbiological function for enigmatic ncRNAs. We propose specific mechanisms by \nwhich ncRNA molecules, or some aspect of RNA metabolism associated with ncRNA \nloci, help to position recombination protein complexes at DSB hotspots within \nchromosomes.", "Double-strand DNA breaks (DSBs) occur at recombination hotspots during \nSaccharomyces cerevisiae meiosis and are thought to initiate exchange at these \nloci. Analysis of DSB sites in three regions of the yeast genome indicated that \nbreaks occur at or near many potential transcription promoters and that DSBs \ninitiate most, if not all, meiotic recombination. DSB sites displayed \ndeoxyribonuclease I hypersensitivity in chromatin from mitotic and meiotic \ncells, and changes in chromatin structure produced parallel changes in the \noccurrence of DSBs. Thus, features of chromatin structure that are established \nbefore meiosis play a role in determining where meiotic recombination events \ninitiate.", "In the yeast, meiotic recombination is initiated by double-strand DNA breaks \n(DSBs) which occur at relatively high frequencies in some genomic regions \n(hotspots) and relatively low frequencies in others (coldspots). Although \nobservations concerning individual hot/cold spots have given clues as to the \nmechanism of recombination initiation, the prediction of hot/cold spots from DNA \nsequence information is a challenging task. In this article, we introduce a \nrandom forest (RF) prediction model to detect recombination hot/cold spots from \nyeast genome. The out-of-bag (OOB) estimation of the model indicated that the RF \nclassifier achieved high prediction performance with 82.05% total accuracy and \n0.638 Mattew's correlation coefficient (MCC) value. Compared with an alternative \nmachine-learning algorithm, support vector machine (SVM), the RF method \noutperforms it in both sensitivity and specificity. The prediction model is \nimplemented as a web server (RF-DYMHC) and it is freely available at \nhttp://www.bioinf.seu.edu.cn/Recombination/rf_dymhc.htm. Given a yeast genome \nand prediction parameters (RI-value and non-overlapping window scan size), the \nprogram reports the predicted hot/cold spots and marks them in color.", "Meiotic recombination arises from Rec12/Spo11-dependent formation of DNA \ndouble-strand breaks (DSBs) and their subsequent repair. We identified \nRec12-binding peaks across the Schizosaccharomyces pombe genome using chromatin \nimmunoprecipitation after reversible formaldehyde cross-linking combined with \nwhole-genome DNA microarrays. Strong Rec12 binding coincided with previously \nidentified DSBs at the recombination hotspots ura4A, mbs1, and mbs2 and \ncorrelated with DSB formation at a new site. In addition, Rec12 binding \ncorresponded to eight novel conversion hotspots and correlated with crossover \ndensity in segments of chromosome I. Notably, Rec12 binding inversely correlated \nwith guanine-cytosine (GC) content, contrary to findings in Saccharomyces \ncerevisiae. Although both replication origins and Rec12-binding sites preferred \nAT-rich gene-free regions, they seemed to exclude each other. We also uncovered \na connection between binding sites of Rec12 and meiotic cohesin Rec8. \nRec12-binding peaks lay often within 2.5 kb of a Rec8-binding peak. Rec12 \nbinding showed preference for large intergenic regions and was found to bind \npreferentially near to genes expressed strongly in meiosis. Surprisingly, Rec12 \nbinding was also detected in centromeric core regions, which raises the \nintriguing possibility that Rec12 plays additional roles in meiotic chromosome \ndynamics." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015003', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006312', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0010844', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012441', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0051598', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D011995', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D016678']
552440452c8b63434a00000b	[ 15564032, 22407809, 16945536, 12805120, 19648653, 11257471, 11166164, 20012312, 22358459, 15495263 ]	train	Are ACTA1 (alpha actin) and NEB (nebulin) genes related to nemaline myopathy?	yesno	Yes, most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal muscle alpha-actin (ACTA1) genes.	yes	[ "We report muscle MRI findings of 10 patients from 8 families with nemaline \nmyopathy. Patients with involvement of the nebulin (NEB) gene showed a \nconsistent pattern of selective muscle involvement corresponding to clinical \nseverity. In mild cases, there was complete sparing of thigh muscles and \nselective involvement of tibialis anterior and soleus. In moderate cases, there \nwas predominant involvement of rectus femoris, vastus lateralis and hamstring \nmuscles and diffuse involvement of anterior compartment and soleus. Patients \nwith nemaline myopathy secondary to mutations in the skeletal muscle alpha-actin \n(ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative \nsparing of the gastrocnemii. Selective muscle involvement in both genetic \ncategories was distinct from what has been reported in other congenital \nmyopathies. We conclude that muscle MRI may be applied to distinguish nemaline \nmyopathy from other conditions with similar clinical and histopathological \nfeatures, to supplement clinical assessment in individual patients and to help \ndirect genetic testing.", "Nemaline myopathy (NM) is a group of congenital myopathies, characterized by the \npresence of distinct rod-like inclusions \"nemaline bodies\" in the sarcoplasm of \nskeletal muscle fibers. To date, ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 have \nbeen found to cause NM. We have identified recessive RYR1 mutations in a patient \nwith severe congenital NM, through high-throughput screening of congenital \nmyopathy/muscular dystrophy-related genes using massively parallel sequencing \nwith target gene capture. The patient manifested fetal akinesia, neonatal severe \nhypotonia with muscle weakness, respiratory insufficiency, swallowing \ndisturbance, and ophthalomoplegia. Skeletal muscle histology demonstrated \nnemaline bodies and small type 1 fibers, but without central cores or minicores. \nCongenital myopathies, a molecularly, histopathologically, and clinically \nheterogeneous group of disorders are considered to be a good candidate for \nmassively parallel sequencing.", "Most nemaline myopathy patients have mutations in the nebulin (NEB) or skeletal \nmuscle alpha-actin (ACTA1) genes. Here we report for the first time three \npatients with severe nemaline myopathy and mutations of the ACTA1 stop codon: \nTAG>TAT (tyrosine), TAG>CAG (glutamine) and TAG>TGG (tryptophan). All three \nmutations will cause inclusion of an additional 47 amino acids, translated from \nthe 3' UTR of the gene, into the mature actin protein. Western blotting of one \npatient's muscle demonstrated the presence of the larger protein, while \nexpression of one of the other mutant proteins fused to EGFP in C2C12 cells \ndemonstrated the formation of rod bodies.", "Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle \nweakness and the presence of nemaline rods. Five genes have now been associated \nwith nemaline myopathy: alpha-tropomyosin-3 (TPM3), alpha-actin (ACTA1), nebulin \n(NEB), beta-tropomysin (TPM2) and troponin T (TNNT1). In addition, mutations in \nthe ryanodine receptor gene (RYR1) have been associated with core-rod myopathy. \nHere we report linkage in two unrelated families, with a variant of nemaline \nmyopathy, with associated core-like lesions. The clinical phenotype consists of \nmuscle weakness in addition to a peculiar kind of muscle slowness. A genome-wide \nscan revealed a locus for nemaline myopathy with core-like lesions on chromosome \n15q21-q23 for both families. Combining the two families gave a two-point LOD \nscore of 10.65 for D15S993. The alpha-tropomyosin-1 gene (TPM1) located within \nthis region is the strongest candidate gene. However, no mutations were found in \nthe protein-coding region of TPM1, although small deletions or mutations in an \nintron cannot be excluded. The critical region contains few other candidate \ngenes coding for muscle proteins and several genes of unknown function, and has \nnot yet been sequenced completely. The novel phenotype of nemaline myopathy in \nthe two presented families corresponds to an also novel, as yet uncharacterized, \ngenotype.", "Nemaline myopathy is a heterogenous form of congenital myopathy characterised by \na variable spectrum of clinical features, predominated in the severe form by \nprofound muscle hypotonia and weakness accompanied by respiratory insufficiency. \nThe clinical variability, with differing age of onset and severity of symptoms \nmakes the diagnosis of nemaline myopathy difficult in some cases. Severe forms \nof nemaline myopathy may be caused by mutation of a number of different genes: \nskeletal muscle actin (ACTA1), nebulin (NEB) and alpha-tropomyosin (TPM3), all \nof which encode components of the sarcomeric thin filaments of skeletal muscle. \nWe describe the severe form of nemaline myopathy diagnosed in two brothers who \ndied at the age of 12 days and 9 months, due to respiratory insufficiency caused \nby severe muscle weakness. Polyhydramnios and weakness of foetal movements in \nthe IIIrd trimester of pregnancy, as well as variable clinical severity were \nnoted in both cases. Microscopically visible significant immaturity of muscle \nfibers was found in the skeletal muscle biopsy performed in one of the brothers. \nThe diagnosis of nemaline myopathy was confirmed by the presence of nemaline \nbodies (rods) in sections stained using the Gomori trichrome method. Molecular \nstudies of DNA isolated from blood leucocytes showed no mutation in the ACTA1 or \nthe TPM3 genes. Linkage analysis with polymorphic markers did not rule out \nlinkage to part of the NEB gene locus. Results of the clinical evaluation and \nthe investigations performed in the family members confirm that it is essential \nto consider congenital myopathies in the differential diagnosis of neonatal and \ninfantile hypotonia with respiratory insufficiency. Molecular verification of \nthe clinical diagnosis is also important for genetic counselling of the \nfamilies.", "Nemaline myopathy is a structural congenital myopathy which may show both \nautosomal dominant and autosomal recessive inheritance patterns. Mutations in \nthree different genes have been identified as the cause of nemaline myopathy: \nthe gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) \nat 2q21.1-q22, and the actin gene (ACTA1) at 1q42. The typical autosomal \nrecessive form appears to be the most common one and is caused by mutations in \nthe nebulin gene. We have studied the pattern of nebulin labeling, in patients \nwith the typical congenital form (ten patients), the severe congenital form (two \npatients) or the mild, childhood-onset form (one patient), using antibodies \nagainst three different domains of nebulin. A qualitative and quantitative \nnebulin analysis in muscle tissue showed the presence of nebulin in myofibers \nfrom all patients. Some differences relating to the rod structure were observed. \nThe majority of the largest subsarcolemmal rods were not labeled with the N2 \nnebulin antibody (I-band epitope) and showed an indistinct pattern with the two \nantibodies directed to the Z-band portion of nebulin (epitopes M176-181 and \nserine-rich domain). Diffuse rods were not revealed using the three antibodies. \nA discordant pattern of nebulin N2 epitope labeling was found in two affected \nsisters with a mutation in the nebulin gene, suggesting that modifications in \nnebulin distribution inside the rods might occur with the progression of the \ndisease. Western blot analysis showed no direct correlation with \nimmunofluorescence data. In nine patients, the band had a molecular weight \ncomparable to the normal control, while in one patient, it was detected with a \nhigher molecular weight. Our results suggest that presence/absence of specific \nnebulin Z-band epitopes in rod structures is variable and could depend on the \ndegree of rod organization.", "Nemaline myopathy is a clinically and genetically heterogeneous condition. The \nclinical spectrum ranges from severe cases with antenatal or neonatal onset and \nearly death to late onset cases with only slow progression. Three genes are \nknown to cause nemaline myopathy: the genes for nebulin (NEB) on chromosome \n2q22, slow alpha-tropomyosin (TPM3) on chromosome 1q21 and skeletal muscle \nalpha-actin (ACTA1) on chromosome 1q42. We present a 39-year-old lady with a \nmild form of nemaline myopathy, whom we have followed over a period of 25 years. \nShe presented at the age of 7 years with symptoms of mild axial and proximal \nmuscle weakness. The overall course was essentially static, but at 36 years, she \nwent into life-threatening respiratory failure, for which she is currently \ntreated with night-time ventilation. Muscle biopsies at 12, 17 and 39 years of \nage showed typical nemaline rods, particularly in type 1 fibres. Areas with \nunevenness of oxidative stain were present in the second and third biopsies. The \npresence of rods and core-like areas was confirmed on electron microscopy. There \nwas no detectable alteration in actin expression immunocytochemically. A \ndominant missense mutation in the skeletal muscle alpha-actin gene (ACTA1) was \nfound. This case illustrates the clinical and genetic heterogeneity of nemaline \nmyopathy, and one phenotype of the wide spectrum of severity caused by mutations \nin the skeletal muscle alpha-actin (ACTA1) gene. In addition, it shows the \ndiversity of pathological features that can occur in congenital myopathies due \nto mutations in the same gene.", "Nemaline myopathy (NM) is a genetically and clinically heterogenous muscle \ndisorder, which is myopathologically characterized by nemaline bodies. Mutations \nin six genes have been reported to cause NM: Nebulin (NEB Pelin 1999), \nalpha-skeletal muscle actin (ACTA1 Nowak 1999), alpha-slow tropomyosin (TPM3 \nLaing 1995), beta-tropomyosin (TPM2 Donner 2002), slow troponin T (TNNT1 \nJohnston 2000) and cofilin 2 (CFL2 Agrawal 2007). The majority of cases are due \nto mutation in NEB and ACTA1. We report on the clinical, myopathological and \nmuscle MRI findings in a German family with autosomal dominant NM due to a novel \npathogenic TPM3 mutation (p.Ala156Thr).", "Nemaline myopathy (NM) is the most common congenital myopathy and is caused by \nmutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), \nTPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases \ncarry ACTA1 defects and these particular mutations usually induce substitutions \nof single residues in the actin protein. Despite increasing clinical and \nscientific interest, the contractile consequences of these subtle amino acid \nsubstitutions remain obscure. To decipher them, in the present study, we \noriginally recorded and analysed the mechanics as well as the X-ray diffraction \npatterns of human membrane-permeabilized single muscle fibres with a particular \npeptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an \nunexpected cascade of molecular and cellular events. During contraction, \np.Phe352Ser greatly enhances the strain of individual cross-bridges. \nParadoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by \naltering the rate of myosin head attachment to actin monomers. Overall, at the \ncell level, these divergent mechanisms conduct to an improved steady-state force \nproduction. Such results provide new surprising scientific insights and crucial \ninformation for future therapeutic strategies.", "Congenital myopathies are clinical and genetic heterogeneous disorders \ncharacterized by skeletal muscle weakness ranging in severity. Three major forms \nhave been identified: actin myopathy, intranuclear rod myopathy, and nemaline \nmyopathy. Nemaline myopathy is the most common of these myopathies and is \nfurther subdivided into seven groups according to severity, progressiveness, and \nage of onset. At present, five genes have been linked to congenital myopathies. \nThese include alpha-actin (ACTA1), alpha- and beta-tropomyosin (TPM3 and TPM2), \ntroponin T (TNNT1), and nebulin (NEB). Their protein products are all components \nof the thin filament of the sarcomere. The mutations identified within these \ngenes have varying impacts on protein structure and give rise to different forms \nof congenital myopathies. Greater understanding of muscle formation and cause of \ndisease can be established through the study of the effect of mutations on the \nfunctional proteins. However, a major limitation in the understanding of \ncongenital myopathies is the lack of correlation between the degree of \nsarcomeric disruption and disease severity. Consequently, great difficulty may \nbe encountered when diagnosing patients and predicting the progression of the \ndisorders. There are no existing cures for congenital myopathies, although \nimprovements can be made to both the standard of living and the life expectancy \nof the patient through various therapies." ]	['http://www.uniprot.org/uniprot/NEBU_HUMAN', 'http://www.disease-ontology.org/api/metadata/DOID:3191', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D017696', 'http://www.uniprot.org/uniprot/ACTS_CYPCA', 'http://www.uniprot.org/uniprot/ACTS_ORYLA', 'http://www.uniprot.org/uniprot/ACTS_ATRMM', 'http://www.uniprot.org/uniprot/ACTS_CARAU', 'http://www.uniprot.org/uniprot/ACTS_OREMO']
55032179e9bde6963400002e	[ 19666486 ]	train	Are BBS mutations involved in syndromic Hirschsprung disease?	yesno	In 3 families with Bardet-Biedl syndrome (BBS) and Hirschsprung disease (HSCR), concomitant mutations in BBS genes and regulatory RET elements have been identified. Analysis of the data suggests that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease.	yes	[ "Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy \ncharacterized by incomplete innervation along a variable length of the gut. The \npivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR \nalso presents in various syndromes, including Shah-Waardenburg syndrome (WS), \nDown (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR \nwith concomitant mutations in BBS genes and regulatory RET elements, whose \nfunctionality is tested in physiologically relevant assays. Our data suggest \nthat BBS mutations can potentiate HSCR predisposing RET alleles, which by \nthemselves are insufficient to cause disease. We also demonstrate that these \ngenes interact genetically in vivo to modulate gut innervation, and that this \ninteraction likely occurs through complementary, yet independent, pathways that \nconverge on the same biological process." ]	['http://www.disease-ontology.org/api/metadata/DOID:10487']
5512c91b6a8cde6b7200000b	[ 23273605, 23903755, 18375819, 24073999, 23900694, 24202393, 24258972, 24258977, 24258979, 23890088, 24289205, 22614711, 23890105, 24325952, 23594689, 24265154, 24265155, 24265153, 24220097, 24291778, 24283590, 23477830, 23414474, 24259661, 24298448, 24309328, 24201813, 24295639, 23415641, 23893853, 24248543, 23890154, 15917418, 23237741, 14695152, 23843700, 14679157, 16799476, 24252159 ]	train	Are BRAF mutations common in melanoma?	yesno	Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid.	yes	[ "The US Food and Drug Administration (FDA) approved vemurafenib to treat patients \nwith metastatic melanoma harboring the BRAF c.1799T>A (p.V600E) mutation. \nHowever, a subset of melanomas harbor non-p.V600E BRAF mutations, and these data \nare of potential importance regarding the efficacy of current targeted \ntherapies. To better understand the BRAF mutation profile in melanomas, we \nretrospectively analyzed data from 1112 primary and metastatic melanomas at our \ninstitution. The cohort included nonacral cutaneous (n = 774), acral (n = 111), \nmucosal (n = 26), uveal (n = 23), leptomeningeal (n = 1), and metastatic \nmelanomas of unknown primary site (n = 177). BRAF mutation hotspot regions in \nexons 11 and 15 were analyzed by pyrosequencing or with the primer extension \nMassARRAY system. A total of 499 (44.9%) specimens exhibited BRAF mutations, \ninvolving exon 15 [497 (99.6%)] or exon 11 [2 (0.4%)]. p.V600E was detected in \n376 (75.4%) cases; the remaining 123 (24.6%) cases exhibited non-p.V600E \nmutations, of which p.V600K was most frequent [86 (17.2%)]. BRAF mutations were \nmore frequent in nonacral cutaneous (51.4%) than acral melanomas [18 (16.2%)] (P \n< 0.001); however, there was no significant difference among cutaneous \nhistological subtypes. All mucosal, uveal, and leptomeningeal melanomas were \nBRAF wild type (WT). The high frequency of non-p.V600E BRAF mutations in \nmelanoma has important implications because the FDA-approved companion \ndiagnostic test for p.V600E detects some but not all non-p.V600E mutations. \nHowever, the therapeutic efficacy of vemurafenib is not well established in \nthese lesions.", "RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase \nkinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. \nHowever, most responses are partial and short-lived, and many patients fail to \nrespond at all. We found that suppression of TORC1 activity in response to RAF \nor MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein \nS6 (P-S6), effectively predicted induction of cell death by the inhibitor in \nBRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was \nmaintained after treatment with RAF or MEK inhibitors, in some cases despite \nrobust suppression of mitogen-activated protein kinase (MAPK) signaling. In in \nvivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for \ninduction of apoptosis and tumor response. Finally, in paired biopsies obtained \nfrom patients with BRAF-mutant melanoma before treatment and after initiation of \nRAF inhibitor therapy, P-S6 suppression predicted significantly improved \nprogression-free survival. Such a change in P-S6 could be readily monitored in \nreal time by serial fine-needle aspiration biopsies, making quantitation of P-S6 \na valuable biomarker to guide treatment in BRAF-mutant melanoma.", "Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. BRAF that \nis activated by the common V600E and other mutations, as well as by upstream \nNRAS mutations, has been shown to require the molecular chaperone heat shock \nprotein 90 (HSP90) for stabilization and is depleted by the HSP90 inhibitor \n17-allylamino-17-demethoxygeldanamycin (17-AAG)]. Here, we explore the possible \nrelationship between tumor BRAF and NRAS mutations and clinical response to \n17-AAG in six patients with metastatic malignant melanoma who received \npharmacologically active doses of 17-AAG as part of a phase I clinical trial. \nOne patient with disease stabilization for 49 months had a (G13D)NRAS mutation \nand (WT)BRAF. A second patient who had stable disease for 15 months had a \n(V600E)BRAF mutation and (WT)NRAS. These preliminary results suggest that BRAF \nand NRAS mutation status should be determined in prospective phase II studies of \nHSP90 inhibitors in melanoma.", "INTRODUCTION: The clinical activity of BRAF inhibitor (BRAF-I) therapy is a \nmajor breakthrough in the treatment of metastatic melanoma carrying BRAF \nmutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to \nthe onset of intrinsic and acquired drug resistance.\nAREAS COVERED: The role of wild-type BRAF in melanocytes and of the mutated BRAF \nin the pathogenesis of melanoma is described in this article. The results \nobtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms \ndriving the intrinsic and acquired BRAF-I resistance, the development of \ncombinatorial strategies designed to overcome them and their potential \nlimitations are discussed. Lastly, the many questions that have to be addressed \nto optimize therapy with BRAF-I are listed.\nEXPERT OPINION: Melanoma is an aggressive form of skin cancer characterized by \npoor prognosis and high mortality. The discovery of BRAF mutations which drive \nmelanoma tumorigenesis and the development of agents which selectively inhibit \nmutant-activated BRAF represent a major breakthrough in the treatment of \nmetastatic melanoma. However, the development of drug resistance underlies the \nneed of more effective and individualized combinatorial treatments to counteract \nthe multiple escape mechanisms utilized by BRAF-mutant melanoma. Although \ncombinatorial strategies using agents which target different protumorigenic \nsignaling pathway components have been shown to increase the clinical efficacy \nof BRAF-I, novel strategies which utilize different antitumor mechanisms are \nneeded.", "Recent advances in molecular targeted therapies have greatly improved treatment \noutcomes for cancers driven by oncogenic mutations. Despite initial and dramatic \nclinical responses, tumors eventually acquire resistance to these targeted \ntherapies, showing flexible and diverse responses. Interestingly, cancer cells \nsometimes overadapt to the drug treatment environment, leading to a state in \nwhich cancer cells cannot survive without the drug. This interesting phenomenon \n(often called \"drug dependency\" or \"drug addiction\") is exemplified in \npreclinical acquired resistance models of BRAF-mutated melanoma treated with \nvemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase \ninhibitors. A number of intriguing parallels in drug-addicted cancers became \napparent in a comparison of the two models: (i) overexpression of driver \noncogenes as causes of acquired resistance; (ii) overexpression of driver \noncogenes causing MEK-ERK hyperactivation under drug-free conditions; (iii) \nhyperactivation of the MEK-ERK pathway as critical to this drug addiction \nphenomenon; (iv) ongoing dependence on the oncogenic driver; and (v) morphologic \nchanges in resistant cells under drug-free conditions. This Perspective article \nnot only focuses on this interesting and peculiar phenomenon but also discusses \nweapon strategies to exploit this unintentional weakness of cancers.", "RAF kinase inhibitors have substantial therapeutic effects in patients with \nBRAF-mutant melanoma. However, only rarely do tumors regress completely, and the \ntherapeutic effects are often temporary. Several mechanisms of resistance to RAF \ninhibitors have been proposed. The majority of these cause ERK signaling to \nbecome insensitive to treatment with RAF inhibitors by increasing the amount of \nRAF dimers in cells, whereas others bypass the dependence of the tumor on mutant \nRAF. One motivation for studying mechanisms of drug resistance is that such \nefforts may suggest new therapeutic targets or rational combination strategies \nthat delay or prevent the emergence of drug-resistant clones. Here, we review \nthe current model of RAF inhibitor resistance with a focus on the implications \nof this model on ongoing laboratory and clinical efforts to develop more \neffective therapeutic strategies for patients with BRAF-mutant tumors.", "Personalized melanoma medicine has progressed from histopathologic features to \nserum markers to molecular profiles. Since the identification of activating BRAF \nmutations and subsequent development of drugs targeting the mutant BRAF protein, \noncologists now need to incorporate prognostic and predictive biomarkers into \ntreatment decisions for their melanoma patients. Examples include subgrouping \npatients by genotype profiles for targeted therapy and the development of \nserologic, immunohistochemical, and genotype profiles for the selection of \npatients for immunotherapies. In this chapter, we provide an overview of the \ncurrent status of BRAF mutation testing, as well as promising serologic and \nmolecular profiles that will impact patient care. As further research helps \nclarify the roles of these factors, the clinical outcomes of melanoma patients \npromise to be greatly improved.", "The Braf(V600E) mutation has been detected in patients with metastatic melanoma, \ncolon, thyroid, and other cancers. Studies suggested that tumors with this \nmutation are especially sensitive to BRAF inhibitors-hence the need to reliably \ndetermine the BRAF status of tumor specimens. The present technologies used to \nscreen for this mutation fail to address the problems associated with \ninfiltrating stromal and immune cells bearing wild-type BRAF alleles and thus \nmay fail to detect the presence of mutant BRAF(V600E) tumors. We have developed \na rapid, inexpensive method of BRAF analysis that reduces the contamination of \nwild-type BRAF sequences from tumor biopsies. The protocol involves a series of \nPCR amplifications and restriction digestions that take advantage of unique \nfeatures of both wild-type and mutant BRAF RNA at codon 600. Using this \nprotocol, mutant BRAF can be detected in RNA from mixed populations with as few \nas 0.1 % BRAF(V600E) mutant containing cells.", "(V600)BRAF mutation was identified as an ideal target for clinical therapy due \nto its indispensable roles in supporting melanoma initiation and progression. \nDespite the fact that BRAF inhibitors (BRAFi) can elicit anti-tumor responses in \nthe majority of treated patients and confer overall survival benefits, acquired \ndrug resistance is a formidable obstacle to long-term management of the disease. \nSeveral aberrant events including RTK upregulation, NRAS mutation, mutant BRAF \namplification or alternative splicing, and MEK mutation have been reported as \nacquired BRAFi resistance mechanisms. Clinially, detection of these resistance \nmechanisms help understand drug response patterns and help guide combinatorial \ntherapeutic strategies. Therefore, quick and accurate diagnosis of the resistant \nmechanisms in tumor biopsies has become an important starting point for \npersonalized therapy. In this chapter, we review the major acquired BRAFi \nresistance mechanisms, highlight their therapeutic implications, and provide the \ndiagnostic methods from clinical samples.", "BRAF is the most prevalent oncogene and an important therapeutic target in \nmelanoma. In some cancers, BRAF is activated by rearrangements that fuse its \nkinase domain to 5' partner genes. We examined 848 comparative genomic \nhybridization profiles of melanocytic tumors and found copy number transitions \nwithin BRAF in 10 tumors, of which six could be further characterized by \nsequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal \npartners. No other mutations were identified in melanoma oncogenes. One of the \nseven melanoma cell lines without known oncogenic mutations harbored a similar \nBRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, \nbut not vemurafenib, could block MAP kinase pathway activation and proliferation \nof the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) \nmutant melanoma cell lines were significantly more sensitive to vemurafenib. The \npatient from whom the cell line was derived showed a durable clinical response \nto sorafenib.", "BACKGROUND: Vemurafenib, an inhibitor of genetically activated BRAF, is now \ncommonly prescribed for metastatic melanoma harboring a BRAF mutation. Reports \non side effects have focused on cutaneous complications. We here present a case \nof a severe pan-uveitis associated with vemurafenib use.\nCASE PRESENTATION: A 63-year old female was treated with the BRAF inhibitor \nvemurafenib for metastatic melanoma. After seven weeks of treatment, she \ndeveloped near-complete visual loss in the course of a few days, as a result of \nsevere uveitis. Vemurafenib had to be discontinued and systemic and topical \ncorticosteroids were initiated. The visual symptoms improved slowly, however the \ncerebral metastases progressed and the patient died from her disease.\nCONCLUSION: Treatment with vemurafenib has become an important component of \nstandard clinical care for patients with metastatic melanoma. In addition, it is \none of the best examples of genotype-directed therapy. This case illustrates \nthat vemurafenib-induced uveitis can develop fast and be slow to resolve. \nAwareness of this potentially severe side effect is of major importance to \noncologists and aggressive treatment should be considered.", "AIM: Approximately 40-60% of melanomas from Caucasian populations carry \nactivating mutations in the BRAF oncogene, with the most common being the \np.Val600Glu (V600E) hotspot mutation in exon 15. The aim of the present study \nwas to investigate the frequency of the less common p.Val600Lys (V600K) mutation \nin metastatic melanoma from a high incidence region.\nMETHOD: Dideoxy sequencing and fluorescent single strand conformation analysis \nwere used to screen for mutations in exon 15 of BRAF in 183 cases of metastatic \nmelanoma.\nRESULTS: The overall incidence of BRAF mutation (89/183, 49%) was very similar \nto other large studies of Caucasian populations. However, the frequency of the \np.Val600Lys mutation was higher than in most other studies and comprised almost \none-third of all BRAF mutations in our cohort (27/89, 30%).\nCONCLUSION: BRAF p.Val600Lys mutations were present at a relatively high \nfrequency in this cohort of metastatic melanoma patients (27/183, 15%). Assays \nused to screen for BRAF mutations in the clinic should be robust enough to \ndetect the p.Val600Lys mutation, as this may have therapeutic implications.", "BACKGROUND: Treatment of advanced melanoma has been improved with the advent of \nthe BRAF inhibitors. However, a limitation to such treatment is the occurrence \nof resistance. Several mechanisms have been identified to be responsible for the \ndevelopment of resistance, either MEK-dependent or MEK-independent. In order to \novercome resistance due to reactivation of MEK signaling, MEK inhibitors are \nbeing clinically developed with promising results. However, also in this case \nresistance inevitably occurs. It has been recently reported that ErbB3, a member \nof the EGFR receptor family, may be involved in the establishment of drug \nresistance.\nMETHODS: Three melanoma cell lines were tested: LOX IMVI (BRAF V600E), MST-L \n(BRAF V600R) and WM266 (BRAF V600D). Phosphorylation of Receptor Tyrosine \nKinases (RTKs) was assessed by an RTK array. Western blot analysis was performed \non total protein extracts using anti-ErbB3, anti-AKT and anti-ERK 1/2 \nantibodies. The expression of neuregulin after vemurafenib treatment was \nassessed by Real Time PCR and Western blotting. The growth inhibitory effects of \nvemurafenib, GSK1120212b and/or anti-ErbB3 mAbs were evaluated by in vitro \ncolony formation assays.\nRESULTS: In the present study we demonstrate that ErbB3 is the main RTK \nundergoing rapidly hyperphosphorylation upon either treatment with a BRAF \ninhibitor or with a MEK inhibitor in a panel of melanoma cell lines harboring a \nvariety of V600BRAF mutations and that this results in a strong activation of \nphospho-AKT. Importantly, ErbB3 activation is fully abrogated by the \nsimultaneous use of anti-ErbB3 monoclonal antibodies, which are also shown to \npotently synergize with BRAF inhibitors in the inactivation of both AKT and ERK \npathways and in the inhibition of melanoma cell growth. We show that \nupregulation of phospho-ErbB3 is due to an autocrine loop involving increased \ntranscription and production of neuregulin by melanoma cells.\nCONCLUSIONS: On the basis of these results, we propose that initial co-treatment \nwith BRAF and/or MEK inhibitors and anti-ErbB3 antibodies should be pursued as a \nstrategy to reduce the ErbB3-dependent feedback survival mechanism and enhance \nduration of clinical response.", "Activating BRAF mutations, leading to constitutive activation of the MAPK \nsignaling pathway, are common in a variety of human cancers. Several small \nmolecule BRAF inhibitors have been developed during the last years and shown \npromising results in clinical trials, especially for metastatic melanoma, while \nthey have been less effective in colon cancer. Two inhibitors, vemurafenib and \ndabrafenib, have been approved for treatment of melanoma. Unfortunately, in most \npatients who initially respond the tumors eventually develop acquired resistance \nto the BRAF inhibitors. So far, a number of resistance mechanisms have been \nidentified, including secondary NRAS mutations and BRAF alternative splicing, \nleading to reactivation of the MAPK pathway. Other alterations, both upstream \nand downstream of BRAF can have the same effect, and activation of alternative \npathways can also play a role in resistance to BRAF inhibitors. In addition, \nintra-tumor heterogeneity with the presence of clones of tumor cells lacking \nBRAF mutations needs to be considered, since wildtype BRAF can be activated by \ninhibitors designed to target mutated BRAF. Combination of the BRAF inhibitor \ndabrafenib with the MEK inhibitor trametinib has significantly prolonged \nprogression free survival compared to dabrafenib alone in metastatic melanoma. \nCombination treatments of BRAF inhibitors with other agents may not only \ncircumvent or delay resistance, but may also lead to fewer side effects, such as \ndevelopment of secondary squamous tumors. Several clinical trials are underway \nfor many different BRAF mutation positive cancers with BRAF inhibitors alone or \nin combination with other small molecule inhibitors, immunotherapies or \nconventional chemotherapy.", "BRAF represents one of the most frequently mutated protein kinase genes in human \ntumours. The mutation is commonly tested in pathology practice. BRAF mutation is \nseen in melanoma, papillary thyroid carcinoma (including papillary thyroid \ncarcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal \ncarcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia. In these \ncancers, various genetic aberrations of the BRAF proto-oncogene, such as \ndifferent point mutations and chromosomal rearrangements, have been reported. \nThe most common mutation, BRAF V600E, can be detected by DNA sequencing and \nimmunohistochemistry on formalin fixed, paraffin embedded tumour tissue. \nDetection of BRAF V600E mutation has the potential for clinical use as a \ndiagnostic and prognostic marker. In addition, a great deal of research effort \nhas been spent in strategies inhibiting its activity. Indeed, recent clinical \ntrials involving BRAF selective inhibitors exhibited promising response rates in \nmetastatic melanoma patients. Clinical trials are underway for other cancers. \nHowever, cutaneous side effects of treatment have been reported and therapeutic \nresponse to cancer is short-lived due to the emergence of several resistance \nmechanisms. In this review, we give an update on the clinical pathological \nrelevance of BRAF mutation in cancer. It is hoped that the review will enhance \nthe direction of future research and assist in more effective use of the \nknowledge of BRAF mutation in clinical practice.", "Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which \ntarget RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, \nrespectively, improves progression-free survival and response rates compared \nwith dabrafenib monotherapy. Mechanisms of clinical resistance to combined \nRAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and \nwhole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant \ntumors from five patients with acquired resistance to dabrafenib/trametinib. In \nthree of these patients, we identified additional mitogen-activated protein \nkinase (MAPK) pathway alterations in the resistant tumor that were not detected \nin the pretreatment tumor, including a novel activating mutation in MEK2 \n(MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in \nvitro, but remained sensitive to inhibition of the downstream kinase \nextracellular signal-regulated kinase (ERK). The continued MAPK signaling-based \nresistance identified in these patients suggests that alternative dosing of \ncurrent agents, more potent RAF/MEK inhibitors, and/or inhibition of the \ndownstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.", "BRAF inhibitors elicit rapid antitumor responses in the majority of patients \nwith BRAF(V600)-mutant melanoma, but acquired drug resistance is almost \nuniversal. We sought to identify the core resistance pathways and the extent of \ntumor heterogeneity during disease progression. We show that mitogen-activated \nprotein kinase reactivation mechanisms were detected among 70% of \ndisease-progressive tissues, with RAS mutations, mutant BRAF amplification, and \nalternative splicing being most common. We also detected \nPI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive \nmelanomas. Distinct molecular lesions in both core drug escape pathways were \ncommonly detected concurrently in the same tumor or among multiple tumors from \nthe same patient. Beyond harboring extensively heterogeneous resistance \nmechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed \nbranched evolution marked by altered mutational spectra/signatures and increased \nfitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF \ninhibitor treatment failure, implying upfront, cotargeting of two core pathways \nas an essential strategy for durable responses.", "Author information:\n(1)1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard \nMedical School; 2Department of Pathology, Massachusetts General Hospital Cancer \nCenter, Boston; 3Broad Institute of MIT and Harvard; 4Harvard-MIT Division of \nHealth Sciences and Technology, Massachusetts Institute of Technology (MIT), \nCambridge, Massachusetts; 5Department of Dermatology, University Hospital, West \nGerman Cancer Center, University Duisburg-Essen, Essen; 6German Cancer \nConsortium (DKTK); 7Department of Dermatology, Heidelberg University Hospital, \nHeidelberg; 8Department of Dermatology and Allergy, Hannover Medical School, \nHannover; 9Department of Dermatology, University of Wuerzburg, Wuerzburg; \n10Department of Dermatology, Venerology and Allergology, University of \nSchleswig-Holstein Hospital, Kiel; 11Department of Dermatology and Allergology, \nLudwig-Maximilian University, Munich; 12Department of Dermatology, Venerology \nand Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin; \n13Department of Dermatology, University of Mainz, Mainz; 14University Medical \nCenter, University of Tübingen, Tübingen, Germany; 15Department of Genome \nSciences, University of Washington, Seattle, Washington; 16Department of \nDermatology, University Hospital Zurich, Zurich, Switzerland; and 17First \nDepartment of Medicine, Medical School, University of Athens, Athens, Greece.", "BACKGROUND: Metastatic melanoma involving the esophagus is rare; the occurrence \nof metastatic melanoma in a background of Barrett esophagus is rarer still. We \nreport a case of an 80 year-old male who presented to our institution for workup \nof Barrett esophagus with high-grade dysplasia and who proved to have metastatic \nmelanoma occurring in the background of Barrett esophagus, the first report of \nthis kind, to our knowledge, in the English literature.\nCASE PRESENTATION: An 80 year-old Caucasian male was diagnosed at an outside \ninstitution with Barrett's esophagus with high grade dysplasia and presented to \nour institution for therapy. The patient underwent endoscopic mucosal resection \nusing a band ligation technique of an area of nodularity within the Barrett \nesophagus. Microscopic examination demonstrated extensive Barrett esophagus with \nhigh-grade dysplasia as well as a second tumor which was morphologically \ndifferent from the surrounding high-grade dysplasia and which was positive for \nS-100, HMB 45 and Melan-A on immunohistochemistry, consistent with melanoma. \nFurther workup of the patient demonstrated multiple radiologic lesions \nconsistent with metastases. Molecular studies demonstrated that the melanoma was \npositive for the 1799T>A (V600E) mutation in the BRAF gene. The overall features \nof the tumor were most consistent with metastatic melanoma occurring in a \nbackground of Barrett esophagus with high-grade dysplasia.\nCONCLUSION: This case demonstrates a unique intersection between a premalignant \ncondition (Barrett esophagus with high grade dysplasia) and a separate \nmalignancy (melanoma). This report also shows the utility of molecular testing \nto support the hypothesis of primary versus metastatic disease in melanoma.", "Melanoma is the most aggressive form of skin cancer. The treatment of patients \nwith advanced melanoma is rapidly evolving due to an improved understanding of \nmolecular drivers of this disease. Somatic mutations in BRAF are the most common \ngenetic alteration found in these tumors. Recently, two different \nmutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, \nhave gained regulatory approval based on positive results in randomized phase \nIII trials. While the development of these agents represents a landmark in the \ntreatment of melanoma, the benefit of these agents is limited by the frequent \nand rapid onset of resistance. The identification of several molecular \nmechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical \ntesting of combinatorial strategies to improve the clinical benefit of these \nagents. These mechanisms, and the lessons learned from the initial testing of \nthe BRAF inhibitors, provide multiple insights that may facilitate the \ndevelopment of targeted therapies against other oncogenic mutations in melanoma, \nas well as in other cancers.", "BRAF inhibitors improve melanoma patient survival, but resistance invariably \ndevelops. Here we report the discovery of a novel BRAF mutation that confers \nresistance to PLX4032 employing whole-exome sequencing of drug-resistant \nBRAF(V600K) melanoma cells. We further describe a new screening approach, a \ngenome-wide piggyBac mutagenesis screen that revealed clinically relevant \naberrations (N-terminal BRAF truncations and CRAF overexpression). The novel \nBRAF mutation, a Leu505 to His substitution (BRAF(L505H) ), is the first \nresistance-conferring second-site mutation identified in BRAF mutant cells. The \nmutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with \na larger polar residue. Moreover, we show that BRAF(L505H) , found in human \nprostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic \nmutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are \nsensitive to novel, next-generation BRAF inhibitors, especially the \n'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment \nof melanoma patients with BRAF-mutations.", "Activating mutations in BRAF are the most common genetic alterations in \nmelanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and \napoptosis. We show here that BRAF inhibition also induces an oxidative \nphosphorylation gene program, mitochondrial biogenesis, and the increased \nexpression of the mitochondrial master regulator, PGC1α. We further show that a \ntarget of BRAF, the melanocyte lineage factor MITF, directly regulates the \nexpression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have \nsuppressed levels of MITF and PGC1α and decreased oxidative metabolism. \nConversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders \nthem addicted to oxidative phosphorylation. Our data thus identify an adaptive \nmetabolic program that limits the efficacy of BRAF inhibitors.", "BRAF mutations have been identified as the most common oncogene mutation in \nmelanomas, especially important in those originating on nonchronically \nsun-damaged skin. There is a large and continually growing body of evidence \nregarding the importance of this mutation in targeted therapy for melanoma. In \nthis review, we outline these findings including: molecular pathways used by \nBRAF, the importance in nonmalignant neoplasms, histologic associations, the \nrelationship of BRAF to KIT and NRAS mutations, and their impact on survival, as \nwell as resistance mechanisms to BRAF inhibitors employed by melanoma. \nUnderstanding these topics and how they relate to one another may facilitate the \ndevelopment of new treatments and eventually improve the prognosis for those \npatients afflicted with this disease.", "OBJECTIVE: To summarize the clinical development of dabrafenib and to highlight \nthe clinically relevant distinct characteristics of dabrafenib in contrast to \nvemurafenib.\nDATA SOURCE: An English-language literature search of MEDLINE/PubMed (1966-June \n2013), using the keywords GSK2118436, dabrafenib, vemurafenib, selective BRAF \ninhibitor, and advanced melanoma, was conducted. Data were also obtained from \npackage inserts, meeting abstracts, and clinical registries.\nSTUDY SELECTION AND DATA EXTRACTION: All relevant published articles on \ndabrafenib and vemurafenib were reviewed. Clinical trial registries and meeting \nabstracts were used for information about ongoing studies.\nDATA SYNTHESIS: BRAF(V600E) mutation confers constitutive BRAK kinase activation \nin melanoma cells, promoting tumor growth. This discovery led to the development \nof BRAF kinase inhibitors like vemurafenib and dabrafenib. Dabrafenib has been \napproved to treat patients with BRAF(V600E)-positive unresectable or metastatic \nmelanoma based on its clinical benefit demonstrated in a randomized phase III \nstudy. It has also been shown to be safe and effective in patients with BRAF \nmutant advanced melanoma involving the brain. Dabrafenib is well tolerated, with \nthe most common adverse effects being hyperkeratosis, headache, pyrexia, and \narthralgia. Currently, there is no evidence to suggest that one BRAF inhibitor \nis superior to the other. With similar efficacy, therapy selection will likely \nbe influenced by differential tolerability and cost.\nCONCLUSIONS: Dabrafenib joins vemurafenib to confirm the superior clinical \noutcome of the BRAF inhibitors when compared with dacarbazine in patients with \nBRAF(V600E)-positive advanced melanoma. Active research is ongoing to expand its \nutility into the adjuvant setting and to circumvent rapid emergence of drug \nresistance.", "Different genetic aberrations of BRAF have been reported in various \nmalignancies. BRAF is member of the RAS/RAF/MEK/ERK pathway and constitutive \nactivity of this pathway can lead to increased cellular growth, invasion, and \nmetastasis. The most common activating BRAF mutation in colorectal cancer is the \nV600E mutation, which is present in 5-15% of all tumors, and up to 80% of tumors \nwith high microsatellite instability (MSI) harbor this mutation. BRAF mutation \nis associated with proximal location, higher age, female gender, MSI-H, high \ngrade, and mucinous histology, and is a marker of poor prognosis in colorectal \ncancer. The role of BRAF mutation as a predictive marker in respect of EGFR \ntargeted treatments is controversial. BRAF V600 selective inhibitors have been \napproved for the treatment of V600 mutation positive metastatic melanoma, but \nthe response rates in colorectal cancer are poor. This might be due to innate \nresistance mechanisms of colorectal cancers against the treatment solely \ntargeting BRAF. To overcome resistance the combination of treatments, \nsimultaneous inhibition of BRAF and MEK or PI3K/mTOR, might emerge as a \nsuccessful therapeutic concept.", "BRAF mutations have emerged as an important predictive biomarker for \nmetastasized melanoma. Other types of cancer may also benefit from BRAF \nmutation-targeted therapies. In biliary tract cancer, reported BRAF mutation \nrates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the \ngallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue \nmicroarrays of a large cohort of biliary tract cancer (n=377) including 159 \nintrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 \nadenocarcinomas of the gallbladder for BRAF V600E mutation using a highly \nsensitive immunohistochemical screening approach implementing the BRAF V600E \nprotein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative \ncases were additionally analyzed by Sanger sequencing. In total, only 5 \nVE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed \nby direct sequencing in all cases. All 5 mutated cases were intrahepatic \ncholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas \nand adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype \nrestriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a \nfemale predominance (4 female, 1 male), no significant correlation with \nclinicopathological data and patient outcome was detected. In conclusion, we \ndemonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, \naccounting for only 1% of all subtypes, and is restricted to intrahepatic \ncholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is \na feasible approach to routinely screen for BRAF V600E mutation in biliary tract \ncancer patients, thereby facilitating the detection of rare patients who may \nbenefit from BRAF mutation-targeted therapies.", "An activating BRAF (V600E) kinase mutation occurs in approximately half of \nmelanomas. Recent clinical studies have demonstrated that vemurafenib (PLX4032) \nand dabrafenib, potent and selective inhibitors of mutant v-raf murine sarcoma \nviral oncogene homolog B1 (BRAF), exhibit remarkable activities in patients with \nV600 BRAF mutant melanomas. However, acquired drug resistance invariably \ndevelops after the initial treatment. Identification of acquired resistance \nmechanisms may inform the development of new therapies that elicit long-term \nresponses of melanomas to BRAF inhibitors. Here we report that increased \nexpression of AEBP1 (adipocyte enhancer-binding protein 1) confers acquired \nresistance to BRAF inhibition in melanoma. AEBP1 is shown to be highly \nupregulated in PLX4032-resistant melanoma cells because of the hyperactivation \nof the PI3K/Akt-cAMP response element-binding protein (CREB) signaling pathway. \nThis upregulates AEBP1 expression and thus leads to the activation of NF-κB via \naccelerating IκBa degradation. In addition, inhibition of the \nPI3K/Akt-CREB-AEBP1-NF-κB pathway greatly reverses the PLX4032-resistant \nphenotype of melanoma cells. Furthermore, increased expression of AEBP1 is \nvalidated in post-treatment tumors in patients with acquired resistance to BRAF \ninhibitor. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-κB \npathway whose activation contributes to acquired resistance to BRAF inhibition, \nand suggest that this pathway, particularly AEBP1, may represent a novel \ntherapeutic target for treating BRAF inhibitor-resistant melanoma.", "BACKGROUND & AIM: Brain metastases are frequent in patients with metastatic \nmelanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor \nvemurafenib in patients with advanced melanoma with symptomatic brain \nmetastases.\nMETHODS: This open-label trial assessed vemurafenib (960mg twice a day) in \npatients with BRAF(V600) mutation-positive metastatic melanoma with \nnon-resectable, previously treated brain metastases. The primary end-point was \nsafety. Secondary end-points included best overall response rate, and \nprogression-free and overall survival.\nRESULTS: Twenty-four patients received vemurafenib for a median treatment \nduration of 3.8 (0.1-11.3) months. The majority of discontinuations were due to \ndisease progression (n=22). Twenty-three of 24 patients reported at least one \nadverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence \ninterval [CI], 4.7-37.4%) patients and included cutaneous squamous cell \ncarcinoma in four patients. Median progression-free survival was 3.9 (95% CI, \n3.0-5.5) months, and median survival was 5.3 (95% CI, 3.9-6.6) months. An \noverall partial response (PR) at both intracranial and extracranial sites was \nachieved in 10 of 24 (42%; 95% CI, 22.1-63.4) evaluable patients, with stable \ndisease in nine (38%; 95% CI, 18.8-59.4) patients. Of 19 patients with \nmeasurable intracranial disease, seven (37%) achieved >30% intracranial tumour \nregression, and three (16%; 95% CI, 3.4-39.6%) achieved a confirmed PR. Other \nsigns of improvement included reduced need for corticosteroids and enhanced \nperformance status.\nCONCLUSIONS: Vemurafenib can be safely used in patients with advanced \nsymptomatic melanoma that has metastasised to the brain and can result in \nmeaningful tumour regression.", "Melanoma is an aggressive form of skin cancer that causes the greatest number of \nskin cancer-related deaths worldwide. In its early stages malignant melanoma can \nbe cured by surgical resection, but once it has progressed to the metastatic \nstage it is extremely difficult to treat and does not respond to current \ntherapies. A majority of cutaneous melanomas show activating mutations in the \nNRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk (MAPK) signal \ntransduction pathway. The discovery of activating BRAF mutations in ∼50% of all \nmelanomas has proved to be a turning point in the therapeutic management of the \ndisseminated disease. This review summarizes the critical role of BRAF in \nmelanoma pathophysiology, the clinical and pathological determinants of BRAF \nmutation status and finally addresses the current state of the art of BRAF \ninhibitors. We further outline the most recent findings on the mechanisms that \nunderlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing \npreclinical and clinical studies designed to delay or abrogate the onset of \ntherapeutic escape.", "The RAS/RAF/MEK/ERK pathway has been reported to be activated in over 80% of all \ncutaneous melanomas, making it the focus of many scientific studies in the \nmelanoma field. Discoveries of mutations and aberrant expression of components \nin this cascade, in particular, BRAF and NRAS render a deeper understanding of \nthe mechanisms responsible for oncogenesis and provide new therapeutic \nstrategies for this deadly disease. This review starts with a comprehensive \ndiscussion on the role of this pathway in initiation and progress of melanoma. \nMechanistically, mutated BRAF and NRAS exert most of the oncogenic effects \nthrough the activation of the MAPK pathway, which both drive the uncontrolled \ngrowth of melanoma cells and regulate the cell survival. In a subsequent \nsection, clinical efficacy of targeted small-molecule inhibitors is highlighted. \nBRAF-targeted therapies (e.g., vemurafenib, dabrafenib) have showed impressive \nresults in systemic therapy for melanoma harboring activating BRAF V600E \nmutations. MEK inhibitors show limited activity in phase I trials, and \ninhibitors directly targeting mutated NRAS, to date, have not been realized. \nFurthermore, the emerging mechanisms underlying both intrinsic and acquired drug \nresistance as well as approaches to prevent or abrogate the onset of therapeutic \nescape are addressed. Finally, the promising vistas and major challenges \ninvolving small-molecule inhibitors targeting this MAPK pathway in melanoma \ntherapy are briefly discussed. It can be envisaged that disseminated melanoma is \nno longer such a bleak prognosis in future given the research and development of \nnew signal transduction inhibitors based on our evolving understanding of \nmelanoma genetics and intracellular signaling.", "Vemurafenib is a selective and potent small molecule inhibitor of the V600 \nmutant form of the BRAF protein used in the treatment of melanoma and colorectal \ncancer. However, vemurafenib has less effect in BRAF mutant colorectal cancer \ndue to the resistance of tumor cell to vemurafenib. To verify whether or not \nmiR-145, a short RNA molecule of microRNA which has been supposed to be a tumor \nsuppressor, is involved in this process, we established vemurafenib-resistant \ncell line colo205/V and found that the miR-145 expression was significantly \ndownregulated in colo205/V cells compared to normal colo205 cells. Moreover, the \noverexpression of miR-145 could increase the sensitivity of colo205/V cells to \nvemurafenib both in vitro and in vivo. In conclusion, miR-145 might be used as a \ntherapeutic target in the treatment of colorectal cancer patients with BRAF \nV600E mutation.", "Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients \npresent with metastatic disease without an evident primary site. To determine \ntheir likely site of origin, we combined exome sequencing from 33 MUPs to assess \nthe total rate of somatic mutations and degree of UV mutagenesis. An independent \ncohort of 91 archival MUPs was also screened for 46 hot spot mutations highly \nprevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed \nthat the majority of MUPs exhibited high somatic mutation rates, high ratios of \nC>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of \n101, 32%) mutations, collectively indicating a mutation profile consistent with \ncutaneous sun-exposed melanomas. These data suggest that a significant \nproportion of MUPs arise from regressed or unrecognized primary cutaneous \nmelanomas or arise de novo in lymph nodes from nevus cells that have migrated \nfrom the skin.", "BACKGROUND: Malignant melanoma arising from different body compartments may be \nassociated with differing aetiological factors and clinical behaviour, and may \nmanifest diverse molecular genetic profiles. Although many studies have focused \non cutaneous melanoma, little is known of mucosal and other types of melanoma. \nIn particular, malignant melanoma of soft parts is different from other \nmelanomas in many respects, yet manifests a common melanocytic differentiation. \nMutation of BRAF is now known to be common in cutaneous melanomas, and raises \npossible new therapeutic options of anti-RAF treatment for these patients. Few \ndata are available for non-cutaneous melanomas.\nAIMS: To study the incidence of BRAF and NRAS mutations in melanomas arising in \ndiverse internal organs.\nMETHODS: Fifty one melanomas from various internal organs were investigated for \nBRAF and NRAS mutation by direct DNA sequencing.\nRESULTS: BRAF and NRAS mutations were found in two and five mucosal melanomas \narising from the aerodigestive and female genital tracts (n = 36). Their \noccurrence is mutually exclusive, giving a combined mutation incidence rate of \n19.4% in mucosal melanomas. Both BRAF and NRAS mutations were absent in \nmalignant melanoma of soft parts (n = 7). BRAF mutation was also absent in uveal \nmelanoma (n = 6), but was seen in two of five cutaneous melanomas. The incidence \nof BRAF or combined BRAF/NRAS mutations in all non-cutaneous groups was \nsignificantly lower than published rates for cutaneous melanomas.\nCONCLUSION: Each melanoma subtype may have a unique oncogenetic pathway of \ntumour development, and only a small fraction of non-cutaneous melanomas may \nbenefit from anti-RAF treatment.", "Activating mutations in the BRAF gene occur in approximately 50% of melanomas. \nMore than 70% of BRAF mutations are V600E and 10-30% are V600K. Potent and \nselective BRAF inhibitors have demonstrated significant clinical benefits in \npatients with V600E and V600K BRAF-mutated melanoma. V600R mutations constitute \napproximately 3-7% of all BRAF mutations and the activity of BRAF inhibitors in \npatients with this mutation is unknown. We have treated 45 patients with V600 \nmutated melanoma including patients with V600R mutation between July 2011 and \nOctober 2012 with the selective BRAF inhibitor dabrafenib (n=43) or vemurafenib \n(n=2) via a compassionate access programme. The overall response rate was 50% \nfor the whole population with a progression-free survival of 5.5 months. Five \nobjective responses were seen in six assessable patients with V600R BRAF \nmutation (n=9). Our experience suggests that patients with V600R BRAF mutations \ncan be treated successfully with oral BRAF inhibitors, and molecular diagnostic \nassays should include detection of this type of mutation.", "PURPOSE: Recently, it was reported that BRAF mutations are frequent in melanoma. \nPreviously, we analyzed a large series of paired primary and metastatic \nmelanomas for NRAS codon 61 mutations and showed that they arise early and are \npreserved during tumor progression. Here, we have screened the same tumor \nsamples for BRAF mutations.\nEXPERIMENTAL DESIGN: Primary melanomas (n = 71) and corresponding metastases (n \n= 88) from 71 patients were screened for BRAF exon 11 and exon 15 mutations \nusing single-strand conformational polymorphism and nucleotide sequence analysis\nRESULTS: BRAF mutations were found in 42 of 71 patients (59%). Thirty-seven \npatients had mutations that lead to a Val599Glu change, whereas mutations \nresulting in Gly468Ser, Val599Arg, Val599Lys, and Lys600Glu changes were \ndetected in one patient each. Furthermore, one patient had a 6-bp insertion \nbetween codons 598 and 599, encoding two threonine residues. In most cases, \npaired primary and metastatic lesions had the same BRAF genotype (i.e., \nmutations present in the primary tumors were preserved in the corresponding \nmetastases, and mutations did not arise at the metastatic stage if they were not \npresent in the primary lesion). Using laser-capture microdissection, BRAF \nmutations were found in the radial growth phase of the primary lesions. BRAF \nmutations occurred exclusively in tumors that were wild type for NRAS, and in \ntotal, 89% of the patients analyzed (63 of 71) had mutations in either of these \ntwo genes.\nCONCLUSIONS: The Ras-Raf-mitogen-activated protein kinase/extracellular \nsignal-regulated kinase-extracellular signal-regulated kinase signaling pathway \nis activated in the vast majority of melanomas. Activation occurs through either \nNRAS or BRAF mutations, both of which arise early during melanoma pathogenesis \nand are preserved throughout tumor progression.", "The advent of personalized medicine has ushered in a new era for cancer therapy \nwith a significant impact on the management of advanced melanoma. Molecular \ntargeted therapies have shown promise in the management of various malignancies, \nincluding melanoma, with lower toxicity profiles and better overall survival as \ncompared with conventional therapy. The discovery of BRAF mutations in melanoma \nled to the development of BRAF inhibitors for the treatment of advanced \nmelanoma. However, growing concerns over drug resistance to molecular targeted \ntherapies including BRAF inhibitors, have spurred efforts to elucidate \nadditional molecular targets for the treatment of advanced melanoma. In this \nreview, we discuss the known molecular aberrations in melanoma, current and \nnovel targeted approaches in its treatment, and drug resistance patterns.", "The RAS/mitogen-activated protein kinase pathway sends external growth-promoting \nsignals to the nucleus. BRAF, a critical serine/threonine kinase in this \npathway, is frequently activated by somatic mutation in melanoma. Using a cohort \nof 115 patients with primary invasive melanomas, we show that BRAF mutations are \nstatistically significantly more common in melanomas occurring on skin subject \nto intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, \ntwo-sided Fisher's exact test). By contrast, BRAF mutations in melanomas on \nchronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively \nor completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 \npatients), and mucosal membranes (2 of 21 patients) are rare. We found no \nassociation of mutation status with clinical outcome or with the presence of an \nassociated melanocytic nevus. The mutated BRAF allele was frequently found at an \nelevated copy number, implicating BRAF as one of the factors driving selection \nfor the frequent copy number increases of chromosome 7q in melanoma. In summary, \nthe uneven distribution of BRAF mutations strongly suggests distinct genetic \npathways leading to melanoma. The high mutation frequency in melanomas arising \non intermittently sun-exposed skin suggests a complex causative role of such \nexposure that mandates further evaluation.", "BRAF mutations are common events in a variety of melanocytic nevi and primary \ncutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, \nconsisting of congenital, common acquired and dysplastic types, and 33% of \nprimary cutaneous melanomas other than the spitzoid type, similar to other \npublished reports. A small number of studies have evaluated Spitz nevi and have \nfailed to detect any lesions possessing a BRAF mutation. Only one study included \ncategories of atypical Spitz nevus and borderline lesions suspected to be \nspitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas. We \nexamined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with \natypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid \nmelanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which \ntwo were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi \nwith BRAF mutations were altered by more than usual cytologic atypia and/or \narchitectural atypia overlapping with dysplastic nevi, or \nirritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation. These \nresults indicate that a small subset of Spitz nevi, some with atypical \nhistologic features, possess BRAF mutations. Therefore, the BRAF mutational \nstatus does not separate all Spitz nevi from spitzoid melanomas and non-Spitz \ntypes of melanocytic proliferations, contrary to previous reports.", "BACKGROUND: BRAF mutations occur in approximately 8% of all human cancers and \napproach 50% in melanoma and papillary carcinoma of thyroid. These mutations \nprovide potentially valuable diagnostic, prognostic and treatment response \nprediction markers. A sensitive, specific, low-cost assay to detect these \nmutations is needed.\nRESULTS: To detect BRAF V600E mutation in formalin-fixed, paraffin-embedded \n(FFPE) tissue, we developed a method using Amplification Refractory Mutation \nSystem (ARMS)-PCR. This method was designed to amplify three products in a \nsingle reaction tube: a 200 bp common product serving as an amplification \ncontrol, a 144 bp BRAF V600E specific product, and a 97 bp wild-type (wt) \nspecific product. The sensitivity of this method was determined to be as low as \n0.5% for the BRAF V600E allele in a wild-type background. This method was \nsuccessfully validated in 72 thyroid tumors. It detected V600E mutation in 22 \nout of 33 (67%) of the conventional papillary thyroid carcinoma (PTC), 8 out of \n12 (75%) of the tall-cell variant of PTC, whereas none of the 10 follicular \nvariant of PTC showed BRAF V600E mutation. In addition, none of the 14 \nfollicular adenomas and 3 follicular carcinomas had BRAF V600E mutation. As a \ncomparison method, direct dideoxy sequencing found only 27 out of 30 (90%) \nmutations detected by ARMS-PCR method, suggesting that this ARMS-PCR method has \nhigher sensitivity.\nCONCLUSIONS: Our ARMS-PCR method provides a new tool for rapid detection of BRAF \nV600E mutation. Our results indicate that ARMS-PCR is more sensitive than \nautomated dideoxy sequencing in detecting low BRAF V600E allele burdens in FFPE \ntumor specimen. The strategy of this ARMS-PCR design may be adapted for early \ndetection of point mutations of a variety of biomarker genes." ]	['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008545', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009154', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D048493', 'http://www.uniprot.org/uniprot/BRAF_CHICK', 'http://www.uniprot.org/uniprot/BRAF_COTJA', 'http://www.disease-ontology.org/api/metadata/DOID:1909']
533bf29cc45e133714000001	[ 9413216, 9815811, 7544777, 7585612, 7587629, 12747468, 12842543, 11751503, 8869105, 9224749, 9849582, 9742519, 10601048, 9949626, 9732216 ]	train	Are CD44 variants (CD44v) associated with poor prognosis of metastasis?	yesno	Yes, several isoforms (obtained by by usage of ten variant exons in various combinations) have been causally related to metastasis.	yes	[ "Standard CD44 (CD44s) and variant isoforms (CD44v) are expressed on different \nmalignant cells and tissues. Their upregulation has been implicated, in the \nprogression and metastasis of malignomas. In this work we addressed the question \nof whether these molecules are also expressed on xenografted human breast \ncarcinomas and if certain expression patterns are correlated with biological \nparameters like tumour size, hormone receptor status, histology, growth rate, \nchemoresistance and microenvironment. Additionally, we were interested in the \nshedding of soluble CD44 (sCD44) into the blood circulation of tumour bearing \nnude mice. The human breast carcinomas MCF-7, MCF-7/ADR, 4296 and MDA-MB435, \n4134 and 4151 were transplanted subcutaneously (sc.) or into the mammary fat pad \n(mfp.) of nude mice. The expression of the CD44s, -v6, and -v9 isoforms was \ndetermined at different time points on tissue samples by immunohistochemistry or \nRT-PCR employing human-specific antibodies or primers, respectively. The serum \nconcentration of CD44s and -v6 was measured by human specific ELISAs. All \ntumours expressed CD44s. The lowest level was observed in the MCF-7 cancer. The \nCD44v6 and -v9 sequences and epitopes were distinctly expressed in MCF-7/ADR. \nMDA-MB435, 4134, 4151 and 4296, while MCF-7 lacked these isoforms. The highest \nserum concentration of the v6 isoform was detected in mice bearing the tumour \n4296 with a high tendency for lymphogenic metastasis. The serum levels of sCD44 \nwere in 5/6 xenografts linearly correlated with the tumour size. Interestingly, \nthere was a remarkable difference between the two sublines MCF-7 and MCF-7/ADR: \nBoth the tissue and serum levels of CD44 isoforms indicated that the development \nof multidrug resistance is accompanied by an alteration in the expression of \nmembrane proteins discussed to be involved in metastasis. There was no relation \nof tissue expression with the transplantation site and the hormone receptor \nstatus of the tumour lines. CD44s and its variant isoforms are expressed in \nhuman xenotransplanted breast cancers in very different levels and patterns. The \nhighest expression in the tumour 4296 is related to lymphogenic metastasis while \nthe absence of isoforms in the model MCF-7 is related to non-metastatic \nbehaviour. CD44 is shed into the serum and can be used for monitoring of tumour \ngrowth.", "Recently, it was suggested that splice variants of the surface glycoprotein CD44 \n(CD44v) were associated with tumor metastasis in some cancers. We examined the \nexpression of variant forms of CD44 in 31 non-small cell lung carcinomas \n(NSCLCs) and in 8 normal lung tissue samples by reverse transcription-PCR \n(RT-PCR). CD44v3, CD44v5, CD44v6, and CD44v7 were not expressed or were weakly \nexpressed in normal lung tissue (0 of 8). In contrast, CD44v3, CD44v5, CD44v6, \nor CD44v7 was expressed in 28 of 31 (90.3%) NSCLCs. Additionally, we examined \nthe expression of CD44v6, which has been shown to be related to metastasis, in 5 \nnormal lungs and 30 NSCLCs by RT-PCR and immunohistochemical analysis to clarify \nwhich cells express CD44v6 in NSCLC specimens. Thirty-six of 61 (59%) NSCLCs \nvariably expressed CD44v6 by RT-PCR, and cancer cells were selectively \nimmunostained by anti-CD44v6 antibodies in 23 of 30 (76.7%) NSCLCs. The results \nof immunohistochemical analysis almost correlated with those of RT-PCR. NSCLCs \nwith lymph node metastasis expressed significantly more v6 exon than did those \nwithout lymph node metastasis [23 of 29 (79.3%) versus 13 of 32 (40.6%); P < \n0.01]. There was a significant association between the intensity of v6 \nexpression by RT-PCR and the frequency of cases showing lymph node metastasis \n(Cochran-Armitage's test, P < 0.002). In conclusion, this study demonstrated \nthat in NSCLC, a number of variant forms of CD44 are frequently expressed, \nalthough these variants are infrequently expressed in normal lung tissue, and \nthat the expression of CD44v6 is particularly associated with lymph node \nmetastasis in NSCLC.", "CD44 designates a large family of proteins generated from one gene by \nalternative splicing. Variants of CD44 (CD44v) differ from the standard form \n(CD44s) by usage of ten variant exons in various combinations. Some variants \nhave been causally related to the metastatic spread of rat tumor cells. In human \nmammary carcinomas and colorectal carcinomas, the expression of CD44v has also \nbeen correlated with more progressed tumor stages. Moreover, the expression of \nCD44v on mammary and colorectal carcinomas correlates with a bad prognosis for \npatient survival. The biochemical features of these CD44 isoforms that may \naccount for both their normal functions and their roles in tumor progression are \ndiscussed.", "CD44 is a transmembrane glycoprotein occurring in several isoforms with \ndifferent extracellular regions. The various transcripts are encoded by one gene \nlocus containing 20 exons, of which at least 10 can be alternatively spliced in \nnascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly \nrestricted in their distribution in nonmalignant tissue as opposed to the \nstandard form of CD44 (CD44s) abundant in many tissues. Specific variant \nisoforms containing exon 6v have been shown to render nonmetastatic rat tumor \ncells metastatic. Based on the prominent role in rat metastasis formation, CD44v \nisoforms were suggested to be involved in human tumor progression. Correlations \nbetween prognosis and expression of CD44v have been reported for gastric and \ncolon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. \nWe evaluated the expression of CD44 isoforms in node-positive (n = 119) and \nnode-negative (n = 108) cases of breast carcinoma by immunohistochemistry using \nCD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse \ntranscription-PCR was used to determine the exon composition of the transcripts. \nProtein and RNA expression data were probed statistically for their correlation \nto survival of the patients and clinical risk factors. In contrast to recently \npublished data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort \ndisease-free and overall survival data did not indicate significant correlations \nwith the expression of the analyzed isoforms in univariate and multivariate \nanalyses. Comparison of CD44 protein expression with established clinical risk \nfactors for survival such as tumor size (pT1+pT2) and histological grading \nrevealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, \nrespectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues \nwith elevated estrogen and progesterone receptor levels showed positive \ncorrelation with CD44-6v (P = 0.001), while a trend for significant coexpression \nof CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues \n(P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v \nare apparently markers for cellular differentiation but not for tumor \nprogression. Our data suggest that steroid hormone receptors may be associated \nwith the in vivo expression of CD44-6v-containing isoforms in human mammary \ncarcinoma.", "The large family of CD44 splice variants are likely to serve multiple functions \nin the embryo and in the adult organism. This is reflected in their complex \npatterns of expression. In molecular terms these functions are largely unknown. \nCertain splice variants (CD44v) can promote the metastatic behaviour of cancer \ncells. In human colon and breast cancer the presence of epitopes encoded by exon \nv6 on primary resected tumour material indicates poor prognosis. \nMetastasis-promoting splice variants differ from those that seem not to have a \nrole in the induction of metastasis by the formation of homomultimeric complexes \nin the plasma membrane of cells. This may increase their affinity to ligands \nsuch as hyaluronate. The affinity can be further regulated over a range from low \nto very high by cell-specific modification. The fact that CD44v epitopes are \nfound on normal epithelial cells such as skin, cervical epithelium and bladder \nenforces cautious evaluation of the significance of CD44v expression in human \ncancer. Nevertheless, certain epitopes can serve as tools in early diagnosis of \ncertain cancers and will facilitate the development of specific targeted \ntherapy.", "The expression of variant isoforms of CD44 (CD44v) correlates with the \nmetastatic potential of various carcinomas. In endometrial cancer, however, the \nsignificance of CD44v-expression as a prognostic indicator has not been fully \ninvestigated, nor has it been compared with that of p53, estrogen receptor or \nKi67. Surgical material consisted of 14 atypical endometrial hyperplasias (AEH) \nand 163 endometrial carcinomas (EC). Expression of CD44s, v3 and v6 in carcinoma \ntissue, and other prognostic markers were immunohistochemically evaluated. The \nexpression in the squamous differentiation was strictly excluded for the \nevaluation of immunohistochemistry, because the significance was different from \nthat in the adenocarcinoma component. CD44s was frequently expressed in AEH and \nEC. On the other hand, CD44v3- and v6-positivities were rare or nonexistent in \nAEH, but were observed in 8 and 35% of EC, respectively. CD44v3-expression \ncorrelated significantly with histologic grade and lymph node metastasis. \nHowever, there was no correlation between CD44v6 expression and any \nclinicopathologic factor, nor were other prognostic markers expressed. \nUnivariate analysis revealed that each CD44 was a prognostic determinant in the \npatients with EC. However, employing multivariate analysis, there were only \nthree independent factors: p53 overexpression, CD44v6 expression and myometrial \ninvasion. CD44v6 expression in the adenocarcinoma component may directly affect \nthe behavior of carcinoma and the prognosis of patients with EC.", "BACKGROUND: Cell surface glycoproteins of the CD44 family play roles in \ncell-cell and cell-matrix interactions. Their aberrant expression has been \nimplicated in tumor invasion and metastasis of a variety of neoplasms, but not, \nto date, of thymic epithelial tumors.\nMETHODS: To investigate the expression of CD44 molecules, immunohistochemical \nstaining using monoclonal antibodies against human CD44 standard form (CD44 s) \nand two common splicing variant (CD44v) isoforms, CD44v5 and CD44v6, was \nperformed on 64 resected thymomas and 20 normal thymuses. These tumors were \ncategorized histologically according to the World Health Organization (WHO) \nhistologic classification, and the pathologic staging was classified according \nto the definitions of Masaoka.\nRESULTS: The positive expression rates in these patients were as follows: CD44 s \n(normal thymuses, 10%; thymomas, 22%), CD44v5 (normal thymuses, 0%; thymomas, \n67%), and CD44v6 (normal thymuses, 0%; thymomas, 26%). CD44 s and CD44v5 \nimmunoreactivity showed a positive correlation with tumor stages (p = 0.034 and \n0.027, respectively). The CD44v5 expression of neoplastic cells in tumor \ncapsules has significant correlation with tumor stages (II, 5%; III, 70%; IVA, \n100%; p < 0.001). On the basis of univariate survival analysis, the Masaoka \nstaging system, WHO histologic classification, and CD44v5 expression showed a \nstatistically significant positive relation to survival (p < 0.001, 0.002, \n0.011, respectively). Using Cox's regression model, increasing CD44v5 \nexpression, the Masaoka staging, and the WHO classification system were found to \nbe significant independent prognostic factors.\nCONCLUSIONS: CD44v5 expression is independently positively correlated with the \naggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a \npotential trigger of tumor invasion in thymomas.", "CD44 variant exon (CD44v) 3 is a heparan sulfate-binding isoform of CD44. The \nrole of CD44v3 in invasion and metastasis associated with heparan sulfate in \ncolon cancer cell lines and cases of colon cancer was examined. Expression of \nCD44v3 mRNA and protein was observed in five of six human colorectal cancer cell \nlines. Colo320 and WiDr cells expressed CD44v3 at high levels. Heparan sulfate \ntreatment increased the invasive activity of Colo320 and WiDr cells to rates \n14.3 and 12.6 times higher, respectively, than that of untreated cells. However, \nheparan sulfate treatment did not affect cell growth. Repression of CD44v3 \nprotein production by antisense S-oligodeoxynucleotide treatment reduced the \nbinding affinities and capacities for heparan sulfate by Colo320 and WiDr cells \nin comparison with that of control cells, and it also reduced the invasiveness \nof both cell lines to one-fifth that of control cells. In heparan \nsulfate-treated Colo320 cells, the levels of CD44v3 protein in the Triton \nX-100-insoluble fraction and moesin-precipitated fraction were increased, \nsuggesting that heparan sulfate treatment facilitates association of CD44 \nmolecules with the cytoskeleton. Immunohistochemical analysis showed CD44v3 to \nbe expressed in 21 of 37 (57%) colorectal cancer cases. Positive CD44v3 \nexpression was associated with more advanced pathological stage and poorer \nprognosis than negative CD44v3 expression. These data support a role for CD44v3 \nin invasion and metastasis by colorectal carcinoma cells.", "In animal models, isoforms of CD44 (CD44v) containing sequences encoded by one \nor several of ten different exons (v1-v10) contribute to tumour metastasis. In \ncertain human cancers, CD44v6 expression is associated with poor prognosis. This \npaper examines CD44v expression in skin carcinogenesis and skin cancer \nmetastasis. CD44v expression was studied in basal cell carcinoma (BCC), squamous \ncell carcinoma (SCC), primary malignant melanoma (PMM), metastases of MM (MMM), \nbenign melanocytic naevi (BMN) and normal skin (NS) by immunohistochemistry and \nreverse transcript polymerase chain reaction (RT-PCR). BCC, SCC and NS expressed \nseveral CD44v, including v6, albeit in different distributions and intensities. \nPMM, MMM and BMN expressed isoforms containing v7/8 and v10, but failed to \nexpress epitopes encoded by v5 or v6. Thus, different CD44 isoforms are found in \nhuman skin cancers and are modulated during carcinogenesis. However, we did not \nobserve a correlation of CD44v6 expression with metastatic potential.", "CD44, a cell adhesion molecule, has been implicated in tumor invasion and \nmetastasis in certain malignancies. We studied the expression of CD44 standard \n(CD44s) and variant isoforms (CD44v) in 98 non-small cell lung carcinomas \n(NSCLCs) by immunohistochemistry and correlated the observations with clinical \noutcome. Formalin-fixed, paraffin-embedded archival tissues from 49 squamous \ncell carcinomas (SCCs) and 49 adenocarcinomas (ACs) were immunostained after \nmicrowave irradiation with monoclonal antibodies against CD44s and CD44v3, v4/5, \nv6, v7/8, and v10, and the results were correlated with histological tumor type, \ntumor stage, recurrence, and survival rates. SCCs of the lung showed strong \nmembranous expression of each of the CD44s, v3, v4/5, v6, and v10 proteins in \ncomparison with ACs (P < .0001). Staining for CD44 v4/5 was overwhelmingly \npositive in SCCs (72%) as compared with ACs (2.2%). Intense immunoreactivity for \nCD44v6 was present in 19 of 20 (95%) metastatic lung carcinomas. The bronchiolar \nbasal cells and alveolar pneumocytes were positive for CD44s, v3, and v6. CD44s \nand variant isoform expression did not correlate with tumor stage, recurrence, \nand survival rates. In conclusion, there is significant immunopositivity of \nCD44s and variant isoforms in SCCs over ACs of the lung. Expression of CD44v6 \nmay suggest an increased risk for local lymph node metastasis in NSCLCs. \nCD44v4/5 reactivity may be useful to discriminate squamoid differentiation in \npoorly differentiated NSCLCs.", "Since the CD44 variant 6(v6) molecule has been noted as a marker for tumor \nmetastasis and prognosis in several tumors, we examined whether or not v6 is a \nuseful marker for evaluating the prognosis of pancreatic cancer patients. In \naddition, we attempted to assess the clinicopathological implications for \npancreatic cancer of the variant 2 (v2) isoform using a recently developed \nmonoclonal antibody against a v2 epitope. The expression of CD44 variants was \nevaluated immunohistochemically in paraffin-embedded pancreatic cancer tissues \nfrom 42 patients who were confirmed surgically and histologically to have \nreceived curative resection. An indirect immunoperoxidase method was used with \nmonoclonal antibodies against epitopes of the standard (CD44s) portion, v6 and \nv2. Protein expression data were evaluated statistically for any correlations \nwith the length of survival or with histological parameters. The expression of \nCD44v6 and v2 was observed only in tumor cells, if at all. On the other hand, \nexpression of total CD44 (including CD44v, as well as CD44s) was observed in \nboth tumors and adjacent normal sites. Tumor tissue from 21 (50%) and 16 (38%) \npatients showed positive immunoreactivity with mAb 2F10 (anti-CD44v6) and mAb \nM23.6.1 (anti-CD44v2), respectively. The expression of CD44v6 and v2 was \ncorrelated with decreased overall survival (P = 0.0160 and P = 0.0125, \nrespectively). A significant correlation was obtained between CD44v2 peptide \nexpression and vessel invasion (P = 0.026). These results suggest that CD44v2 \nand CD44v6 may be useful markers for poor prognosis in curatively resected \nprimary pancreatic cancer.", "A number of different isoforms of CD44 generated by alternative splicing have \nbeen isolated and sequenced. There have been several reports that CD44v plays a \nrole in the steps of the metastatic process. We examined the role of the variant \nCD44v8-10 in metastases of human colon cancer cell line HT29m using a monoclonal \nantibody reactive with the v9 product (mAb 44-1V). Pretreatment with mAb 44-1V \nprevented the formation of liver metastases. In addition, we found that the \nattachment of HT29m cells to the basement membrane matrix was inhibited by mAb \n44-1V. Several reports have shown correlations between metastatic potential and \nexpression of CD44v in human colorectal cancer. We demonstrated that CD44v8-10 \nand CD44v6 RNA expression was higher in carcinomas associated with liver \nmetastases than in those without by Northern blotting. We analyzed the \nexpression of the CD44v8-10 product in colorectal cancer immunohistochemically \nusing mAb 44-1V, and evaluated its prognostic significance. There were \nsignificant correlations between CD 44v8-10 immunoreactivity and both lymph node \nand liver metastases. Patients with CD44v8-10-positive tumors had a greater \nrelative risk of death compared with those whose tumors were CD44v8-10 negative. \nThese results suggest that CD44v8-10 may play an important role in the adhesion \nof tumor cells to the capillaries of distant organs in the metastatic process, \nand that immunohistochemical detection of CD44v8-10 may be a biologic marker of \nprognostic significance.", "BACKGROUND: The CD44 variant (CD44v) isoforms have been noted as markers for \ntumour metastasis and prognosis in several adenocarcinomas.\nAIMS: To investigate whether CD44v, especially the CD44v2 (v2) isoform, may be a \nuseful prognostic factor for patients with oesophageal squamous cell carcinoma, \nusing a recently developed monoclonal antibody against a v2 epitope.\nPATIENTS: 233 patients (211 men and 22 women; mean age 61.9 years), with \noesophageal squamous cell carcinomas curatively removed without additional \ntreatment between 1987 and 1996 at the National Cancer Center Hospital, were \nanalysed for CD44v expression.\nMETHODS: The expression of CD44v was evaluated immunohistochemically using \nmonoclonal antibodies against epitopes of the standard and variant protein, in \nparaffin embedded oesophageal squamous cell carcinoma tissue from 233 patients \nwho had undergone cervical, mediastinal, and abdominal lymphadenectomy (three \nfield dissection) for oesophagectomy. The data were evaluated for any \ncorrelation with clinicopathological indices or prognosis.\nRESULTS: Although total CD44 and CD44v6 (v6) were respectively observed in 99% \nand 97% of the cancer specimens, the expression of v2 was only 30%. Patients \nwhose tumours were v2 positive had a significantly better prognosis than those \nwhose tumours were v2 negative (p = 0.031). Furthermore, in patients without \nlymph node metastasis, v2 positivity alone was a significant independent factor \nof prognosis (relative risk of death associated with v2 negativity, 4.7; p = \n0.037) in multivariate analysis.\nCONCLUSIONS: These results indicate that v2 is a useful marker for clinical \nprognosis in patients with oesophageal squamous cell carcinoma. Particularly in \npatients without lymph node metastasis, v2 status may thus have implications for \nthe use of adjuvant chemotherapy and/or radiotherapy in patients with \noesophageal cancer at an early stage.", "BACKGROUND AND OBJECTIVE: Recent studies have shown that expression of adhesion \nmolecules of the Ig superfamily, of integrins and of selectins allows definition \nof high vs low risk B-cell chronic lymphocytic leukemia (B-CLL). The \nproteoglycan CD44 is an adhesion molecule that may be expressed as a standard \nform of 85-95 KD or as several variant isoforms. The presence of certain CD44 \nvariant (v) isoforms on neoplastic cells indicates poor prognosis in epithelial \nand lymphoid malignancies, as it is associated with tumor progression and \nmetastasis.\nDESIGN AND METHODS: The expression of CD44 v3, 4, 5, 6, 7, 9 and 10 was analyzed \nin cells from 85 B-CLL patients. Indirect immunofluorescence and flow cytometry \nwere used to identify CD44v. Functional studies were performed by analysis of \nadhesion to hyaluronate (HA), one CD44 ligand, and HA-induced Ca2+ influx. A \nvariety of statistical methods were used to define phenotypic and functional \ndifferences between the various clones, to calculate survival curves, and for \nmultivariate analyses.\nRESULTS: In 17/85 B-CLL (20%), one or more CD44v were detectable by indirect \nimmunofluorescence, whereas in 68/85 cases (80%) this technique yielded negative \nresults. However, moAb \"mixes\" against CD44v and patching of surface molecules \non B-CLL cells have shown that all B-CLL clones express CD44v. This has been \nconfirmed by Western blot in a number of cases. Thus, two groups of patients \nwhose cells bear CD44v at high or low density, are distinguished. Functions of \nthe two clonotypes were investigated, namely their adhesion to a CD44 ligand and \nhyaluronate (HA), and effect on HA-induced Ca2+ influx. Cells expressing high \ndensity CD44v adhere to HA-coated substrates more efficiently than cells with \nlow density CD44v. In all clones, HA-signaling via CD44 yields Ca2+ influx. This \nindicates that CD44 mediates activatory signals following interaction with the \nligand.\nINTERPRETATION AND CONCLUSIONS: The clinical relevance of these findings has \nbeen ascertained. The 17/85 cases whose cells bore high density CD44v had \nsignificantly worse prognostic features than those of patients with low density \nCD44v, namely more advanced disease stage, LDT < 12 months and therapy \nrequirement. Moreover, the median survival in the former group of patients was < \n5 years as opposed to > 12 years in the latter. Therefore, analysis of CD44v \nexpression provides indications of biological and clinical relevance also in low \ngrade lymphoproliferative disorders.", "To evaluate their prognostic value, the expressions of CD44v and sialyl LeX \n(SLX) in colorectal cancers were studied immunohistochemically. Tissue specimens \nwere reacted with monoclonal antibodies (mAb) CD44-1V and CSLEX-1. Of the 145 \ncolorectal cancer patients undergoing curative resection, 59 (40.7%) were \npositive for mAb CD44-1V, and 40 (27.6%) were positive for mAb CSLEX-1. There \nwas a significant correlation between the combined expression of SLX and \nCD44v8-10 and lymph node metastasis. The patients with tumors negative for \nCD44v8-10 and SLX had the most favorable prognoses. Conversely, the patients \nwith tumors positive for both CD44v8-10 and SLX had a high recurrence rate and \nthe poorest prognoses. In a multivariate analysis using the Cox regression \nmodel, the combined expression of SLX and CD44v8-10 emerged as an independent \nprognostic indicator. These results suggested that the combined expression of \nCD44v8-10 and SLX may be a biologic marker of prognostic significance." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009362', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D011379', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018960', 'http://www.uniprot.org/uniprot/CD44_BOVIN']
5e2e1017fbd6abf43b000020	[ 10761920, 7904067, 29677476, 25591463, 26301869, 10882415, 2573519, 28382035, 1533274 ]	train	Are CD8+ (cytotoxic) T cells and CD4+ Helper T cells generated in the thyroid and express the T-cell receptor?	yesno	Through positive selection, double-positive cells in the thymus differentiate into CD4(+) or CD8(+) T single-positive cells that subsequently develop into different types of effective T cells, such as T-helper and cytotoxic T lymphocyte cells, These two cell types are derived from common precursors in the thymus.	no	[ "Signals elicited by binding of the T-cell antigen receptor and the CD4/CD8 \nco-receptor to major histocompatibility complex (MHC) molecules control the \ngeneration of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors \nthat initially express both co-receptor proteins. These precursors have unique, \nclonally distributed T-cell receptors with unpredictable specificity for the \nself-MHC molecules involved in this differentiation process. However, the mature \nT cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC \nclass I-binding) co-receptor that complements the MHC class-specificity of the \nT-cell receptor. How this matching of co-receptor-defined lineage and \nT-cell-receptor specificity is achieved remains unknown, as does whether \nsignalling by the T-cell receptors, co-receptors and/or general cell-fate \nregulators such as Notch-1 contributes to initial lineage choice, to subsequent \ndifferentiation processes or to both. Here we show that the CD4 versus CD8 \nlineage fate of immature thymocytes is controlled by the co-receptor-influenced \nduration of initial T-cell receptor-dependent signalling. Notch-1 does not \nappear to be essential for this fate determination, but it is selectively \nrequired for CD8+ T-cell maturation after commitment directed by T-cell \nreceptors. This indicates that the signals constraining CD4 versus CD8 lineage \ndecisions are distinct from those that support subsequent differentiation events \nsuch as silencing of co-receptor loci.", "The mechanism by which an initially uncommitted cell chooses between alternative \nfates is a central issue in developmental biology. In the mammalian thymus, CD4 \nhelper T cells and CD8 cytotoxic T cells arise from a common precursor that \nexpresses both CD4 and CD8. The choice between the CD4 and CD8 lineage is linked \nto the specificity of the T-cell antigen receptor expressed by a thymocyte, but \nwhether lineage commitment is stochastic or instructed has not been definitively \nresolved. We present evidence that expression of a constitutive CD8 transgene \nduring thymic selection permits development of mature CD4 cells bearing the \nclass I-restricted F5 T-cell antigen receptor. These results suggest that there \nis a stochastic component to the development of class I major histocompatibility \ncomplex-restricted T cells.", "A fundamental question in developmental immunology is how bipotential thymocyte \nprecursors generate both CD4+ helper and CD8+ cytotoxic T cell lineages. The MHC \nspecificity of αβ T cell receptors (TCRs) on precursors is closely correlated \nwith cell fate-determining processes, prompting studies to characterize how \nvariations in TCR signaling are linked with genetic programs establishing \nlineage-specific gene expression signatures, such as exclusive CD4 or CD8 \nexpression. The key transcription factors ThPOK and Runx3 have been identified \nas mediating development of helper and cytotoxic T cell lineages, respectively. \nTogether with increasing knowledge of epigenetic regulators, these findings have \nadvanced our understanding of the transcription factor network regulating the \nCD4/CD8 dichotomy. It has also become apparent that CD4+ T cells retain \ndevelopmental plasticity, allowing them to acquire cytotoxic activity in the \nperiphery. Despite such advances, further studies are necessary to identify the \nmolecular links between TCR signaling and the nuclear machinery regulating \nexpression of ThPOK and Runx3.", "During blood cell development, hematopoietic stem cells generate diverse mature \npopulations via several rounds of binary fate decisions. At each bifurcation, \nprecursors adopt one fate and inactivate the alternative fate either \nstochastically or in response to extrinsic stimuli and stably maintain the \nselected fates. Studying of these processes would contribute to better \nunderstanding of etiology of immunodeficiency and leukemia, which are caused by \nabnormal gene regulation during the development of hematopoietic cells. The \nCD4(+) helper versus CD8(+) cytotoxic T-cell fate decision serves as an \nexcellent model to study binary fate decision processes. These two cell types \nare derived from common precursors in the thymus. Positive selection of their \nTCRs by self-peptide presented on either MHC class I or class II triggers their \nfate decisions along with mutually exclusive retention and silencing of two \ncoreceptors, CD4 and CD8. In the past few decades, extensive effort has been \nmade to understand the T-cell fate decision processes by studying regulation of \ngenes encoding the coreceptors and selection processes. These studies have \nidentified several key transcription factors and gene regulatory networks. In \nthis chapter, I will discuss recent advances in our understanding of the binary \ncell fate decision processes of T cells.", "Through positive selection, double-positive cells in the thymus differentiate \ninto CD4(+) or CD8(+) T single-positive cells that subsequently develop into \ndifferent types of effective T cells, such as T-helper and cytotoxic T \nlymphocyte cells, that play distinctive roles in the immune system. Development, \ndifferentiation, and function of thymocytes and CD4(+) and CD8(+) T cells are \ncontrolled by a multitude of secreted and intracellular factors, ranging from \ncytokine signaling modules to transcription factors and epigenetic modifiers. \nMembers of the E26 transformation specific (Ets) family of transcription \nfactors, in particular, are potent regulators of these CD4(+) or CD8(+) T-cell \nprocesses. In this review, we summarize and discuss the functions and underlying \nmechanisms of the Ets family members that have been characterized as involved in \nthese processes. Ongoing research of these factors is expected to identify \npractical applications for the Ets family members as novel therapeutic targets \nfor inflammation-related diseases.", "CD4(+) T cells are generally specialized to function as helper cells and CD8(+) \nT cells are generally specialized to function as cytotoxic effector cells. To \nexplain how such concordance is achieved between co-receptor expression and \nimmune function, we considered two possibilities. In one case, immature \nCD4(+)CD8(+) thymocyte precursors might first down-regulate expression of one \nco-receptor molecule, with the remaining co-receptor molecule subsequently \nactivating the appropriate helper or cytotoxic functional program. \nAlternatively, we considered that the same intrathymic signals that selectively \nextinguished expression of one or the other co-receptor molecule might \nsimultaneously initiate the appropriate helper or cytotoxic functional program. \nIn the present study, we attempted to distinguish between these alternatives by \nexamining thymocyte precursors of CD8(+) T cells for expression of Cathepsin C \nand Cathepsin W, molecules important for cytotoxic effector function. We report \nin developing thymocytes that Cathepsin C and Cathepsin W are expressed \ncoordinately with extinction of CD4 co-receptor expression. We conclude that CD4 \nextinction and initiation of the cytotoxic functional program occurs \nsimultaneously during differentiation of CD8(+) T cells in the thymus.", "Individual T cell populations are characterized by specific surface proteins, \nnamely by the T cell receptor complex (TCR) and by two accessory molecules, CD8 \n(Lyt2) and CD4 (L3T4). CD8 and CD4 are required for T cell interactions with \nclass I or class II major histocompatibility complex molecules. In the thymus, \nimmature CD8(-4)-TCR- cells differentiate, possibly via a short stage of CD8+4- \nthymocytes, into CD8+4+ TCR+ T cells and mature further into the main T cell \npopulations, the CD8+4- TCR+ cytotoxic T lymphocytes and the CD4+8- TCR+ T \nhelper cells. In order to analyse the differentiation steps involving CD8, we \ngenerated transgenic mice expressing mu heavy chain genes from an anti-Lyt2.2 \nhybridoma. Transgenic lines expressing either the complete (mu sm) or only the \nsecreted mu protein (mu s) suffer from a severe depletion of their CD8+4+ \nthymocytes affecting also the mature CD8+4- and CD4+8- populations. The \ndepletion is correlated to the expression of transgenic mu-chain proteins within \nthymocytes. This intrathymocyte expression of the mu chain prevents CD8-4- \nthymocytes from further differentiation, most probably via intracellular \ninteractions between mu heavy chain and CD8 proteins. These results show that \nCD8 plays an important role during thymocyte maturation.", "The adaptive immune system is dependent on functionally distinct lineages of T \ncell antigen receptor αβ-expressing T cells that differentiate from a common \nprogenitor in the thymus. CD4+CD8+ progenitor thymocytes undergo selection \nfollowing interaction with MHC class I and class II molecules bearing peptide \nself-antigens, giving rise to CD8+ cytotoxic and CD4+ helper or regulatory T \ncell lineages, respectively. The strict correspondence of CD4 and CD8 expression \nwith distinct cellular phenotypes has made their genes useful surrogates for \ninvestigating molecular mechanisms of lineage commitment. Studies of Cd4 and Cd8 \ntranscriptional regulation have uncovered cis-regulatory elements that are \ncritical for mediating epigenetic modifications at distinct stages of \ndevelopment to establish heritable transcriptional programs. In this review, we \nexamine the epigenetic mechanisms involved in Cd4 and Cd8 gene regulation during \nT cell lineage specification and highlight the features that make this an \nattractive system for uncovering molecular mechanisms of heritability.", "Mature T cells express either CD4 or CD8 on their surface. Most helper T cells \nexpress CD4, which binds to class II major histocompatibility complex (MHC) \nproteins, and most cytotoxic T cells express CD8, which binds to class I MHC \nproteins. In the thymus, mature CD4+CD8- and CD4-CD8+ T cells expressing alpha \nbeta T-cell antigen receptors (TCR) develop from immature thymocytes through \nCD4+CD8+ alpha beta TCR+ intermediates. Experiments using mice transgenic for \nalpha beta TCR suggest that the specificity of the TCR determines the CD4/CD8 \nphenotype of mature T cells. These results, however, do not indicate how a T \ncell differentiates into the CD4 or CD8 lineage. Here we show that the CD4 \ntransmembrane region and/or cytoplasmic tail mediates the delivery of a specific \nsignal that directs differentiation of T cells to a CD4 lineage. We generated \ntransgenic mice expressing a hybrid molecule composed of the CD8 alpha \nextracellular domains linked to the CD4 transmembrane region and cytoplasmic \ntail. We predicted that this hybrid molecule would bind to class I MHC proteins \nthrough the extracellular domains but deliver the intracellular signals \ncharacteristic of CD4. By crossing our transgenic mice with mice expressing a \ntransgenic alpha beta TCR specific for a particular antigen plus class I MHC \nprotein, we were able to express the hybrid molecule in developing thymocytes \nexpressing the class I MHC-restricted TCR. Our results show that the signal \ntransduced by the hybrid molecule results in the differentiation of immature \nthymocytes expressing a class I-restricted TCR into mature T cells expressing \nCD4." ]	nan
56a375f8496b62f23f000002	[ 21465478, 23390377, 21811597, 16140943, 16140944, 17962299, 12191639, 24657531 ]	train	Are CTCF and BORIS involved in genome regulation and cancer?	yesno	Yes. CTCF is ubiquitously expressed and plays diverse roles in gene regulation, imprinting, insulation, intra/interchromosomal interactions, nuclear compartmentalisation, and alternative splicing. CTCF has a single paralogue, the testes-specific CTCF-like gene (CTCFL)/BORIS. CTCF and BORIS can be deregulated in cancer. The tumour suppressor gene CTCF can be mutated or deleted in cancer, or CTCF DNA binding can be altered by epigenetic changes. BORIS is aberrantly expressed frequently in cancer, leading some to propose a pro-tumourigenic role for BORIS. However, BORIS can inhibit cell proliferation, and is mutated in cancer similarly to CTCF suggesting BORIS activation in cancer may be due to global genetic or epigenetic changes typical of malignant transformation.	yes	[ "CTCF is an evolutionary conserved and ubiquitously expressed protein that binds \nthousands of sites in the human genome. Ectopic expression of CTCF in various \nnormal and tumoral human cell lines inhibits cell division and clonogenicity, \nwith the consequence to consider CTCF a potential tumor-suppressor factor. In \nthis review article, we focused on the molecular mechanisms engaged by CTCF to \nmodulate the expression of several key-regulators of differentiation, cellular \nsenescence, cell cycle control and progression, whose expression is frequently \naltered in tumors. Moreover, we discussed common features of CTCF at each \ntumor-related DNA-binding sequence, such as protein-partners, post-translational \nmodifications, and distinctive epigenetic marks establishment. The investigation \nof the molecular mechanisms engaged by CTCF to modulate tumor-related genes \nemphasizes the cell-type dependency of its tumor suppressor role. Indeed, the \nability of CTCF to bind their promoters strictly depends by cell-type features \nas DNA methylation, BORIS-binding and post-translational modifications as \nPARYlation.", "Cancer germline (CG) genes are normally expressed in germ cells and aberrantly \nexpressed in a variety of cancers; their immunogenicity has led to the \nwidespread development of cancer vaccines targeting these antigens. BORIS/CTCFL \nis an autosomal CG antigen and promising cancer vaccine target. BORIS is the \nonly known paralog of CTCF, a gene intimately involved in genomic imprinting, \nchromatin insulation, and nuclear regulation. We have previously shown that \nBORIS is expressed in epithelial ovarian cancer (EOC) and that its expression \ncoincides with promoter and global DNA hypomethylation. Recently, 23 different \nBORIS mRNA variants have been described, and have been functionally grouped into \nsix BORIS isoform families (sf1-sf6). In the present study, we have \ncharacterized the expression of BORIS isoform families in normal ovary (NO) and \nEOC, the latter of which were selected to include two groups with widely varying \nglobal DNA methylation status. We find selective expression of BORIS isoform \nfamilies in NO, which becomes altered in EOC, primarily by the activation of \nBORIS sf1 in EOC. When comparing EOC samples based on methylation status, we \nfind that BORIS sf1 and sf2 isoform families are selectively activated in \nglobally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and \nthe ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is \nelevated in hypomethylated tumors. Finally, the expression of all BORIS isoform \nfamilies was induced to varying extents by epigenetic modulatory drugs in EOC \ncell lines, particularly when DNMT and HDAC inhibitors were used in combination.", "BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a \nubiquitously expressed DNA-binding protein with diverse roles in gene expression \nand chromatin organisation. BORIS and CTCF have virtually identical zinc finger \ndomains, yet display major differences in their respective C- and N-terminal \nregions. Unlike CTCF, BORIS expression has been reported only in the testis and \ncertain malignancies, leading to its classification as a \"cancer-testis\" \nantigen. However, the expression pattern of BORIS is both a significant and \nunresolved question in the field of DNA binding proteins. Here, we identify \nBORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. \nWe compare the localization of CTCF and BORIS in the nucleus and demonstrate \nenrichment of BORIS within the nucleolus, inside the nucleolin core structure \nand adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF \nis not enriched in the nucleolus. Live imaging of cells transiently transfected \nwith GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS \ntranscript levels are low compared to CTCF, its protein levels are readily \ndetectable. These findings show that BORIS expression is more widespread than \npreviously believed, and suggest a role for BORIS in nucleolar function.", "Brother of the Regulator of Imprinted Sites (BORIS) is a mammalian CTCF paralog \nwith the same central 11Zn fingers (11ZF) that mediate specific interactions \nwith varying approximately 50-bp target sites. Regulated in vivo occupancy of \nsuch sites may yield structurally and functionally distinct CTCF/DNA complexes \ninvolved in various aspects of gene regulation, including epigenetic control of \ngene imprinting and X chromosome inactivation. The latter functions are mediated \nby meCpG-sensitive 11ZF binding. Because CTCF is normally present in all somatic \ncells, whereas BORIS is active only in CTCF- and 5-methylcytosine-deficient \nadult male germ cells, switching DNA occupancy from CTCF to BORIS was suggested \nto regulate site specificity and timing of epigenetic reprogramming. In addition \nto 11ZF-binding paternal imprinting control regions, cancer-testis gene \npromoters also undergo remethylation during CTCF/BORIS switching in germ cells. \nOnly promoters of cancer testis genes are normally silenced in all somatic cells \nbut activated during spermatogenesis when demethylated in BORIS-positive germ \ncells and are found aberrantly derepressed in various tumors. We show here that \nBORIS is also expressed in multiple cancers and is thus itself a cancer-testis \ngene and that conditional expression of BORIS in normal fibroblasts activates \ncancer-testis genes selectively. We tested if replacement of CTCF by BORIS on \nregulatory DNA occurs in vivo on activation of a prototype cancer-testis gene, \nMAGE-A1. Transition from a hypermethylated/silenced to a \nhypomethylated/activated status induced in normal cells by \n5-aza-2'-deoxycytidine (5-azadC) was mimicked by conditional input of BORIS and \nis associated with complete switching from CTCF to BORIS occupancy at a single \n11ZF target. This site manifested a novel type of CTCF/BORIS 11ZF binding \ninsensitive to CpG methylation. Whereas 5-azadC induction of BORIS takes only \nfew hours, derepression of MAGE-A1 occurred 1 to 2 days later, suggesting that \nBORIS mediates cancer-testis gene activation by 5-azadC. Indeed, infection of \nnormal fibroblasts with anti-BORIS short hairpin RNA retroviruses before \ntreatment with 5-azadC blocked reactivation of MAGE-A1. We suggest that BORIS is \nlikely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target \nsequences that mediate induction of cancer-testis genes.", "Regulatory sequences recognized by the unique pair of paralogous factors, CTCF \nand BORIS, have been implicated in epigenetic regulation of imprinting and X \nchromosome inactivation. Lung cancers exhibit genome-wide demethylation \nassociated with derepression of a specific class of genes encoding cancer-testis \n(CT) antigens such as NY-ESO-1. CT genes are normally expressed in \nBORIS-positive male germ cells deficient in CTCF and meCpG contents, but are \nstrictly silenced in somatic cells. The present study was undertaken to \nascertain if aberrant activation of BORIS contributes to derepression of \nNY-ESO-1 during pulmonary carcinogenesis. Preliminary experiments indicated that \nNY-ESO-1 expression coincided with derepression of BORIS in cultured lung cancer \ncells. Quantitative reverse transcription-PCR analysis revealed robust, \ncoincident induction of BORIS and NY-ESO-1 expression in lung cancer cells, but \nnot normal human bronchial epithelial cells following 5-aza-2'-deoxycytidine \n(5-azadC), Depsipeptide FK228 (DP), or sequential 5-azadC/DP exposure under \nclinically relevant conditions. Bisulfite sequencing, methylation-specific PCR, \nand chromatin immunoprecipitation (ChIP) experiments showed that induction of \nBORIS coincided with direct modulation of chromatin structure within a CpG \nisland in the 5'-flanking noncoding region of this gene. Cotransfection \nexperiments using promoter-reporter constructs confirmed that BORIS modulates \nNY-ESO-1 expression in lung cancer cells. Gel shift and ChIP experiments \nrevealed a novel CTCF/BORIS-binding site in the NY-ESO-1 promoter, which unlike \nsuch sites in the H19-imprinting control region and X chromosome, is insensitive \nto CpG methylation in vitro. In vivo occupancy of this site by CTCF was \nassociated with silencing of the NY-ESO-1 promoter, whereas switching from CTCF \nto BORIS occupancy coincided with derepression of NY-ESO-1. Collectively, these \ndata indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter \nmediates epigenetic regulation of this CT gene in lung cancer cells, and suggest \nthat induction of BORIS may be a novel strategy to augment immunogenicity of \npulmonary carcinomas.", "BORIS, like other members of the 'cancer/testis antigen' family, is normally \nexpressed in testicular germ cells and repressed in somatic cells, but is \naberrantly activated in cancers. To understand regulatory mechanisms governing \nhuman BORIS expression, we characterized its 5'-flanking region. Using 5' RACE, \nwe identified three promoters, designated A, B and C, corresponding to \ntranscription start sites at -1447, -899 and -658 bp upstream of the first ATG. \nAlternative promoter usage generated at least five alternatively spliced BORIS \nmRNAs with different half-lives determined by varying 5'-UTRs. In normal testis, \nBORIS is transcribed from all three promoters, but 84% of the 30 cancer cell \nlines tested used only promoter(s) A and/or C while the others utilized \nprimarily promoters B and C. The differences in promoter usage between normal \nand cancer cells suggested that they were subject to differential regulation. We \nfound that DNA methylation and functional p53 contributes to the negative \nregulation of each promoter. Moreover, reduction of CTCF in normally \nBORIS-negative human fibroblasts resulted in derepression of BORIS promoters. \nThese results provide a mechanistic basis for understanding cancer-related \nassociations between haploinsufficiency of CTCF and BORIS derepression, and \nbetween the lack of functional p53 and aberrant activation of BORIS.", "CTCF is a ubiquitous 11 zinc finger (ZF) protein with highly versatile \nfunctions: in addition to transcriptional silencing or activating in a \ncontext-dependent fashion, it organizes epigenetically controlled chromatin \ninsulators that regulate imprinted genes in soma. Recently, we have identified a \nCTCF paralogue, termed BORIS for Brother of the Regulator of Imprinted Sites, \nthat is expressed only in the testis. BORIS has the same exons encoding the 11 \nZF domain as mammalian CTCF genes, and hence interacts with similar cis \nelements, but encodes amino and carboxy termini distinct from those in CTCF. \nNormally, CTCF and BORIS are expressed in a mutually exclusive pattern that \ncorrelates with re-setting of methylation marks during male germ cell \ndifferentiation. The antagonistic features of these two gene siblings are \nunderscored by showing that while CTCF overexpression blocks cell proliferation, \nexpression of BORIS in normally BORIS-negative cells promotes cell growth which \ncan lead to transformation. The suggestion that BORIS directs epigenetic \nreprogramming at CTCF target sites impinges on the observations that human BORIS \nis not only abnormally activated in a wide range of human cancers, but also maps \nto the cancer-associated amplification region at 20q13. The sibling rivalry \noccasioned by aberrant expression of BORIS in cancer may interfere with normal \nfunctions of CTCF including growth suppression, and contribute to epigenetic \ndysregulation which is a common feature in human cancer.", "CTCF plays a vital role in chromatin structure and function. CTCF is \nubiquitously expressed and plays diverse roles in gene regulation, imprinting, \ninsulation, intra/interchromosomal interactions, nuclear compartmentalisation, \nand alternative splicing. CTCF has a single paralogue, the testes-specific \nCTCF-like gene (CTCFL)/BORIS. CTCF and BORIS can be deregulated in cancer. The \ntumour suppressor gene CTCF can be mutated or deleted in cancer, or CTCF DNA \nbinding can be altered by epigenetic changes. BORIS is aberrantly expressed \nfrequently in cancer, leading some to propose a pro-tumourigenic role for BORIS. \nHowever, BORIS can inhibit cell proliferation, and is mutated in cancer \nsimilarly to CTCF suggesting BORIS activation in cancer may be due to global \ngenetic or epigenetic changes typical of malignant transformation." ]	nan
5e338cf5fbd6abf43b00005d	[ 16506213, 20569256, 28230825, 29531473, 29787442, 26695891, 19956182, 23691737 ]	train	Are Chernobyl survivors at increased risk for breast cancer?	yesno	Yes, Chernobyl survivors are at increased risk for breast cancer.	yes	[ "An increase in breast cancer incidence has been reported in areas of Belarus and \nUkraine contaminated by the Chernobyl accident and has become an issue of public \nconcern. The authors carried out an ecological epidemiological study to describe \nthe spatial and temporal trends in breast cancer incidence in the most \ncontaminated regions of Belarus and Ukraine, and to evaluate whether increases \nseen since 1986 correlate to radiation exposure from the Chernobyl accident. The \nauthors investigated the trends through age-cohort-period-region analyses of \ndistrict-specific incidence rates of breast cancer for Gomel and Mogilev regions \nof Belarus and Chernigiv, Kyiv and Zhytomir regions of Ukraine. Dose-response \nanalyses were based on Poisson regression, using average district-specific whole \nbody doses accumulated since the accident from external exposure and ingestion \nof long-lived radionuclides. The study demonstrated increases in breast cancer \nincidence in all areas following the Chernobyl accident, reflecting improvements \nin cancer diagnosis and registration. In addition, a significant 2-fold increase \nin risk was observed, during the period 1997-2001, in the most contaminated \ndistricts (average cumulative dose of 40.0 mSv or more) compared with the least \ncontaminated districts (relative risk [RR] in Belarus 2.24, 95% confidence \ninterval [CI] 1.51-3.32 and in Ukraine 1.78, 95% CI=1.08-2.93). The increase, \nthough based on a relatively small number of cases, appeared approximately 10 \nyears after the accident, was highest among women who were younger at the time \nof exposure and was observed for both localised and metastatic diseases. It is \nunlikely that this excess could be entirely due to the increased diagnostic \nactivity in these areas.", "Breast cancer and ovarian cancer are common malignancies in Belarus accounting \nfor about 3500 and 800 new cases per year, respectively. For breast cancer, the \nrates and age of onset appear to vary significantly in regions differentially \naffected by the Chernobyl accident. We assessed the frequency and distribution \nof three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two \nhospital-based series of 1945 unselected breast cancer patients and of 201 \nunselected ovarian cancer patients from Belarus as well as in 1019 healthy \ncontrol females from the same population. Any of these mutations were identified \nin 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and \n0.5% of the controls. In the breast cancer patients, BRCA1 mutations were \nstrongly associated with earlier age at diagnosis, with oestrogen receptor (ER) \nnegative tumours and with a first-degree family history of breast cancer, \nalthough only 35% of the identified BRCA1 mutation carriers had such a family \nhistory. There were no marked differences in the regional distribution of BRCA1 \nmutations, so that the significant differences in age at diagnosis and family \nhistory of breast cancer patients from areas afflicted by the Chernobyl accident \ncould not be explained by BRCA1. We next observed a higher impact and a shifted \nmutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer \npatients where the three founder mutations accounted for 26.4% (53/201). While \nthe Cys61Gly mutation appeared underrepresented in ovarian cancer as compared \nwith breast cancer cases from the same population (p = 0.01), the 4153delA \nmutation made a higher contribution to ovarian cancer than to breast cancer (p < \n0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases \nwith a first-degree family history of breast or ovarian cancer, whereas the \nmedian age at ovarian cancer diagnosis was not different between mutation \ncarriers and non-carriers. Taken together, these results identify three BRCA1 \nfounder mutations as key components of inherited breast and ovarian cancer \nsusceptibility in Belarus and might have implications for cancer prevention, \ntreatment and genetic counselling in this population.", "During the past three decades, the deleterious consequences of Chornobyl \naccident including carcinogenic effects in the people who were accidentally \nexposed to radiation have been intensively studied. In particular, recent \nstudies provided increased knowledge of the molecular pathogenesis of thyroid \ntumors in children exposed to Chornobyl fallout. The risk of several forms of \nleukemia including myelodysplastic syndromes is elevated in Chornobyl \nliquidators. Furthermore, the upward trends of increases in a variety of other \ntumors including breast cancer, cancers of central nervous system and renal \ncancer have been reported in the persons exposed to Chornobyl fallout. There is \ngrowing evidence that insufficient apoptosis allows irradiated cells to survive \nand thereby contributes to carcinogenesis. The purpose of the present survey is \nto summarize the recent findings related to apoptotic biomarkers among cancer \npatients from the different populations affected by the Chornobyl catastrophe. \nAmong the particularly radiosensitive cancer sites, we focused on thyroid cancer \nand leukemia. Several genes and/or proteins controlling apoptosis directly or \nindirectly have been incorporated into the analysis. The data reviewed here \nprovide a mechanistic link between the apoptosis alterations and development of \nradiation-related cancer in the 30-year post-Chornobyl period. We suggest that \nthe type of mutations arising from misrepair of DNA double strand breaks (gene \nfusion and amplification) is the initial signature event in radiation-induced \nthyroid cancer. Much work has to be done over the next years to elucidate \ncentral questions related to the nature of human radiation carcinogenesis. This \narticle is part of a Special Issue entitled \"The Chornobyl Nuclear Accident: \nThirty Years After\".", "BACKGROUND: The study aims to evaluate the current state and tendencies in \nmultiple primary breast cancer incidence, behavior, and treatment in Ukraine.\nMETHODS: A total of 2032 patients who received special treatment at the \nDepartment of Breast Tumors and Reconstructive Surgery of the National Cancer \nInstitute from 2008 to 2015 were included in the study. Among them, there were \n195 patients with multiple primary malignant neoplasms: 54.9% patients with \nsynchronous cancer and 45.1% patients with metachronous cancer. The average age \nof patients was 46.6 years, and the percentage of postmenopausal women was \n63.1%. Among patients with synchronous cancer, there were 56.1% patients with \nonly breast localizations and 43.9% with combination of breast and other \nlocalizations, and among patients with metachronous cancer, there were 46.6% \npatients with only breast localizations and 53.4% with combination of breast and \nother localizations. All the patients were evaluated in terms of aggressiveness \nof the disease, survival rates, as well as risk factors and treatment options.\nRESULTS: A more aggressive course of breast cancer is observed in patients \nexposed to radiation from the Chernobyl accident under the age of 30 years \n(P < .01). The clinical course of disease in patients with synchronous cancer is \nworse and prognostically unfavorable compared with metachronous cancer \n(P < .01). The course of the disease in patients who underwent mastectomy is \nworse compared with patients who underwent breast-conserving surgery (P < .01). \nPlastic and reconstructive surgery in patients with synchronous cancer was \nproven to be reasonable in terms of increase in survival (P < .01).\nCONCLUSIONS: The patients with multiple primary breast cancer should have \nattentive management and treatment. Multidisciplinary team should concern all \nthe risk factors and provide the most sufficient option of management. This is \ncrucial to continue research in this oncological area.", "This article summarizes the results of 30 y of follow-up of cancer and noncancer \neffects in Ukrainian cleanup workers after the Chornobyl accident. The number of \npower plant employees and first responders with acute radiation syndrome under \nfollow-up by the National Research Center for Radiation Medicine decreased from \n179 in 1986-1991 to 105 in 2011-2015. Cancers and leukemia (19) and \ncardiovascular diseases (21) were the main causes of deaths among acute \nradiation syndrome survivors (54) during the postaccident period. Increased \nradiation risks of leukemia in the Ukrainian cohort of 110,645 cleanup workers \nexposed to low doses are comparable to those among survivors of the atomic bomb \nexplosions in Japan in 1945. Additionally, an excess of chronic lymphocytic \nleukemia was demonstrated in the cleanup workers cohort for 26 y after the \nexposure. A significant excess of multiple myeloma incidence [standardized \nincidence rate (SIR) 1.61 %, 95% confidence interval (CI) 1.01-2.21], thyroid \ncancer (SIR 4.18, 95% CI 3.76-4.59), female breast cancer (SIR 1.57 CI \n1.40-1.73), and all cancers combined (SIR 1.07; 95% CI 1.05-1.09) was \nregistered. High prevalence was demonstrated for cardio- and cerebrovascular \ndiseases and mental health changes. However, the reasons for the increases \nrequire further investigation. To monitor other possible late effects of \nradiation exposure in Chornobyl cleanup workers, analytical cohort and \ncase-control studies need to include cardiovascular pathology, specifically \ntypes of potentially radiogenic cancers using a molecular epidemiology approach. \nPossible effects for further study include increased rates of thyroid, breast, \nand lung cancers and multiple myeloma; reduction of radiation risks of leukemia \nto population levels; and increased morbidity and mortality of cleanup workers \nfrom cardio- and cerebrovascular pathology.", "Publisher: Shchorichnyy zvit vidobrazhuie osnovni rezul'taty diial'nosti \nDerzhavnoI ustanovy „Natsional'nyy naukovyy tsentr radiatsiynoI medytsyny \nNatsional'noI akademiI medychnykh nauk UkraIny ” (NNTsRM) z medychnykh problem \nChorno byl's'koI katastrofy, radiatsiynoI medytsyny, radiobiologiI, radiatsiynoI \ngigiieny ta epidemiologiI, spivpratsi z VOOZ v merezhi medychnoI gotovnosti ta \ndopomogy pry radiatsiynykh avariiakh u 2014 r.Epidemiologichnymy kogortnymy \ndoslidzhenniamy vstanovleno zrostannia zakhvoriuvanosti (1990–2012 rr.) na rak \nshchytopodibnoI zalozy u postrazhdalykh vnaslidok avariI na ChAES (ULNA – u 4,6 \nraza, evakuyovanykh – u 4,0 ra zy, meshkantsiv zabrudnenykh terytoriy – u 1,3 \nraza) ta zrostannia chastoty raku molochnoI zalozy u zhinok ULNA 1986–1987 rr. \n(u 1994–2012 rr. SIR = 160,0%, 95% DI: 142,4–177,6). Spil'no z Natsional'nym \ninstytutom raku CShA prodovzheno retrospektyvne doslidzhennia raku \nshchytopodibnoI zalozy „vypadok kontrol' ” v kogorti 152 tys. likvidatoriv. \nVstanovleno radiatsiyni ryzyky miielomnoI khvoroby ta khronichnoI limfotsytarnoI \nleykemiI.Molekuliarni efekty viddalenogo periodu pislia oprominennia vkliuchaly \nzminy ekspresiI geniv TERF1, TERF2, CCND1, dovzhyny telomer, ekspresiI bilka \ncyclin D1, gistonu gamma H2AX. Vyznacheno asotsiatsiiu molekuliarnykh zmin z \nkognityvnym defitsytom. Vyvcheno genetychni polimorfizmy rs2981582 gena FGFR2, \nrs12443621 gena TNRC9, rs3817198 gena LSP1, rs3803662 gena TNRC9 i rs889312 gena \nMAP3K1 ta Ikh asotsiatsiiu z rakom molochnoI zalozy; ekspresiiu klitynamy \npukhlyny retseptoriv estrogenu ta progesteronu, antygeniv c kit, tsytokeratynu \n5/6, TP53 ta ki67, amplifikatsiynyy status gena Her2/neu, mutatsiynyy status \ngeniv BRCA1 (mutatsiI 185delAG ta 5382insC) i BRCA2 (mutatsiia 6174delT). \nDovedeno mozhlyvist' persystentsiI radiatsiyno modyfikovanoI prykhovanoI \nkhromosom noI nestabil'nosti u poslidovnykh generatsiiakh somatychnykh klityn \nliudyny.U naselennia vyvcheno stan reproduktyvnoI funktsiI, osoblyvosti \ndytiachogo kharchuvannia na radioaktyvno zabrud nenykh terytoriiakh. V ramkakh \nvykonannia Zagal'noderzhavnoI sotsial'noI programy polipshennia stanu bezpeky, \ngigiieny pratsi ta vyrobnychogo seredovyshcha na 2014–2018 roky vpershe v \nUkraIni rozrobleno y uspishno vykonano interkalibruvannia dlia 18 laboratoriy \nindyvidual'nogo dozymetrychnogo kontroliu. Rozpochato doslidzhennia efektiv \nmedychnogo oprominennia u interventsiynykh kardiologiv.Eksperymental'ni \ndoslidzhennia stosuvalysia vplyvu radiomodyfikatoriv na klitynni systemy.V zviti \ntakozh vidobrazheno rezul'taty naukovo organizatsiynoI, likuval'no \nprofilaktychnoI roboty, pidgotovky kadriv ta vprovadzhennia.Zvit NNTsRM \nzatverdzheno na zasidanni NaukovoI rady NAMN UkraIny 17.03.2015 r.", "Radiation is a carcinogen, interacting with DNA to produce a range of mutations. \nIrradiated cells also show genomic instability, as do adjacent non-irradiated \ncells (the bystander effect); the importance to carcinogenesis remains to be \nestablished. Current knowledge of radiation effects is largely dependent on \nevidence from exposure to atomic bomb whole body radiation, leading to increases \nin a wide range of malignancies. In contrast, millions of people were exposed to \nradioactive isotopes in the fallout from the Chernobyl accident, within the \nfirst 20 years there was a large increase in thyroid carcinoma incidence and a \npossible radiation-related increase in breast cancer, but as yet there is no \ngeneral increase in malignancies. The increase in thyroid carcinoma, \nattributable to the very large amounts of iodine 131 released, was first noticed \nin children with a strong relationship between young age at exposure and risk of \ndeveloping papillary thyroid carcinoma (PTC). The extent of the increase, the \nreasons for the relationship to age at exposure, the reduction in attributable \nfraction with increasing latency and the role of environmental factors are \ndiscussed. The large number of radiation-induced PTCs has allowed new \nobservations. The subtype and molecular findings change with latency; most early \ncases were solid PTCs with RET-PTC3 rearrangements, later cases were classical \nPTCs with RET-PTC1 rearrangements. Small numbers of many other RET \nrearrangements have occurred in 'Chernobyl' PTCs, and also rearrangement of \nBRAF. Five of the N-terminal genes found in papillary carcinoma rearrangements \nare also involved in rearrangements in hematological malignancies; three are \nputative tumor suppressor genes, and two are further genes fused to RET in PTCs. \nRadiation causes double-strand breaks; the rearrangements common in these \nradiation-induced tumors reflect their etiology. It is suggested that oncogenic \nrearrangements may commonly involve both a tumor-suppressor gene (or a DNA \nrepair gene) as well as an oncogene. Involvement of two relevant genes would \ngive a greater chance of progression and a shorter latency than a single-gene \nmutation. More information is needed on germline mutations conferring \nsusceptibility to radiation-induced PTCs, particularly DNA repair genes. The \nradiation exposure to the fallout after Chernobyl was very different from the \nwhole body radiation after the atomic bombs. The type and molecular pathology of \nthe thyroid tumors is changing with increasing latency, long latency tumors in \nother organs could occur in the future. A comprehensive follow up must continue \nfor the lifetime of those exposed.", "The lessons learned from the Chernobyl disaster have become increasingly \nimportant after the second anniversary of the Fukushima, Japan nuclear accident. \nHistorically, data from the Chernobyl reactor accident 27 years ago demonstrated \na strong correlation with thyroid cancer, but data on the radiation effects of \nChernobyl on breast cancer incidence have remained inconclusive. We reviewed the \npublished literature on the effects of the Chernobyl disaster on breast cancer \nincidence, using Medline and Scopus from the time of the accident to December of \n2010. Our findings indicate limited data and statistical flaws. Other \nconfounding factors, such as discrepancies in data collection, make \ninterpretation of the results from the published literature difficult. \nRe-analyzing the data reveals that the incidence of breast cancer in \nChernobyl-disaster-exposed women could be higher than previously thought. We \nhave learned little of the consequences of radiation exposure at Chernobyl \nexcept for its effects on thyroid cancer incidence. Marking the 27th year after \nthe Chernobyl event, this report sheds light on a specific, crucial and \nunderstudied aspect of the results of radiation from a gruesome nuclear power \nplant disaster." ]	nan
5a6e18d8b750ff4455000038	[ 28417603, 28637293 ]	train	Are Conserved Nonexonic Elements (CNEEs) important in phylogenomics research?	yesno	Yes. Conserved Nonexonic Elements (CNEEs) appear to be promising as phylogenomic markers, yielding phylogenetic resolution as high as for UCEs and introns but with fewer gaps, less ambiguity in alignments and with patterns of nucleotide substitution more consistent with the assumptions of commonly used methods of phylogenetic analysis.	yes	[ "The identification of conserved loci across genomes, along with advances in \ntarget capture methods and high-throughput sequencing, has helped spur a \nphylogenomics revolution by enabling researchers to gather large numbers of \nhomologous loci across clades of interest with minimal upfront investment in \nlocus design. Target capture for vertebrate animals is currently dominated by \ntwo approaches-anchored hybrid enrichment (AHE) and ultraconserved elements \n(UCE)-and both approaches have proven useful for addressing questions in \nphylogenomics, phylogeography and population genomics. However, these two sets \nof loci have minimal overlap with each other; moreover, they do not include many \ntraditional loci that that have been used for phylogenetics. Here, we combine \nacross UCE, AHE and traditional phylogenetic gene locus sets to generate the \nSquamate Conserved Loci set, a single integrated probe set that can generate \nhigh-quality and highly complete data across all three loci types. We use these \nprobes to generate data for 44 phylogenetically disparate taxa that collectively \nspan approximately 33% of terrestrial vertebrate diversity. Our results \ngenerated an average of 4.29 Mb across 4709 loci per individual, of which an \naverage of 2.99 Mb was sequenced to high enough coverage (≥10×) to use for \npopulation genetic analyses. We validate the utility of these loci for \nboth phylogenomic and population genomic questions, provide a comparison \namong these locus sets of their relative usefulness and suggest areas for future \nimprovement.", "Noncoding markers have a particular appeal as tools for phylogenomic analysis \nbecause, at least in vertebrates, they appear less subject to strong variation \nin GC content among lineages. Thus far, ultraconserved elements (UCEs) and \nintrons have been the most widely used noncoding markers. Here we analyze and \nstudy the evolutionary properties of a new type of noncoding marker, conserved \nnonexonic elements (CNEEs), which consists of noncoding elements that are \nestimated to evolve slower than the neutral rate across a set of species. \nAlthough they often include UCEs, CNEEs are distinct from UCEs because they are \nnot ultraconserved, and, most importantly, the core region alone is analyzed, \nrather than both the core and its flanking regions. Using a data set of 16 birds \nplus an alligator outgroup, and ∼3600-∼3800 loci per marker type, we found that \nalthough CNEEs were less variable than bioinformatically derived UCEs or introns \nand in some cases exhibited a slower approach to branch resolution as determined \nby phylogenomic subsampling, the quality of CNEE alignments was superior to \nthose of the other markers, with fewer gaps and missing species. Phylogenetic \nresolution using coalescent approaches was comparable among the three marker \ntypes, with most nodes being fully and congruently resolved. Comparison of \nphylogenetic results across the three marker types indicated that one branch, \nthe sister group to the passerine + falcon clade, was resolved differently and \nwith moderate (>70%) bootstrap support between CNEEs and UCEs or introns. \nOverall, CNEEs appear to be promising as phylogenomic markers, yielding \nphylogenetic resolution as high as for UCEs and introns but with fewer gaps, \nless ambiguity in alignments and with patterns of nucleotide substitution more \nconsistent with the assumptions of commonly used methods of phylogenetic \nanalysis." ]	nan
5c51f44c07ef653866000004	[ 30137632 ]	train	Are Copy Number Variants (CNVs) depleted in regions of low mappability?	yesno	No. Low-mappability regions are approximately 5 times more likely to harbor germline CNVs, in stark contrast to the nearly uniform distribution observed for somatic CNVs in 95 cancer genomes.	no	[ "Copy number variants (CNVs) are known to affect a large portion of the human \ngenome and have been implicated in many diseases. Although whole-genome \nsequencing (WGS) can help identify CNVs, most analytical methods suffer from \nlimited sensitivity and specificity, especially in regions of low mappability. \nTo address this, we use PopSV, a CNV caller that relies on multiple samples to \ncontrol for technical variation. We demonstrate that our calls are stable across \ndifferent types of repeat-rich regions and validate the accuracy of our \npredictions using orthogonal approaches. Applying PopSV to 640 human genomes, we \nfind that low-mappability regions are approximately 5 times more likely to \nharbor germline CNVs, in stark contrast to the nearly uniform distribution \nobserved for somatic CNVs in 95 cancer genomes. In addition to known enrichments \nin segmental duplication and near centromeres and telomeres, we also report that \nCNVs are enriched in specific types of satellite and in some of the most recent \nfamilies of transposable elements. Finally, using this comprehensive approach, \nwe identify 3455 regions with recurrent CNVs that were missing from existing \ncatalogs. In particular, we identify 347 genes with a novel exonic CNV in \nlow-mappability regions, including 29 genes previously associated with disease." ]	nan
5133b15e5274a5fb0700000b	[ 16474211, 9990116, 3186440, 9632720, 1968658, 17591602, 15784181, 1505946, 15546139, 8128314, 3656447 ]	train	Are CpG islands located close to housekeeping genes?	yesno	Our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands. It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes.	yes	[ "Abnormal development and fetal loss during postimplantation period are concerns \nfor production of nuclear transferred animals. Aberrant DNA methylation is one \nof the reasons for poor survival of cloned animals. In mammalian genome DNA, CpG \nislands are preferentially located at the start of transcription of housekeeping \ngenes and are associated with tissue-specific genes. The correct and consecutive \nmechanisms of DNA methylation in the CpG islands are necessary for selective \ngene expressions that determine the properties of individual cells, tissues, and \norgans. In this study, we investigated the methylation status of the CpG islands \nof the bovine Leptin and POU5F1 genes in fetal and placental tissues from \nfetuses produced by artificial insemination (AI) and nuclear transfer (NT) at \ndays 48 and 59 of pregnancy. Altered DNA methylation was observed in the normal \nand cloned fetal, placental, and endometrial tissues using bisulfite sequencing \nand pyrosequencing. Different tissue-specific methylated regions in the bovine \nLeptin and POU5F1 genes show a variable methylation status in NT fetuses \ncompared to AI control.", "CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat \nand are present in close association with all housekeeping genes as well as some \ntissue-specific genes in the mammalian genome. Methylation of CpG islands \nstrongly influences both structural organization and function of chromatin. The \npresence of a CpG island in a given chromosomal domain can, by itself, give rise \nto relatively open and active chromatin. Recently, several histone \nacetyltransferases, histone deacetylases, and chromatin remodeling factors have \nbeen found to be part of the transcription machinery. It is becoming \nincreasingly clear that CpG islands and their methylation status may influence \nthe function or recruitment of these newly discovered chromatin remodeling \nfactors, especially the histone deacetylases. In addition, CpG islands may also \nplay a significant role in the reorganization of chromatin during mammalian \nspermiogenesis.", "Unmethylated CpG rich islands are a feature of vertebrate DNA: they are \nassociated with housekeeping and many tissue specific genes. CpG islands on the \nactive X chromosome of mammals are also unmethylated. However, islands on the \ninactive X chromosome are heavily methylated. We have identified a CpG island in \nthe 5' region of the G6PD gene, and two islands forty Kb 3' from the G6PD gene, \non the human X chromosome. Expression of the G6PD gene is associated with \nconcordant demethylation of all three CpG islands. We have shown that one of the \ntwo islands is in the promoter region of a housekeeping gene, GdX. In this paper \nwe show that the second CpG island is also associated with a gene, P3. The P3 \ngene has no homology to previously described genes. It is a single copy, 4 kb \ngene, conserved in evolution, and it has the features of a housekeeping two \ngenes is within the CpG island and that sequences in the islands have promoter \nfunction.", "In vivo and in vitro experiments carried out on L929 mouse fibroblasts suggested \nthat the poly(ADP-ribosyl) ation process acts somehow as a protecting agent \nagainst full methylation of CpG dinucleotides in genomic DNA. Since CpG islands, \nwhich are found almost exclusively at the 5'-end of housekeeping genes, are rich \nin CpG dinucleotides, which are the target of mammalian DNA methyltransferase, \nwe examined the possibility that the poly(ADP-ribosyl)ation reaction is involved \nin maintaining the unmethylated state of these DNA sequences. Experiments were \nconducted by two different strategies, using either methylation-dependent \nrestriction enzymes on purified genomic DNA or a sequence-dependent restriction \nenzyme on an aliquot of the same DNA, previously modified by a bisulfite \nreaction. With the methylation-dependent restriction enzymes, it was observed \nthat the \"HpaII tiny fragments\" greatly decreased when the cells were \npreincubated with 3-aminobenzamide, a well known inhibitor of poly(ADP-ribose) \npolymerase. The other experimental approach allowed us to prove that, as a \nconsequence of the inhibition of the poly(ADP-ribosyl)ation process, an \nanomalous methylation pattern could be evidenced in the CpG island of the \npromoter fragment of the Htf9 gene, amplified from DNA obtained from fibroblasts \npreincubated with 3-aminobenzamide. These data confirm the hypothesis that, at \nleast for the Htf9 promoter region, an active poly(ADP-ribosyl)ation protects \nthe unmethylated state of the CpG island.", "Patterns of DNA methylation at CpG dinucleotides and their relations with gene \nexpression are complex. Methylation-free CpG clusters, so-called HTF islands, \nare most often associated with the promoter regions of housekeeping genes, \nwhereas genes expressed in a single-cell type are usually deficient in these \nsequences. However, in the human carbonic anhydrase (CA) gene family, both the \nubiquitously expressed CAII and the muscle specific CAIII appear to have such \nCpG islands although erythrocyte-specific CAI does not. The CAII island is \nquantitatively more CpG rich than that of CAIII, with a CpG:GpC ratio of 0.94 \ncompared with 0.82 for CAIII. Estimation of CpG:GpC ratios in the \nproximal-promoter regions of 44 vertebrate genes suggest that 40% of genes with \ntissue-specific or limited tissue distribution may show methylation-free CpG \nclusters in their promoter regions. In many cases the CpG:GpC ratio is less than \nthat found in housekeeping genes and this may reflect variation in the \ninteraction of CpG clusters with regulatory factors that define different \npatterns of tissue expression.", "CpG islands (CGIs) are often considered as gene markers, but the number of CGIs \nvaries among mammalian genomes that have similar numbers of genes. In this \nstudy, we investigated the distribution of CGIs in the promoter regions of 3,197 \nhuman-mouse orthologous gene pairs and found that the mouse genome has notably \nfewer CGIs in the promoter regions and less pronounced CGI characteristics than \ndoes the human genome. We further inferred CGI's ancestral state using the dog \ngenome as a reference and examined the nucleotide substitution pattern and the \nmutational direction in the conserved regions of human and mouse CGIs. The \nresults reveal many losses of CGIs in both genomes but the loss rate in the \nmouse lineage is two to four times the rate in the human lineage. We found an \nintriguing feature of CGI loss, namely that the loss of a CGI usually starts \nfrom erosion at the both edges and gradually moves towards the center. We found \nfunctional bias in the genes that have lost promoter-associated CGIs in the \nhuman or mouse lineage. Finally, our analysis indicates that the association of \nCGIs with housekeeping genes is not as strong as previously estimated. Our study \nprovides a detailed view of the evolution of promoter-associated CGIs in the \nhuman and mouse genomes and our findings are helpful for understanding the \nevolution of mammalian genomes and the role of CGIs in gene function.", "It has been envisaged that CpG islands are often observed near the \ntranscriptional start sites (TSS) of housekeeping genes. However, neither the \nprecise positions of CpG islands relative to TSS of genes nor the correlation \nbetween the presence of the CpG islands and the expression specificity of these \ngenes is well-understood. Using thousands of sequences with known TSS in human \nand mouse, we found that there is a clear peak in the distribution of CpG \nislands around TSS in the genes of these two species. Thus, we classified human \n(mouse) genes into 6600 (2948) CpG+ genes and 2619 (1830) CpG- ones, based on \nthe presence of a CpG island within the -100: +100 region. We estimated the \ndegree of each gene being a housekeeper by the number of cDNA libraries where \nits ESTs were detected. Then, the tendency that a gene lacking CpG islands \naround its TSS is expressed with a higher degree of tissue specificity turned \nout to be evolutionarily conserved. We also confirmed this tendency by analyzing \nthe gene ontology annotation of classified genes. Since no such clear \ncorrelation was found in the control data (mRNAs, pre-mRNAs, and chromosome \nbanding pattern), we concluded that the effect of a CpG island near the TSS \nshould be more important than the global GC content of the region where the gene \nresides.", "CpG islands are short, dispersed regions of unmethylated DNA with a high \nfrequency of CpG dinucleotides relative to the bulk genome. We have analyzed 375 \ngenes and 58 pseudogenes from the human entries in the EMBL Database for the \npresence of CpG islands. All 240 islands identified are associated with genes, \nand almost all cover at least a part of one exon; i.e., they are useful \nlandmarks in the genome for identifying genes. More than half of the genes \nanalyzed were associated with islands. All housekeeping and widely expressed \ngenes have a CpG island covering the transcription start, whereas 40% of the \ngenes with a tissue-specific or limited expression are associated with islands. \nIn this latter group of genes, the position of the islands was not biased toward \nthe 5' end of the transcription unit.", "DNA methylation is the epigenetic modification, which introduces 5mC as fifth \nbase onto DNA. As for the distribution of 5mCs, it is well known that they \ndistribute themselves in a non-random fashion in genomic DNA so that methylation \npattern is characterized by the presence of methylated cytosines on the bulk of \nDNA while the unmethylated ones are mainly located within particular regions \ntermed CpG islands. These regions represent about 1% of genomic DNA and are \ngenerally found in the promoter region of housekeeping genes. Their unmethylated \nstate, which is an essential condition for the correct expression of correlated \ngenes, is paradoxical if one considers that these regions are termed CpG islands \nbecause they are particularly rich in this dinucleotide, which is the best \nsubstrate for enzymes involved in DNA methylation. Anomalous insertion of methyl \ngroups in these regions generally leads to the lack of transcription of \ncorrelated genes. An interesting scientific problem is to clarify the \nmechanism(s) whereby CpG islands, which remain protected from methylation in \nnormal cells, are susceptible to methylation in tumor cells. How the CpG \nmoieties in CpG islands become vulnerable or resistant to the action of DNA \nmethyltransferases and can thus lose or maintain their characteristic pattern of \nmethylation is still an open question. Our aim is to gather some mechanisms \nregarding this intriguing enigma, which, despite all energy spent, still remains \nan unresolved puzzle.", "In housekeeping and many tissue-specific genes, the promoter is embedded in a \nso-called CpG island. We have compared the available human and mouse DNA \nsequences with respect to their CpG island properties. While mouse sequences \nshowed a simple gradient distribution of G + C content and CpG densities, man \nhad a distinct peak of sequences with typical CpG island characteristics. \nPairwise comparison of 23 orthologous genes revealed that mouse almost always \nhad a less pronounced CpG island than man, or none at all. In both species the \nrequirements for a functional CpG island may be similar in that most DNA regions \nwith a density of six or more CpG per 100 bp remain unmethylated. However, the \nmouse has apparently experienced more accidental CpG island methylation, \nsuggested by local TpG and CpA excess. We propose that: (1) in mouse the CpG \nislands do not represent the ancestral state but have been eroded during \nevolution, and (2) this erosion may be related to the mouse's small body mass \nand short life-span, allowing for a more relaxed control of gene activity.", "Although vertebrate DNA is generally depleted in the dinucleotide CpG, it has \nrecently been shown that some vertebrate genes contain CpG islands, regions of \nDNA with a high G+C content and a high frequency of CpG dinucleotides relative \nto the bulk genome. In this study, a large number of sequences of vertebrate \ngenes were screened for the presence of CpG islands. Each CpG island was then \nanalysed in terms of length, nucleotide composition, frequency of CpG \ndinucleotides, and location relative to the transcription unit of the associated \ngene. CpG islands were associated with the 5' ends of all housekeeping genes and \nmany tissue-specific genes, and with the 3' ends of some tissue-specific genes. \nA few genes contained both 5' and 3' CpG islands, separated by several thousand \nbase-pairs of CpG-depleted DNA. The 5' CpG islands extended through 5'-flanking \nDNA, exons and introns, whereas most of the 3' CpG islands appeared to be \nassociated with exons. CpG islands were generally found in the same position \nrelative to the transcription unit of equivalent genes in different species, \nwith some notable exceptions. The locations of G/C boxes, composed of the \nsequence GGGCGG or its reverse complement CCGCCC, were investigated relative to \nthe location of CpG islands. G/C boxes were found to be rare in CpG-depleted DNA \nand plentiful in CpG islands, where they occurred in 3' CpG islands, as well as \nin 5' CpG islands associated with tissue-specific and housekeeping genes. G/C \nboxes were located both upstream and downstream from the transcription start \nsite of genes with 5' CpG islands. Thus, G/C boxes appeared to be a feature of \nCpG islands in general, rather than a feature of the promoter region of \nhousekeeping genes. Two theories for the maintenance of a high frequency of CpG \ndinucleotides in CpG islands were tested: that CpG islands in methylated genomes \nare maintained, despite a tendency for 5mCpG to mutate by deamination to \nTpG+CpA, by the structural stability of a high G+C content alone, and that CpG \nislands associated with exons result from some selective importance of the \narginine codon CGX. Neither of these theories could account for the distribution \nof CpG dinucleotides in the sequences analysed. Possible functions of CpG \nislands in transcriptional and post-transcriptional regulation of gene \nexpression were discussed, and were related to theories for the maintenance of \nCpG islands as \"methylation-free zones\" in germline DNA." ]	['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018899', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006796', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D020043']
5c891d5075a4a5d219000011	[ 28471166 ]	train	Are Crocus sativus compounds being considered against Alzheimer's disease?	yesno	Yes, it has been observed that Crocus sativus extracts and compounds have a positive effect against Alzheimer's disease.	yes	[ "Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and \nother folk medicines for various purposes as an aphrodisiac, antispasmodic, and \nexpectorant. Previous evidence suggested that Crocus sativus is linked to \nimproving cognitive function in Alzheimer's disease (AD) patients. The aim of \nthis study was to in vitro and in vivo investigate the mechanism(s) by which \nCrocus sativus exerts its positive effect against AD. The effect of Crocus \nsativus extract on Aβ load and related toxicity was evaluated. In vitro results \nshowed that Crocus sativus extract increases the tightness of a cell-based \nblood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo \nstudies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to \nmice diet) on the BBB tightness and function that was associated with reduced Aβ \nload and related pathological changes in 5XFAD mice used as an AD model. Reduced \nAβ load could be explained, at least in part, by Crocus sativus extract effect \nto enhance Aβ clearance pathways including BBB clearance, enzymatic degradation \nand ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated \nsynaptic proteins and reduced neuroinflammation associated with Aβ pathology in \nthe brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus \nand known for its antioxidant and anti-inflammatory effect, was also tested \nseparately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ \nload but to a lesser extent when compared to Crocus sativus extract. \nCollectively, findings from this study support the positive effect of Crocus \nsativus against AD by reducing Aβ pathological manifestations." ]	nan
5319a752b166e2b806000027	[ 16987878, 10984715, 17131053, 15743670, 15734684 ]	train	Are DNA helicases involved in progeroid syndromes?	yesno	Yes, mutations in genes coding for DNA helicases were found to induce progeroid syndromes, such as Werner syndrome (WS) or Bloom syndrome (BS).	yes	[ "Progeroid syndromes (PSs) constitute a group of disorders characterized by \nclinical features mimicking physiological aging at an early age. In some of \nthese syndromes, biological hallmarks of aging are also present, whereas in \nothers, a link with physiological aging, if any, remains to be elucidated. These \nsyndromes are clinically and genetically heterogeneous and most of them, \nincluding Werner syndrome and Hutchinson-Gilford progeria, are known as \n'segmental aging syndromes', as they do not feature all aspects usually \nassociated to physiological aging. However, all the characterized PSs enter in \nthe field of rare monogenic disorders and several causative genes have been \nidentified. These can be separated in subcategories corresponding to (i) genes \nencoding DNA repair factors, in particular, DNA helicases, and (ii) genes \naffecting the structure or post-translational maturation of lamin A, a major \nnuclear component. In addition, several animal models featuring premature aging \nhave abnormal mitochondrial function or signal transduction between membrane \nreceptors, nuclear regulatory proteins and mitochondria: no human pathological \ncounterpart of these alterations has been found to date. In recent years, \nidentification of mutations and their functional characterization have helped to \nunravel the cellular processes associated to segmental PSs. Recently, several \nstudies allowed to establish a functional link between DNA repair and A-type \nlamins-associated syndromes, evidencing a relation between these syndromes, \nphysiological aging and cancer. Here, we review recent data on molecular and \ncellular bases of PSs and discuss the mechanisms involved, with a special \nemphasis on lamin A-associated progeria and related disorders, for which \ntherapeutic approaches have started to be developed.", "Progeria and progeroid syndromes are characterized by the earlier onset of \ncomplex senescent phenotypes. WRN was originally identified as a gene \nresponsible for Werner syndrome (WS; \"Progeria of Adults\"). The WRN gene product \nhas RecQ-type helicase domains in the central region of the protein. Subsequent \nstudies also revealed that the WRN protein displays exonuclease activity and \nacts as a transcriptional activation factor. These biochemical studies, combined \nwith cell biological studies, suggested that this protein is likely to be \ninvolved in the response to DNA damage during replication, as well as \nrecombination and transcription processes. However, the precise molecular \nmechanisms by which mutations in WRN cause the WS phenotype remain unknown. \nRecent progress in the understanding of the WRN protein and its implication in \nthe normal aging process are discussed.", "Disorders in which individuals exhibit certain features of aging early in life \nare referred to as segmental progeroid syndromes. With the progress that has \nbeen made in understanding the etiologies of these conditions in the past \ndecade, potential therapeutic options have begun to move from the realm of \nimprobability to initial stages of testing. Among these syndromes, relevant \nadvances have recently been made in Werner syndrome, one of several progeroid \nsyndromes characterized by defective DNA helicases, and Hutchinson-Gilford \nprogeria syndrome, which is characterized by aberrant processing of the nuclear \nenvelope protein lamin A. Although best known for their causative roles in these \nillnesses, Werner protein and lamin A have also recently emerged as key players \nvulnerable to epigenetic changes that contribute to tumorigenesis and aging. \nThese advances further demonstrate that understanding progeroid syndromes and \nintroducing adequate treatments will not only prove beneficial to patients \nsuffering from these dramatic diseases, but will also provide new mechanistic \ninsights into cancer and normal aging processes.", "The molecular mechanisms leading to human senescence are still not known mostly \nbecause of the complexity of the process. Different research approaches are used \nto study ageing including studies of monogenic segmental progeroid syndromes. \nNone of the known progerias represents true precocious ageing. Some of them, \nincluding Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well \nas combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by \nfeatures resembling precocious ageing and the increased risk of malignant \ndisease. Such phenotypes result from the mutations of the genes encoding \nproteins involved in the maintenance of genomic integrity, in most cases DNA \nhelicases. Defective functioning of these proteins affects DNA repair, \nrecombination, replication and transcription. Other segmental progeroid \nsyndromes, such as Hutchinson-Gilford progeria (HGPS) and Cockayne syndrome are \nnot associated with an increased risk of cancer. In this paper we present the \nclinical and molecular features of selected progeroid syndromes and describe the \npotential implications of these data for studies of ageing and cancer \ndevelopment.", "Single-gene mutations can produce human progeroid syndromes--phenotypes that \nmimic usual or \"normative\" aging. These can be divided into two classes--those \nthat have their impacts upon multiple organs and tissues (segmental progeroid \nsyndromes) and those that have their major impacts upon a single organ or tissue \n(unimodal progeroid syndromes). The prototypic example of the former is the \nWerner syndrome, a condition caused by mutations of the RecQ family of DNA \nhelicases. Research on the Werner syndrome and a surprising number of other \nprogeroid syndromes support the importance of the maintenance of genomic \nstability as a partial antidote to aging. The prototypic examples of the latter \nare Alzheimer type dementias. The three gene products that cause rare \nautosomal-dominant early-onset varieties of these disorders all participate in \nthe modulation of the beta amyloid precursor protein. They thus support the \nimportance of the maintenance of proper protein processing and folding as a \npartial antidote to aging." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004265', 'http://www.disease-ontology.org/api/metadata/DOID:225', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0033202', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D003057', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D013577', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0003678', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D053484']
56ae69fb0a360a5e4500000d	[ 22726460, 23524404 ]	train	Are DNA methylation maps applicable to the diagnosis of non-small-cell lung carcinomas?	yesno	Yes.	yes	[ "BACKGROUND: Non-small cell lung carcinoma (NSCLC) is a complex malignancy that \nowing to its heterogeneity and poor prognosis poses many challenges to \ndiagnosis, prognosis and patient treatment. DNA methylation is an important \nmechanism of epigenetic regulation involved in normal development and cancer. It \nis a very stable and specific modification and therefore in principle a very \nsuitable marker for epigenetic phenotyping of tumors. Here we present a \ngenome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, \nwhere we combine MethylCap and next generation sequencing (MethylCap-seq) to \nprovide comprehensive DNA methylation maps of the tumor and paired lung samples. \nThe MethylCap-seq data were validated by bisulfite sequencing and \nmethyl-specific polymerase chain reaction of selected regions.\nRESULTS: Analysis of the MethylCap-seq data revealed a strong positive \ncorrelation between replicate experiments and between paired tumor/lung samples. \nWe identified 57 differentially methylated regions (DMRs) present in all NSCLC \ntumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to \nany particular functional category of genes, the hypermethylated DMRs were \nstrongly associated with genes encoding transcriptional regulators. Furthermore, \nsubtelomeric regions and satellite repeats were hypomethylated in the NSCLC \nsamples. We also identified DMRs that were specific to two of the major subtypes \nof NSCLC, adenocarcinomas and squamous cell carcinomas.\nCONCLUSIONS: Collectively, we provide a resource containing genome-wide DNA \nmethylation maps of NSCLC and their paired lung tissues, and comprehensive lists \nof known and novel DMRs and associated genes in NSCLC.", "INTRODUCTION: DNA methylation is part of the epigenetic regulatory mechanism \npresent in all normal cells. It is tissue-specific and stably maintained \nthroughout development, but often abnormally changed in cancer. Non-small-cell \nlung carcinoma (NSCLC) is the most deadly type of cancer, involving different \ntumor subtypes. This heterogeneity is a challenge for correct diagnosis and \npatient treatment. The stability and specificity make of DNA methylation a very \nsuitable marker for epigenetic phenotyping of tumors.\nMETHODS: To identify candidate markers for use in NSCLC diagnosis, we used \ngenomewide DNA methylation maps that we had previously generated by MethylCap \nand next-generation sequencing and listed the most significant differentially \nmethylated regions (DMRs). The 25 DMRs with highest significance in their \nmethylation scores were selected. The methylation status of these DMRs was \ninvestigated in 61 tumors and matching control lung tissues by \nmethylation-specific polymerase chain reaction.\nRESULTS: We found 12 novel DMRs that showed significant differences between \ntumor and control lung tissues. We also identified three novel DMRs for each of \nthe two most common NSCLC subtypes, adenocarcinomas and squamous cell \ncarcinomas. We propose a panel of five DMRs, composed of novel and known markers \nthat exhibit high specificity and sensitivity to distinguish tumors from control \nlung tissues.\nCONCLUSION: Novel markers will aid the development of a highly specific \nepigenetic panel for accurate identification and subtyping of NSCLC tumors." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002289', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D003933', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008745', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008168', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004247', 'http://www.disease-ontology.org/api/metadata/DOID:3908', 'http://amigo.geneontology.org/amigo/term/GO:0044030', 'http://amigo.geneontology.org/amigo/term/GO:0006306', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D055752', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D019175', 'http://www.disease-ontology.org/api/metadata/DOID:5409', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018288']
56d1accb67f0cb3d66000001	[ 25618141 ]	train	Are Drosophila ultraconserved elements candidate ncRNAs?	yesno	Yes. Highly constrained intergenic Drosophila ultraconserved elements are candidate ncRNAs.	yes	[ "Eukaryotes contain short (∼80-200 bp) regions that have few or no substitutions \namong species that represent hundreds of millions of years of evolutionary \ndivergence. These ultraconserved elements (UCEs) are candidates for containing \nessential functions, but their biological roles remain largely unknown. Here, we \nreport the discovery and characterization of UCEs from 12 sequenced Drosophila \nspecies. We identified 98 elements ≥80 bp long with very high conservation \nacross the Drosophila phylogeny. Population genetic analyses reveal that these \nUCEs are not present in mutational cold spots. Instead we infer that they \nexperience a level of selective constraint almost 10-fold higher compared with \nmissense mutations in protein-coding sequences, which is substantially higher \nthan that observed previously for human UCEs. About one-half of these Drosophila \nUCEs overlap the transcribed portion of genes, with many of those that are \nwithin coding sequences likely to correspond to sites of ADAR-dependent RNA \nediting. For the remaining UCEs that are in nongenic regions, we find that many \nare potentially capable of forming RNA secondary structures. Among ten chosen \nfor further analysis, we discovered that the majority are transcribed in \nmultiple tissues of Drosophila melanogaster. We conclude that Drosophila species \nare rich with UCEs and that many of them may correspond to novel noncoding RNAs." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004330']
551910c5622b194345000007	[ 15834508, 12355085, 9094028, 21915282, 18693272, 16145050, 15294878, 20009762, 14669347, 10664228, 11484199, 12574515, 8852660, 11302967, 11471546, 14633923, 9035203, 11434563, 22132166, 10792313, 20633936, 10964697, 12631670, 16618617 ]	train	Are EDNRB mutations involved in the development of Hirschsprung disease?	yesno	Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR.	yes	[ "Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a \nrelatively common disorder characterized by the absence of ganglion cells in the \nnerve plexuses of the lower digestive tract, resulting in intestinal obstruction \nin neonates. Mutations in genes of the RET receptor tyrosine kinase and \nendothelin receptor B (EDNRB) signaling pathways have been shown to be \nassociated in HSCR patients. In this study, we collected genomic DNA samples \nfrom 55 HSCR patients in central Taiwan and analyzed the coding regions of the \nRET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, \nan A to G transition was detected in two (identical twin brothers). The mutation \nwas at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site \nfor the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, \n11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were \ndetected. The differences between patients and controls in allele distribution \nof the five RET polymorphic sites were statistically significant. The most \nfrequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with \nthe highest percentage of heterozygotes) was AA/GG in patients, which was \ndifferent from the AG/GT in the normal controls. Transmission disequilibrium was \nobserved in exons 2, 7, and 13, indicating nonrandom association of the \nsusceptibility alleles with the disease in the patients. This study represents \nthe first comprehensive genetic analysis of HSCR disease in Taiwan.", "Genetic studies of Hirschsprung disease, a common congenital malformation, have \nidentified eight genes with mutations that can be associated with this \ncondition. Mutations at individual loci are, however, neither necessary nor \nsufficient to cause clinical disease. We conducted a genome-wide association \nstudy in 43 Mennonite family trios using 2,083 microsatellites and \nsingle-nucleotide polymorphisms and a new multipoint linkage disequilibrium \nmethod that searches for association arising from common ancestry. We identified \nsusceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, \nencoding a G protein-coupled receptor (GPCR) and the gene at 10q11 is RET, \nencoding a receptor tyrosine kinase (RTK). Statistically significant joint \ntransmission of RET and EDNRB alleles in affected individuals and \nnon-complementation of aganglionosis in mouse intercrosses between Ret null and \nthe Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB \nand RET. Thus, genetic interaction between mutations in RET and EDNRB is an \nunderlying mechanism for this complex disorder.", "To date, three genes have been identified as susceptibility genes for \nHirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor \ngene (EDNRB) and the endothelin-3 gene (EDN3). However, the question of whether \nthese genes play a role in sporadically occurring HSCR has not been fully \nclarified. In this study, the authors performed mutation analysis of these three \ngenes in 41 sporadic HSCR patients without any family history by using \nsingle-strand conformational polymorphism or denaturing gradient gel \nelectrophoresis methods. Exon 2, 3, 5, 6, 12, 13, 15, and 17 of the RET gene, 7 \nexons of the EDNRB gene, and the region of the EDN3 gene including sequences \ncorresponding to proteolytic cleavage sites and mature endothelin-3 were \nanalysed. By direct sequencing, three causative RET mutations were confirmed; a \nPhe to Ser substitution at codon 174, a Cys to Tyr substitution at codon 197, \nand a point mutation at the splice acceptor site of intron 12, in patients with \naganglionosis confined to the rectosigmoid colon, the transverse colon, and the \ntotal colon, respectively. In the EDNRB locus, two mutations were observed; a \nnonsense mutation of Trp to stop at codon 275, and a T insertion at nucleotide \n878, in patients with aganglionosis confined to the rectosigmoid colon, and the \ndescending colon, respectively. No mutation was detected in the EDN3 gene. \nMutation rates were 7.3% in the RET and 5% in the EDNRB gene. Our data indicate \nthat RET and EDNRB mutations have a role in the aetiology of some sporadically \noccurring HSCR. However, the low mutation rate of susceptibility genes in \nsporadically occurring HSCR suggests that other genes or environmental factors \nare involved in the development of the disease.", "Hirschsprung disease (HSCR) is thought to result as a consequence of multiple \ngene interactions that modulate the ability of enteric neural crest cells to \npopulate the developing gut. However, it remains unknown whether the single \ncomplete deletion of important HSCR-associated genes is sufficient to result in \nHSCR disease. In this study, we found that the null mutation of the Ednrb gene, \nthought indispensable for enteric neuron development, is insufficient to result \nin HSCR disease when bred onto a different genetic background in rats carrying \nEdnrb(sl) mutations. Moreover, we found that this mutation results in serious \ncongenital sensorineural deafness, and these strains may be used as ideal models \nof Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same \nchanged genetic background modifies three features of WS4 syndrome, \naganglionosis, hearing loss, and pigment disorder in these congenic strains. We \nfound that the same genetic background markedly changed the aganglionosis, but \nresulted in only slight changes to hearing loss and pigment disorder. This \nprovided the important evidence, in support of previous studies, that different \nlineages of neural crest-derived cells migrating along with various pathways are \nregulated by different signal molecules. This study will help us to better \nunderstand complicated diseases such as HSCR and WS4 syndrome.", "Endothelin receptor B (Ednrb) plays a critical role in the development of \nmelanocytes and neurons and glia of the enteric nervous system. These distinct \nneural crest-derived cell types express Ednrb and share the property of \nintercalating into tissues, such as the intestine whose muscle precursor cells \nalso express Ednrb. Such widespread Ednrb expression has been a significant \nobstacle in establishing precise roles for Ednrb in development. We describe \nhere the production of an Ednrb allele floxed at exon 3 and its use in excising \nthe receptor from mouse neural crest cells by use of Cre-recombinase driven by \nthe Wnt1 promoter. Mice born with neural crest-specific excision of Ednrb \npossess aganglionic colon, lack trunk pigmentation, and die within 5 weeks due \nto megacolon. Ednrb receptor expression in these animals is absent only in the \nneural crest but present in surrounding smooth muscle cells. The absence of \nEdnrb from crest cells also results in a compensatory upregulation of Ednrb \nexpression in other cells within the gut. We conclude that Ednrb loss only in \nneural crest cells is sufficient to produce the Hirschsprungs disease phenotype \nobserved with genomic Ednrb mutations.", "The endothelin signaling pathway plays a crucial role in melanocyte \ndifferentiation and migration. In this study, we investigated whether germline \nmutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung \ndisease (HSCR), could also predispose for malignant melanoma (MM). The coding \nregion of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched \nCaucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 \npatients (11%), but only two were found in four control subjects (3%, odds ratio \n[OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 \nout of 15 MM patients carried EDNRB mutations reported in HSCR, some of which \nhad previously been shown to lead to loss of function. In multivariable logistic \nregression analysis including skin type, eye and hair color, number of nevi, and \ndorsal lentigines (freckles), the association between EDNRB mutations and MM \nrisk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = \n.03). Our data strongly suggest that EDNRB is involved in predisposition for two \ndifferent multigenic disorders, HSCR and melanoma.", "Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence \nof multiple gene interactions that modulate the ability of enteric neural crest \n(NC) cells to populate the developing gut. One of the essential genes for this \nprocess is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic \nbackground show variation in penetrance and expressivity of enteric \naganglionosis that are analogous to the variable aganglionosis seen in human \nHSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this \nvariation arises from modifiers in the genetic background. To determine whether \nknown HSCR susceptibility loci are acting as modifiers of Sox10, we tested for \nassociation between genes in the endothelin signaling pathway (EdnrB, Edn3, \nEce1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom \nmice. Single locus association analysis in this pedigree identifies interaction \nbetween EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a \nhighly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The \npresence of C57BL/6J alleles at EdnrB is associated with increased penetrance \nand more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and \nSox10 mutants corroborate this gene interaction with double mutant progeny \nexhibiting significantly more severe aganglionosis. The background strain of the \nEdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant \nprogeny implying the action of additional modifiers on this phenotype. Our data \ndemonstrates that Sox10-EdnrB interactions can influence development of the \nenteric nervous system in mouse models and suggests that this interaction could \ncontribute to the epistatic network producing variation between patients with \naganglionosis.", "PURPOSE: Hirschsprung disease is characterized by the absence of intramural \nganglion cells in the myenteric and submucosal plexuses within distal intestine, \nbecause of a fail in the enteric nervous system formations process. \nEndothelin-3-endothelin receptor B signaling pathway is known to play an \nessential role in this process. The aim of this study was to evaluate the \nimplication of the EDN3 and EDNRB genes in a series of patients with \nHirschsprung disease from Spain and determinate their mutational spectrum.\nMETHODS: We performed the mutational screening of both genes in 196 patients \nwith Hirschsprung disease using denaturing high-performance liquid \nchromatography technology. A case-control study using TaqMan Technology was also \ncarried out to evaluate some common polymorphisms and haplotypes as \nsusceptibility factors for Hirschsprung disease.\nRESULTS: Besides several novel mutations in both genes, we found a truncating \nmutation in an alternative isoform of EDNRB. Interestingly, we obtained an \noverrepresentation of a specific EDN3 haplotype in cases versus controls.\nCONCLUSIONS: Our results suggest that the isoform EDNRB Delta 3 might be playing \nan essential role in the formation of enteric nervous system. In addition, based \non the haplotype distribution, EDN3 might be considered as a common \nsusceptibility gene for sporadic Hirschsprung disease in a low-penetrance \nfashion.", "AIM: To investigate the mutation of EDNRB gene and EDN-3 gene in sporadic \nHirschsprung's disease (HD) in Chinese population.\nMETHODS: Genomic DNA was extracted from bowel tissues of 34 unrelated HD \npatients which were removed by surgery. Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 \nof EDN-3 gene were amplified by polymerase chain reaction (PCR) and analyzed by \nsingle strand conformation polymorphism (SSCP).\nRESULTS: EDNRB mutations were detected in 2 of the 13 short-segment HD. One \nmutant was in the exon 3, the other was in the exon 6. EDN-3 mutation was \ndetected in one of the 13 short-segment HD and in the exon 2. Both EDNRB and \nEDN-3 mutations were detected in one short-segment HD. No mutations were \ndetected in the ordinary or long-segment HD.\nCONCLUSION: The mutations of EDNRB gene and EDN-3 gene are found in the \nshort-segment HD of sporadic Hirschsprung's disease in Chinese population, which \nsuggests that the EDNRB gene and EDN-3 gene play important roles in the \npathogenesis of HD.", "We report on mutation analysis of five genes involved in the receptor tyrosine \nkinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese \npatients with Hirschsprung disease. Analysis of DNA obtained from peripheral \nblood cells revealed six mutations in the RET proto-oncogene, four of which were \ndisease-causing mutations in exon 9 (D584G), the splice donor site of intron 10 \n(+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G \ntransition was found in 47 bases upstream from the 5' end of exon 2 in two HD \npatients but was also seen in one control subject (2/28; 1/24). A silent 2307T \nto G transversion was observed in exon 13. Two disease-causing mutations were \ndetected in the endothelin receptor (EDNRB) gene, in the non-coding region of \nexon 1 (-26 G to A) and in exon 4 (A301T); the latter mutation was a novel one. \nOne silent mutation was observed in exon 4 (codon 277). One heterozygous T to C \nmutation was found in the glial cell line-derived neurotrophic factor gene in 25 \nbases upstream of the coding region in exon 1. No nucleotide changes were \ndetected in either the endothelin-3 or neurturin genes. Disease-causing mutation \nrates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% \n(4/28) and 10.7% (3/28), respectively. In addition to mutations in the RET and \nEDNRB genes, embryonic environmental factors and/or other genetic factors appear \nto be involved in the development of Hirschsprung disease. Further systematic \nstudies of genetic variation in a large series of patients and controls are \nnecessary for elucidating the pathogenesis of this disorder.\nCONCLUSION: This study provides further gene alterations as disease-causing \nmutations in Japanese cases of sporadic Hirschsprung disease. However, the low \nmutation rate of the susceptibility genes may indicate that Hirschsprung disease \narises from a combination of genetic and environmental factors.", "Hirschsprung disease is a developmental disorder resulting from the arrest of \nthe craniocaudal migration of enteric neurons from the neural crest along \ngastrointestinal segments of variable length; see Behrman [Nelson textbook of \npediatrics, 1992:954-956]. It is a heterogeneous disorder in which familial \ncases map to at least three loci whose function is necessary for normal neural \ncrest-derived cell development. Homozygous mutations in the endothelin-B \nreceptor gene (EDNRB) on 13q22 have been identified in humans and mice with \nHirschsprung disease type 2 (HSCR2). The auditory pigmentary disorder, \nWaardenburg-Shah syndrome, comprises Waardenburg syndrome and Hirschsprung \ndisease and has also been mapped to the EDNRB locus. Hirschsprung disease, \nmalrotation, isochromia, a profound sensorineural hearing loss, and several \nother anomalies were found in an infant with an interstitial deletion of 13q, \nsuggesting the existence of a contiguous gene syndrome involving developmental \ngenes necessary for the normal growth of the neural crest derivatives of the \neye, inner ear, and colon. We report on an additional patient with a deletion in \n13q and Hirschsprung disease. Congenital anomalies associated with deletions of \nthe distal long arm of chromosome 13 are sufficiently consistent to suggest a \nclinical syndrome.", "Clinical expression of Hirschsprung disease (HSCR) requires the interaction of \nmultiple susceptibility genes. Molecular genetic analyses have revealed that \ninteractions between mutations in the genes encoding the RET receptor tyrosine \nkinase and the endothelin receptor type B (EDNRB) are central to the genesis of \nHSCR. We have established two locus noncomplementation assays in mice, using \nallelic series at Ednrb in the context of Ret kinase-null heterozygotes, to \nunderstand the clinical presentation, incomplete penetrance, variation in length \nof aganglionic segment, and sex bias observed in human HSCR patients. Titration \nof Ednrb in the presence of half the genetic dose of Ret determines the \npresentation of an enteric phenotype in these strains, revealing or abrogating a \nsex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB \nsignaling pathways are also critical for the normal development of other \ntissues, including the kidneys and neural crest-derived melanocytes. Our data \ndemonstrate that interaction between these genes is restricted to the enteric \nnervous system and does not affect renal, coat color, and retinal choroid \ndevelopment.", "Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital \nmalformation regarded as a multigenic neurocristopathy. Two susceptibility genes \nhave been recently identified in HSCR, namely the RET proto-oncogene and the \nendothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB \nmutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we \nreport heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated \nHSCR. These data might suggest that EDNRB mutations could be dosage sensitive: \nheterozygosity would predispose to isolated HSCR with incomplete penetrance, \nwhile homozygosity would result in more complex neurocristopathies associating \nHSCR and WS features. In addition, the present data give further support to the \nrole of the endothelin-signalling pathway in the development of neural \ncrest-derived enteric neurons.", "BACKGROUND: Hirschsprung disease (HSCR) is a frequent congenital disorder with \nan incidence of 1 in 5000 live births, characterised by the absence of \nparasympathetic intramural ganglion cells in the hindgut resulting in intestinal \nobstruction in neonates and severe constipation in infants and adults. \nIntestinal neuronal dysplasia (IND) shares clinical features with HSCR but the \nsubmucosal parasympathetic plexus is affected. IND has been proposed as one of \nthe most frequent causes of chronic constipation and is often associated with \nHSCR.\nMETHODS: We examined 29 patients diagnosed with sporadic HSCR, 20 patients with \nIND, and 12 patients with mixed HSCR/IND for mutations in the coding regions of \nthe RET, GDNF, EDNRB, and EDN3 genes. The entire coding regions were analysed by \nsingle strand conformational polymorphism and DNA sequencing.\nRESULTS: Only three RET mutations were detected in patients with HSCR. In \npatients with IND or a mixed HSCR/IND phenotype, no mutations in these genes \nwere observed. While HSCR and HSCR/IND showed over representation of a specific \nRET polymorphism in exon 2, IND exhibited a significantly lower frequency \ncomparable with that of controls.\nCONCLUSIONS: The mutation frequency found in our sporadic HSCR patients (10%) \nand the allelic distribution of RET polymorphisms are comparable with earlier \npublished data. A significantly different allelic distribution in an established \nHSCR associated polymorphism argues against common genetic pathways for HSCR and \nIND.", "BACKGROUND: Hirschsprung's disease (HSCR) is one the most common congenital \nintestinal disease. It leads to aganglionic megacolon in the early childhood. \nSeveral susceptibility genes have been identified : RET protooncogene and its \nligand, glial cell derived neutrophic factor (GDNF), Sox 10, Endothelin-3 (EDN3) \nand its receptor B (EDNRB). EDNRB mutations are found in 5% of familial or \nsporadic HSCR. Only few EDNRB mutations found in HSCR have been explored and \nsome of them seem to be non fonctional variants.\nMATERIALS AND METHODS: The properties of three mutant human endothelin B \nreceptor (hETB) (G57S, R319W and P383L) in isolated HSCR were analyzed. Stable \nrecombinant cells expressing the three mutants and the wild-type (WT) were \nestablished. The hETB receptors were characterized for 125I ET-1 binding, ET-1 \ninduced signaling: calcium transient, AP-1 transcriptional factor activation and \ncAMP accumulation.\nRESULTS: Immunofluorescence experiments showed normal cellular distributions of \nthe mutant G57S, R319W and WT hETB receptors. In contrast, the P383L hETB mutant \nreceptor was concentrated near the nucleus and essentially no ET-1 binding was \ndetected. The two other mutants (G57S and R319W) bound ET-1 normally, induced \ncalcium transients and activated the AP-1 pathway in the same way as wild type, \nbut did not inhibit adenylate cyclase. The G57S hETB mutant even stimulated cAMP \naccumulation which was blocked by pertussis toxin.\nCONCLUSION: The absence of the P383L mutant receptor from the membrane clearly \nindicates that this mutation could be involved in HSCR. The G57S and R319W \nmutant receptors, despite their normal coupling to Gaq, have a defect in the \nGalphai signaling pathway and the G57S mutation couples to Galphas. These \nobservations allow us to hypothesize that cAMP signaling might be involved in \nthe differenciation of neural cells in the bowel.", "BACKGROUND: Hirschsprung disease (HSCR) is a congenital disorder characterized \nby an absence of ganglion cells in the nerve plexuses of the lower digestive \ntract. HSCR has a complex pattern of inheritance and is sometimes associated \nwith mutations in genes of the receptor tyrosine kinase (RET) and endothelin \nreceptor B (EDNRB) signaling pathways, which are crucial for development of the \nenteric nervous system.\nMETHODS: Using PCR amplification and direct sequencing, we screened for \nmutations and polymorphisms in the coding regions and intron/exon boundaries of \nthe RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically \nmatched controls.\nRESULTS: We identified 10 novel and 2 previously described mutations in RET, and \n4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential \ndisease-causing mutations were detected in 24% of the patients. The overall \nmutation rate was 41% in females and 19% in males (P = 0.06). RET mutations \noccurred in 19% of the patients. R114H in RET was the most prevalent mutation, \nrepresenting 7% of the patients or 37% of the patients with RET mutations. To \ndate, such a high frequency of a single mutation has never been reported in \nunrelated HSCR patients. Mutations in EDNRB, EDN3, and GDNF were found in four, \ntwo, and none of the patients, respectively. Two patients with mutations in \ngenes of the EDNRB pathway also harbored a mutation in RET. Three novel and \nthree reported polymorphisms were found in EDNRB, EDN3, and GDNF.\nCONCLUSION: This study identifies additional HSCR disease-causing mutations, \nsome peculiar to the Chinese population, and represents the first comprehensive \ngenetic analysis of sporadic HSCR disease in Chinese.", "The endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3) have \nrecently been recognized as susceptibility genes for Hirschsprung's disease \n(HD). Novel EDNRB mutations have been detected in non-syndromic HD patients with \nheterozygous forms, and homozygous mutations of the EDNRB or the EDN3 genes have \nbeen reported in HD patients associated with type 2 Waardenburg syndrome. These \nobservations confirm that impaired function of the endothelin-B receptor or \nendothelin-3 is involved in the aetiology of some human HD cases. EDNRB \nmutations appear to be associated with short-segment HD, in contrast to RET \nmutations, which are found mainly in long-segment aganglionosis.", "The study of vertebrate pigmentary anomalies has greatly improved our \nunderstanding of melanocyte biology. One such disorder, Waardenburg syndrome \n(WS), is a mendelian trait characterized by hypopigmentation and sensorineural \ndeafness. It is commonly subdivided into four types (WS1-4), defined by the \npresence or absence of additional symptoms. WS type 4 (WS4), or Shah-Waardenburg \nsyndrome, is also known as Hirschsprung disease Type II (HSCR II) and is \ncharacterized by an absence of epidermal melanocytes and enteric ganglia. \nMutations in the genes encoding the endothelin type-B receptor (EDNRB) and its \nphysiological ligand endothelin 3 (EDN3) are now known to account for the \nmajority of HSCR II patients. Null mutations in the mouse genes Ednrb and Edn3 \nhave identified a key role for this pathway in the normal development of \nmelanocytes and other neural crest-derived lineages. The pleiotropic effects of \ngenes in this pathway, on melanocyte and enteric neuron development, have been \nclarified by the embryologic identification of their common neural crest (NC) \nancestry. EDNRB and EDN3 are transiently expressed in crest-derived melanoblast \nand neuroblast precursors, and in the surrounding mesenchymal cells, \nrespectively. The influence of EDNRB-mediated signaling on the emigration, \nmigration, proliferation, and differentiation of melanocyte and enteric neuron \nprecursors, in vivo and in vitro has recently been the subject of great \nscrutiny. A major emergent theme is that EDN3-induced signaling prevents the \npremature differentiation of melanocyte and enteric nervous system precursors \nand is essential between 10 and 12.5 days post-coitum. We review the present \nunderstanding of pigment cell development in the context of EDNRB/EDN3--a \nreceptor-mediated pathway with pleiotropic effects.", "Hirschsprung disease (HSCR) exhibits complex genetics with incomplete penetrance \nand variable severity thought to result as a consequence of multiple gene \ninteractions that modulate the ability of enteric neural crest cells to populate \nthe developing gut. As reported previously, when the same null mutation of the \nEdnrb gene, Ednrb(sl), was introgressed into the F344 strain, almost 60% of \nF344-Ednrb(sl/sl) pups did not show any symptoms of aganglionosis, appearing \nhealthy and normally fertile. These findings strongly suggested that the \nseverity of HSCR was affected by strain-specific genetic factor (s). In this \nstudy, the genetic basis of such large strain differences in the severity of \naganglionosis in the rat model was studied by whole-genome scanning for \nquantitative trait loci (QTLs) using an intercross of \n(AGH-Ednrb(sl)×F344-Ednrb(sl)) F(1) with the varying severity of aganglionosis. \nGenome linkage analysis identified one significant QTL on chromosome 2 for the \nseverity of aganglionosis. Our QTL analyses using rat models of HSCR revealed \nthat multiple genetic factors regulated the severity of aganglionosis. Moreover, \na known HSCR susceptibility gene, Gdnf, was found in QTL that suggested a novel \nnon-coding sequence mutation in GDNF that modifies the penetrance and severity \nof the aganglionosis phenotype in EDNRB-deficient rats. A further identification \nand analysis of responsible genes located on the identified QTL could lead to \nthe richer understanding of the genetic basis of HSCR development.", "BACKGROUND: Enteric aganglionosis in Hirschsprung disease has been linked to \ngenes coding for endothelin-3 (EDN3) and the endothelin B receptor (EDNRB), but \nthere is no such linkage in most patients with sporadic Hirschsprung disease. \nHowever, the similarity between the distal colonic aganglionosis in Hirschsprung \ndisease and that due to EDN3 or EDNRB mutations led to the hypothesis that \nlevels of expression of these genes might be affected in the absence of \nmutation, thus causing the Hirschsprung disease phenotype. The aim of this study \nwas to determine EDN3 and EDNRB messenger RNA (mRNA) levels in tissue samples \nfrom patients with sporadic Hirschsprung disease.\nMETHODS: RNA and DNA were isolated from the ganglionic and aganglionic colonic \nsegments of ten children with sporadic Hirschsprung disease, and from the colon \nof ten age-matched controls. The DNA was analysed for mutations in the genes \ncoding for endothelin-3 (ET-3) and endothelin B receptor (ET-B) proteins. \nRelative levels of EDN3 and EDNRB mRNA were determined by semi-quantitative \ntranscriptase-polymerase chain reaction.\nRESULTS: Three children had sequence variants in EDN3 and EDNRB. In the \nremaining seven patients, EDN3 mRNA levels were reduced in both the ganglionic \nand aganglionic colon compared with levels in controls; there was no difference \nin expression of EDNRB between groups.\nCONCLUSION: In the absence of mutation, EDN3 is downregulated in short-segment \nHirschsprung disease, suggesting that this may be a common step leading to \naganglionosis.", "Enteric nervous system (ENS) development is relevant to Hirschsprung's disease \n(HSCR; congenital aganglionosis of the terminal bowel), which is still \nimperfectly treated. Mutations in genes encoding the RET receptor tyrosine \nkinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; \nhowever, also important in ENS development are molecules that mediate events \nthat are more restricted than those of RET and EDNRB, act later in development \nand which might not be HSCR-associated. Examples are molecules that function in \nthe guidance of enteric neural crest-derived cells (ENCDCs) and vagal axons, and \nin regulating the terminal differentiation of enteric neurons from ENCDCs. It is \nprobable that highly prevalent disorders of gastrointestinal sensation and \nmotility result from subtle defects in ENS development.", "Several missense mutations of the endothelin-B receptor (EDNRB) associated with \nHirschsprung disease have recently been identified. Five mutated EDNRB (A183G, \nW276C, R319W, M374I and P383L) cDNAs were transiently expressed in several cell \nlines to examine the effects of these mutations. Ligand-receptor binding \nexperiments demonstrated that all mutants examined here accept endothelins with \na high affinity. Especially, the affinity of endothelins to P383L was increased. \nHowever, the number of binding sites of A183G, W276C and P383L was markedly \ndecreased. The subcellular localization of these mutant receptors was the same \nas that of wild-type EDNRB, whereas the amount of protein of each mutant \nreceptor was decreased. All mutant receptors were impaired in intracellular \nCa(2+) mobilization. These findings indicate that these missense mutations \nresult in loss of function of EDNRB, and may provide the molecular pathological \nbasis of Hirschsprung disease in some individuals.", "BACKGROUND: Hirschsprung's disease (HSCR) is a congenital disorder characterised \nby an absence of ganglion cells in the nerve plexuses of the lower digestive \ntract. Manifestation of the disease has been linked to mutations in genes that \nencode the crucial signals for the development of the enteric nervous system-the \nRET and EDNRB signalling pathways. The Phox2b gene is involved in neurogenesis \nand regulates Ret expression in mice, in which disruption of the Phox2b results \nin a HSCR-like phenotype.\nAIMS: To investigate the contribution of PHOX2B to the HSCR phenotype.\nMETHODS: Using polymerase chain reaction amplification and direct sequencing, we \nscreened PHOX2B coding regions and intron/exon boundaries for mutations and \npolymorphisms in 91 patients with HSCR and 71 ethnically matched controls. \nSeventy five HSCR patients with no RET mutations were independently considered. \nHaplotype and genotype frequencies were compared using the standard case control \nstatistic.\nRESULTS: Sequence analysis revealed three new polymorphisms: two novel single \nnucleotide polymorphisms (A-->G(1364); A-->C(2607)) and a 15 base pair deletion \n(DEL(2609)). Statistically significant differences were found for A-->G(1364). \nGenotypes comprising allele G were underrepresented in patients (19% v 36%; \nchi(2)=9.30; p=0.0095 and 22% v 36%; chi(2)=7.38; p=0.024 for patients with no \nRET mutations). Pairwise linkage disequilibrium (LD) analysis revealed no LD \nbetween physically close polymorphisms indicating a hot spot for recombination \nin exon 3.\nCONCLUSION: The PHOX2B A-->G(1364) polymorphism is associated with HSCR. Whether \nit directly contributes to disease susceptibility or represents a marker for a \nlocus in LD with PHOX2B needs further investigation. Our findings are in \naccordance with the involvement of PHOX2B in the signalling pathways governing \nthe development of enteric neurones.", "Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence \nof ganglion cells in the nerve plexuses of the lower digestive tract. Although \nmutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, \nSIP1) have been identified in affected individuals, it is now clear that RET and \nEDNRB are the primary genes implicated in the etiology of HSCR. All eight genes \nare involved in the early development of the enteric nervous system, and most \nact through two distinct biochemical pathways mediated by RET and EDNRB. \nMutations in RET and EDNRB account for up to 50% and 5% of HSCR cases in the \ngeneral population, respectively. Interaction between these two signaling \npathways could modify RET expression and, therefore, HSCR phenotype. Here, we \nreport the case of a 1-year-old Taiwanese boy who presented with abdominal \ndistension since birth and bilious vomiting after feeding. HSCR (short-segment \ntype) was diagnosed based on X-ray, lower gastrointestinal series and biopsy \nfindings. Mutation analysis revealed a heterozygous T>C missense mutation in \nexon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90 \nresidue in the extracellular domain of the G protein-coupled receptor with an \narginine residue (C90R). No RET gene mutation was detected in this patient." ]	['http://www.disease-ontology.org/api/metadata/DOID:10487', 'http://www.uniprot.org/uniprot/EDNRB_MACFA', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D006627', 'http://www.uniprot.org/uniprot/EDNRB_MOUSE']
621ea5a53a8413c653000055	[ 27494529, 24040964, 16380164, 27448715, 22802958, 24490654, 21040800, 24311719, 16113065, 29022765, 10627503, 17150260, 20950340, 1480136, 18812234, 16169934, 27166927, 16490839, 28937442, 21742052, 22009066, 15026029, 28319086, 28328948, 14636671 ]	train	Are Epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 epoxygenases from arachidonic acid?	yesno	Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid	yes	[ "Maintenance of a healthy pool of mitochondria is important for the function and \nsurvival of terminally differentiated cells such as cardiomyocytes. \nEpoxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of \narachidonic acid by cytochrome P450 epoxygenases. We have previously shown that \nEETs trigger a protective response limiting mitochondrial dysfunction and \nreducing cellular death. The aim of this study was to investigate whether \nEET-mediated effects influence mitochondrial quality in HL-1 cardiac cells \nduring starvation. HL-1 cells were subjected to serum- and amino acid free \nconditions for 24h. We employed a dual-acting synthetic analog UA-8 \n(13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic and \nsoluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET \nmolecules. We demonstrated that EET-mediated events significantly improved \nmitochondrial function as assessed by preservation of the ADP/ATP ratio and \noxidative respiratory capacity. Starvation induced mitochondrial hyperfusion \nobserved in control cells was attenuated by UA-8. However, EET-mediated events \ndid not affect the expression of mitochondrial dynamic proteins Fis1, DRP-1 or \nMfn2. Rather we observed increased levels of OPA-1 oligomers and increased \nmitochondrial cristae density, which correlated with the preserved mitochondrial \nfunction. Increased DNA binding activity of pCREB and Nrf1/2 and increased SIRT1 \nactivity together with elevated mitochondrial proteins suggest EET-mediated \nevents led to preserved mitobiogenesis. Thus, we provide new evidence for \nEET-mediated events that preserve a healthier pool of mitochondria in cardiac \ncells following starvation-induced stress.", "In addition to their role as xenobiotic metabolizing enzymes, cytochrome P450 \n(CYP) epoxygenases actively contribute to the metabolism of endogenous \nsubstances such as arachidonic acid. Epoxyeicosatrienoic acids (EETs) are \nepoxide derivative of arachidonic acid. CYP2C8/9 and CYP2J2 are the main \nepoxygenases expressed in human tissues including endothelial cells which are \nthe chief sources of EET formation in human body. Once formed, EETs are \nprimarily metabolized to their less biologically active metabolites, \ndihydroxyeicosatrienoic acids, by soluble epoxy hydrolase (sEH) enzyme. EETs \npossess a wide range of established protective effects on human cardiovascular \nsystem of which vasodilatory, angiogenic and anti-inflammatory actions have been \nmore extensively described. On the other hand, inflammation has shown to \ndecrease the expression and activity of CYP enzyme, including epoxygenases. \nGiven the fact that CYP epoxygenase-derive EETs exhibit potent cardiovascular \nprotective effects, including anti-inflammation, and that inflammation suppress \nCYP activation and EET formation, it would make sense to speculate that under \ninflammatory conditions there exists an \ninflammation-epoxygenase-EET-inflammation vicious cycle in which the \ninflammation-induced downregulation of CYP epoxygenases causes a decrease in the \nEET production. Insufficient EET synthesis would, in turn, lead to an \nineffective EET-mediated anti-inflammatory effect, leading to an augmentation of \nsystemic and regional inflammatory responses and further downregulation of CYP \nepoxygenase activity/EET production. This cycle, if any, might help to better \nunderstanding of pathophysiology of chronic cardiovascular diseases and also \ncould be an emerging target for further pharmacological therapy of disorders in \nwhich increased inflammatory responses are known to occur.", "Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid by \ncytochrome P450 (CYP) epoxygenases. The expression of CYP epoxygenases in \nendothelial cells is determined by a number of physical (fluid shear stress and \ncyclic stretch) and pharmacological stimuli as well as by hypoxia. The \nactivation of CYP epoxygenases in endothelial cells is an important step in the \nnitric oxide and prostacyclin (PGI2)-independent vasodilatation of several \nvascular beds and EETs have been identified as endothelium-derived \nhyperpolarizing factors (EDHFs). However, in addition to regulating vascular \ntone, EETs modulate several signaling cascades and affect cell proliferation, \ncell migration, and angiogenesis. Signaling molecules modulated by EETs include \ntyrosine kinases and phosphatases, mitogen-activated protein kinases, protein \nkinase A (PKA), cyclooxygenase (COX)-2, and several transcription factors. This \nreview summarizes the role of CYP-derived EETs in cell signaling and focuses \nparticularly on their role as intracellular amplifiers of endothelial cell \nhyperpolarization as well as in cell proliferation and angiogenesis. The \nangiogenic properties of CYP epoxygenases and CYP-derived EETs implicate that \nthese enzymes may well be accessible targets for anti-angiogenic as well as \nangiogenic therapies.", "Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action \nof P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by \nhydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic \nacids. Studies in rodent models provide compelling evidence that \nepoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either \nby enhancing pancreatic islet cell function or by increasing insulin sensitivity \nin peripheral tissues. Specifically, the tissue expression of soluble epoxide \nhydrolase appears to be increased in rodent models of obesity and diabetes. \nPharmacological inhibition of epoxide hydrolase or deletion of the gene encoding \nsoluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type \n1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as \ndoes administration of epoxyeicosatrienoic acids or their stable analogues. In \nhumans, circulating concentrations of epoxyeicosatrienoic acids correlate with \ninsulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is \nassociated with insulin sensitivity.", "Epoxyeicosatrienoic acids (EETs), synthesized from arachidonic acid by \ncytochrome P450 epoxygenases, are converted to dihydroxyeicosatrienoic acids by \nsoluble epoxide hydrolase. EETs exert anti-inflammatory effects. However, the \neffect of EETs on humoral immunity is poorly understood. The present study is to \ninvestigate the potential role of EETs on B cell function and mechanisms. We \nexamined the role of EETs on antibody production of splenic B cells from C57BL/6 \nand apolipoprotein E-deficient (ApoE-/-) mice by means of ELISA. Of the 4 EET \nregioisomers, 8,9-EET decreased basal and activation-induced B cell antibody \nsecretion. As well, 8,9-EET significantly inhibited B-cell proliferation and \nsurvival, plasma cell differentiation and class-switch recombination. Western \nblot analysis revealed that lipopolysaccharide-induced nuclear translocation of \nNF-κB could be attenuated by 8,9-EET. Furthermore, germinal center formation was \nimpaired by 8,9-EET in mice in vivo. 8,9-EET may inhibit B-cell function in \nvitro and in vivo, which suggests a new therapeutic strategy for diseases with \nexcess B cell activation.", "INTRODUCTION: Cardiovascular diseases are a leading cause of death in developed \ncountries. Increasing evidence shows that the alteration in the normal functions \nof the vascular endothelium plays a major role in the development of \ncardiovascular diseases. However, specific agents designed to prevent \nendothelial dysfunction and related cardiovascular complications are still \nlacking. One emerging strategy is to increase the bioavailability of \nepoxyeicosatrienoic acids (EETs), synthesized by cytochrome P450 epoxygenases \nfrom arachidonic acid. EETs are endothelium-derived hyperpolarising and relaxing \nfactors and display attractive anti-inflammatory and metabolic properties. \nGenetic polymorphism studies in humans, and experiments in animal models of \ndiseases, have identified soluble epoxide hydrolase (sEH), the major enzyme \ninvolved in EET degradation, as a potential pharmacological target.\nAREAS COVERED: This review presents EET pathway and its functions and summarises \nthe data supporting the development of sEH inhibitors for the treatment of \ncardiovascular and metabolic diseases. Furthermore, the authors present the \ndifferent chemical families of sEH inhibitors developed and their effects in \nanimal models of cardiovascular and metabolic diseases.\nEXPERT OPINION: Several generations of sEH inhibitors have now been designed to \ntreat endothelial dysfunction and cardiovascular complications for a variety of \ndiseases. The safety of these drugs remains to be carefully investigated, \nparticularly in relation to carcinogenesis. The increasing knowledge of the \nbiological role of each of the EET isomers and of their metabolites may improve \ntheir pharmacological profile. This, in turn, could potentially lead to the \nidentification of new pharmacological agents that achieve the cellular effects \nneeded without the deleterious side effects.", "Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites produced by \ncytochrome P450 epoxygenases which are highly expressed in hepatocytes. The \nfunctions of EETs in hepatocytes are not well understood. In this study, we \ninvestigated the effects of 14,15-EETs treatment on the insulin signal \ntransduction pathway in hepatocytes. We report that chronic treatment, not acute \ntreatment, with 30 μM 14,15-EETs prevents palmitate induced insulin resistance \nand potentiates insulin action in cultured HepG2 hepatocytes. 14,15-EETs \nincrease Akt phosphorylation at S473, activating Akt, in an insulin dependent \nmanner in HepG2 cells. Under insulin resistant conditions induced by palmitate, \n14,15-EETs restore the insulin response by increasing S473-phosphorylated Akt. \n8,9-EETs and 11,12-EETs demonstrated similar effects to 14,15-EETs. Furthermore, \n14,15-EETs potentiate insulin-suppression of gluconeogenesis in cultured H4IIE \nhepatocytes. To elucidate the mechanism of EETs function, we analyzed the \ninsulin signaling factors upstream of Akt. Inhibition of phosphatidylinositol \n3-kinase (PI3K) with LY294002 attenuated the 14,15-EETs-induced activating \nphosphorylation of Akt. 14,15-EETs reduced palmitate-stimulated phosphorylation \nof IRS-1 on S312 and phosphorylation of c-Jun N-terminal kinase (JNK) at \nthreonine 183 and tyrosine 185 residues. The regulation of insulin sensitivity \nin cultured hepatocytes by chronic 14,15-EETs treatment appears to involve the \nJNK-IRS-PI3K pathway. The requirement of chronic treatment with EETs suggests \nthat the effects of EETs on insulin response may be indirect.", "The environmental toxin and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin \n(TCDD, dioxin) binds and activates the transcription factor aryl hydrocarbon \nreceptor (AHR), inducing CYP1 family cytochrome P450 enzymes. CYP1A2 and its \navian ortholog CYP1A5 are highly active arachidonic acid epoxygenases. \nEpoxygenases metabolize arachidonic acid to four regioisomeric \nepoxyeicosatrienoic acids (EETs) and selected monohydroxyeicosatetraenoic acids \n(HETEs). EETs can be further metabolized by epoxide hydrolases to \ndihydroxyeicosatrienoic acids (DHETs). As P450-arachidonic acid metabolites \naffect vasoregulation, responses to ischemia, inflammation, and metabolic \ndisorders, identification of their production in vivo is needed to understand \ntheir contribution to biologic effects of TCDD and other AHR activators. Here we \nreport use of an acetonitrile-based extraction procedure that markedly increased \nthe yield of arachidonic acid products by lipidomic analysis over a standard \nsolid-phase extraction protocol. We show that TCDD increased all four EETs \n(5,6-, 8,9-, 11,12-, and 14,15-), their corresponding DHETs, and 18- and 20-HETE \nin liver in vivo and increased 5,6-EET, the four DHETs, and 18-HETE in heart, in \na chick embryo model. As the chick embryo heart lacks arachidonic \nacid-metabolizing activity, the latter findings suggest that arachidonic acid \nmetabolites may travel from their site of production to a distal organ, i.e., \nheart. To determine if the TCDD-arachidonic acid-metabolite profile could be \naltered pharmacologically, chick embryos were treated with TCDD and the soluble \nepoxide hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). \nCotreatment with AUDA increased hepatic EET-to-DHET ratios, indicating that the \nin vivo profile of P450-arachidonic acid metabolites can be modified for \npotential therapeutic intervention.", "Epoxyeicosatrienoic acids (EETs), lipid mediators synthesized from arachidonic \nacid by cytochrome P-450 epoxygenases, are converted by soluble epoxide \nhydrolase (SEH) to the corresponding dihydroxyeicosatrienoic acids (DHETs). \nOriginally considered as inactive degradation products of EETs, DHETs have \nbiological activity in some systems. Here we examined the capacity of EETs and \nDHETs to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). \nWe find that among the EET and DHET regioisomers, 14,15-DHET is the most potent \nPPARalpha activator in a COS-7 cell expression system. Incubation with 10 microM \n14,15-DHET produced a 12-fold increase in PPARalpha-mediated luciferase \nactivity, an increase similar to that produced by the PPARalpha agonist Wy-14643 \n(20 microM). Although 10 microM 14,15-EET produced a threefold increase in \nluciferase activity, this was abrogated by the SEH inhibitor dicyclohexylurea. \n14-Hexyloxytetradec-5(Z)-enoic acid, a 14,15-EET analog that cannot be converted \nto a DHET, did not activate PPARalpha. However, PPARalpha was activated by \n2-(14,15-epoxyeicosatrienoyl)glycerol, which was hydrolyzed and the released \n14,15-EET converted to 14,15-DHET. COS-7 cells incorporated 14,15-[3H]DHET from \nthe medium, and the cells also retained a small amount of the DHET formed during \nincubation with 14,15-[3H]EET. Binding studies indicated that 14,15-[3H]DHET \nbinds to the ligand binding domain of PPARalpha with a Kd of 1.4 microM. \nFurthermore, 14,15-DHET increased the expression of carnitine \npalmitoyltransferase 1A, a PPARalpha-responsive gene, in transfected HepG2 \ncells. These findings suggest that 14,15-DHET, produced from 14,15-EET by the \naction of SEH, may function as an endogenous activator of PPARalpha.", "OBJECTIVE: Arachidonic acid metabolism by cytochrome P450 (CYP) epoxygenases \nleads to epoxyeicosatrienoic acids (EETs), which are eicosanoids with \nvasodilator and anti-inflammatory properties. We aim to determine whether \ngenetic variability in these routes may contribute to cardiovascular (CV) risk \nin renal transplant recipients.\nMETHODS: In a cohort of 355 patients, we determined the presence of two \npolymorphisms, CYP2C83 and CYP2J27, known to affect eicosanoid levels. \nAssociations with CV mortality, CV event-free long-term survival and graft \nsurvival were retrospectively investigated by logistic regression models.\nRESULTS: CYP2J27 showed a statistical trend towards higher CV mortality \n(p = .06) and lower cardiac or cerebral event-free long-term survival (p = .05), \nwhilst CYP2C83 displayed a significant inverse association with the risk of CV \nevent (hazard ratio [HR] = 0.34 [0.15-0.78], p = .01). The association of \nCYP2J27 with CV mortality became significant when the analysis was restrained \nto 316 patients without a history of CV events prior to transplantation \n(HR = 15.72 [2.83-91.94], p = .005). In this subgroup of patients both single \nnucleotide polymorphisms (SNPs) were significantly associated with event-free \nsurvival. HR values were 5.44 (1.60-18.51), p = .007 and 0.26 (0.09-0.75), \np = .012 for CYP2J27 and CYP2C8*3, respectively.\nCONCLUSIONS: Our results show, for the first time to our knowledge, that two \nSNPs in CYP2C8 and CYP2J2, which synthesize EETs, may modify CV outcomes in \nrenal transplant recipients, a population that is already at a high risk of \nsuffering these events.", "Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from \narachidonic acid by cytochrome P450 epoxygenases, are inactivated in many \ntissues by conversion to dihydroxyeicosatrienoic acids (DHETs). However, we find \nthat human skin fibroblasts convert EETs mostly to chain-shortened epoxy-fatty \nacids and produce only small amounts of DHETs. Comparative studies with \n[5,6,8,9,11,12,14,15-(3)H]11,12-EET ([(3)H]11,12-EET) and [1-(14)C]11,12-EET \ndemonstrated that chain-shortened metabolites are formed by removal of carbons \nfrom the carboxyl end of the EET. These metabolites accumulated primarily in the \nmedium, but small amounts also were incorporated into the cell lipids. The most \nabundant 11, 12-EET product was 7,8-epoxyhexadecadienoic acid (7,8-epoxy-16:2), \nand two of the others that were identified are 9, 10-epoxyoctadecadienoic acid \n(9,10-epoxy-18:2) and 5, 6-epoxytetradecaenoic acid (5,6-epoxy-14:1). The main \nepoxy-fatty acid produced from 14,15-EET was 10,11-epoxyhexadecadienoic acid \n(10, 11-epoxy-16:2). [(3)H]8,9-EET was converted to a single metabolite with the \nchromatographic properties of a 16-carbon epoxy-fatty acid, but we were not able \nto identify this compound. Large amounts of the chain-shortened 11,12-EET \nmetabolites were produced by long-chain acyl CoA dehydrogenase-deficient \nfibroblasts but not by Zellweger syndrome and acyl CoA oxidase-deficient \nfibroblasts. We conclude that the chain-shortened epoxy-fatty acids are produced \nprimarily by peroxisomal beta-oxidation. This may serve as an alternate \nmechanism for EET inactivation and removal from the tissues. However, it is \npossible that the epoxy-fatty acid products may have metabolic or functional \neffects and that the purpose of the beta-oxidation pathway is to generate these \nproducts.", "Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome \nP450 epoxygenases, are potent vasodilators that function as endothelium-derived \nhyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by \nsoluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent \nreports indicate that EETs have several important non-vasomotor regulatory roles \nin the cardiovascular system. EETs are potent anti-inflammatory agents and might \nfunction as endogenous anti-atherogenic compounds. In addition, EETs and DHETs \nmight stimulate lipid metabolism and regulate insulin sensitivity. Thus, \npharmacological inhibition of soluble epoxide hydrolase might be useful not only \nfor hypertension but also for abating atherosclerosis, diabetes mellitus and the \nmetabolic syndrome. Finally, although usually protective in the systemic \ncirculation, EETs might adversely affect the pulmonary circulation.", "Epoxyeicosatrienoic acids (EETs) are bioactive eicosanoids produced from \narachidonic acid by cytochrome P450 epoxygenases. We previously described the \nexpression of cytochrome P450-2J epoxygenase in rat trigeminal ganglion neurons \nand that EETs signaling is involved in cerebrovascular dilation resulting from \nperivascular nerve stimulation. In this study, we evaluate the presence of the \nEETs signaling pathway in trigeminal ganglion neurons and their role in \nmodulating the release of calcitonin gene-related peptide (CGRP) by trigeminal \nganglion neurons. Liquid chromatography tandem mass spectrometry identified the \npresence of each of the four EETs regio-isomers within primary trigeminal \nganglion neurons. Stimulation for 1 h with the transient receptor potential \nvanilloid-1 channel agonist capsaicin (100 nmol/L) or depolarizing K(+) (60 \nmmol/L) increased CGRP release as measured by ELISA. Stimulation-evoked CGRP \nrelease was attenuated by 30 min pre-treatment with the EETs antagonist \n14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 μmol/L). K(+) stimulation \nelevated CGRP release 2.9 ± 0.3-fold above control levels, whereas in the \npresence of 14,15-EEZE K(+)-evoked CGRP release was significantly reduced to 1.1 \n± 0.2-fold above control release (p < 0.01 anova, n = 6). 14,15-EEZE likewise \nattenuated capsaicin-evoked CGRP release from trigeminal ganglion neurons (p < \n0.05 anova, n = 6). Similarly, pre-treatment with the cytochrome P450 \nepoxygenase inhibitor attenuated stimulation-evoked CGRP release. These data \ndemonstrate that EETs are endogenous constituents of rat trigeminal ganglion \nneurons and suggest that they may act as intracellular regulators of \nneuropeptide release, which may have important clinical implications for \ntreatment of migraine, stroke and vasospasm after subarachnoid hemorrhage.", "Microsomes prepared from COS-1 cells transiently expressing rabbit cytochromes \nP450 2C1 and 2C2 catalyzed the metabolism of arachidonic acid to predominantly \n11,12- and 14,15-epoxyeicosatrienoic acids (EETs) when microsomal epoxide \nhydrolase activity was inhibited by 0.2 mM 1,2-epoxy-3,3,3-trichloropropane. \nP450 2C2 catalyzed the formation of 11,12-EET and 14,15-EET at a ratio of 3.0 \nand also produced 19-hydroxyeicosatetraenoic acid (19-HETE). The 11,12-EET, \n14,15-EET, and 19-HETE represented 48.3, 15.9, and 12.8%, respectively, of the \ntotal metabolites formed. P450 2C1 produced a similar but distinct ratio of \n11,12-EET to 14,15-EET (2.0) and did not produce any detectable 19-HETE. The \n11,12-EET and 14,15-EET represented 63.0 and 31.1%, respectively, of the total \nmetabolites formed. The 8,9- and 5,6-EETs were not detected with either enzyme. \nThe ratio of the 11,12-EET to 14,15-EET was 1.5 with P450 2CAA, a P450 \narachidonic acid epoxygenase (P450 2CAA) that had an amino-terminal sequence \nidentical to that of P450 2C2 [J. Biol. Chem. 267:5552-5559 (1992)]. P450 2C1, \n2C2, and 2CAA metabolized lauric acid. The ratio of omega-1- to \nomega-hydroxylated laurate was 3.6, 3.4, and 2.4 for P450 2CAA, P450 2C2, and \nP450 2C1, respectively. Purified P450 2CAA had a slightly greater apparent \nmolecular weight than expressed P450 2C2 on sodium dodecyl \nsulfate-polyacrylamide gels. The results clearly establish that rabbit P450 2C1 \nand 2C2 are arachidonic acid epoxygenases, and they suggest that P450 2CAA and \n2C2 are very similar but may not be identical isoforms.", "Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid by \ncytochrome P450 epoxygenases in endothelial cells. It has previously been shown \nthat EETs activate K(+) channels, which are important for the hyperpolarization \nand dilation of blood vessels. However, the effects of EETs on other ion \nchannels have been less well studied. We investigated the effects of EETs on \nvolume-activated Cl(-) channels (VACCs) in rat mesenteric arterial smooth muscle \ncells. Whole-cell patch clamp recording demonstrated that hypotonic solution and \nguanosine 5'-[gamma-thio]triphosphate (GTPgammaS) induced a \n5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB)- and \n4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)-sensitive VACC current \nin the primary cultured rat mesenteric arterial smooth muscle cells. The VACC \ncurrent was inhibited by EETs and the order of potency was \n8,9-EET>5,6-EET>11,12-EET>14,15-EET. The inhibitory effects of EETs could be \nreversed by 14,15 epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an EET analog), \nRp-cGMP and KT-5823 (protein kinase G inhibitors). Interestingly, the inhibitory \neffects of EETs on VACCs were not influenced by Rp-cAMP (a protein kinase A \nantagonist) but it could be abolished by NF-449 (a Gs protein inhibitor), \nindicating the involvement of cAMP but not protein kinase A. In conclusion, our \nresults demonstrate that EETs inhibit VACCs in rat mesenteric arterial smooth \nmuscle cells through a cGMP-dependent pathway, which is probably due to the \ncross-activation by cAMP. This mechanism may be involved in the regulation of \ncell volume and membrane potential.", "The epidermis expresses cyclooxygenases, lipoxygenases, and cytochromes P450, \nwhich utilize arachidonic acid to generate a diverse array of lipid mediators \naffecting epidermal cellular differentiation and functions. Recent studies show \nthat mouse epidermis expresses CYP2B19, a keratinocyte-specific epoxygenase that \ngenerates 11,12- and 14,15-epoxyeicosatrienoic (EET) acids from arachidonate. We \nstudied CYP2B19-dependent metabolism in mouse epidermal microsomes, \nreconstituted in the presence of [1-(14)C]arachidonic acid. The majority of the \n(14)C products formed independently of NADPH, indicative of robust epidermal \ncyclooxygenase and lipoxygenase activities. We studied two NADPH-dependent \nproducts generated in a highly reproducible manner from arachidonate. One of \nthese (product I) coeluted with the CYP2B19 product 14,15-EET on a \nreversed-phase high-performance liquid chromatography (HPLC) system; there was \nno evidence for other regioisomeric EET products. Further analyses proved that \nproduct I was not an epoxy fatty acid, based on different retention times on a \nnormal-phase HPLC system and failure of product I to undergo hydrolysis in \nacidic solution. We analyzed purified epidermal (14)C products by liquid \nchromatography negative electrospray ionization mass spectrometry. Structures of \nthe NADPH-dependent products were confirmed to be 12-oxo-5,8,14-eicosatrienoic \nacid (I) and 12-hydroxy-5,8,14-eicosatrienoic acid (II). This was the first \nevidence for a 12-hydroxy-5,8,14-eicosatrienoic acid biosynthetic pathway in \nmouse epidermis. Epidermal microsomes also generated 12-hydroperoxy, 12-hydroxy, \nand 12-oxo eicosatetraenoic acids from arachidonate, possible intermediates in \nthe 12-hydroxy-5,8,14-eicosatrienoic acid biosynthetic pathway. These results \npredict that hydroxyeicosatrienoic acids are synthesized from arachidonate in \nhuman epidermis. This would have important implications for human skin diseases \ngiven the known pro- and anti-inflammatory activities of stereo- and \nregioisomeric hydroxyeicosatrienoic acids.", "Epoxyeicosatrienoic acids (EETs) are potent lipid mediators formed by cytochrome \nP450 epoxygenases from arachidonic acid. They consist of four regioisomers of \ncis-epoxyeicosatrienoic acids: 5,6-, 8,9-, 11,12- and 14,15-EET. Here we \ninvestigated whether these triene epoxides are electrophilic enough to form \ncovalent adducts with DNA in vitro. Using the thin-layer chromatography (TLC) \n(32)P-postlabelling method for adduct detection we studied the reaction of \nindividual deoxynucleoside 3'-monophosphates and calf thymus DNA with the four \nracemic EETs. Under physiological conditions (pH 7.4) only ±11,12-EET11,12-EET \nformed adducts with DNA in a dose dependent manner detectable by the \n(32)P-postlabelling method. However, when pre-incubated at pH 4 all four racemic \nEETs were capable to bind to DNA forming several adducts. Under these conditions \nhighest DNA adduct levels were found with ±11,12-EET followed by ±5,6-EET, \n±8,9-EET, and ±14,15-EET, all of them two orders of magnitude higher (between 3 \nand 1 adducts per 10(5) normal nucleotides) than those obtained with ±11,12-EET \nat pH 7.4. Similar DNA adduct patterns consisting of up to seven spots were \nobserved with all four racemic EETs the most abundant adducts being derived from \nthe reaction with deoxyguanosine and deoxyadenosine. In summary, when analysed \nby the (32)P-postlabelling method all four racemic EETs formed multiple DNA \nadducts after activation by acidic pH, only ±11,12-EET produced DNA adducts in \naqueous solution at neutral pH. Therefore, we conclude from our in vitro studies \nthat EETs might be endogenous genotoxic compounds.", "Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid generated by \ncytochrome P450 (CYP) epoxygenases. The activation of CYP epoxygenases in \nendothelial cells is an important step in the NO and prostacyclin-independent \nvasodilatation of several vascular beds, and EETs have been identified as an \nendothelium-derived hyperpolarizing factor. However, EETs also exert membrane \npotential-independent effects and modulate several signaling cascades that \naffect endothelial cell proliferation and angiogenesis. This review summarizes \nthe role of CYP-derived EETs in endothelium-derived hyperpolarizing \nfactor-mediated responses and highlights the evidence indicating that EETs are \nimportant second messengers involved in endothelial cell signaling pathways \nrelated to angiogenesis.", "Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized \nfrom arachidonic acid by cytochrome P450 epoxygenases of endothelial, \nmyocardial, and renal tubular cells. EETs relax vascular smooth muscle and \ndecrease inflammatory cell adhesion and cytokine release. Renal EETs promote \nsodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce \ninfarct size after ischemia-reperfusion injury and decrease fibrosis and \ninflammation in heart failure. In diabetes, EETs improve insulin sensitivity, \nincrease glucose tolerance, and reduce the renal injury. These actions of EETs \nemphasize their therapeutic potential. To minimize metabolic inactivation, \n14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl \nsurrogates were developed. In preclinical rat models, a subset of agonist \nanalogs, termed EET-A, EET-B, and EET-C22, are orally active with good \npharmacokinetic properties. These orally active EET agonists lower blood \npressure and reduce cardiac and renal injury in spontaneous and angiotensin \nhypertension. Other beneficial cardiovascular actions include improved \nendothelial function and cardiac antiremodeling actions. In rats, EET analogs \neffectively combat acute and chronic kidney disease including drug- and \nradiation-induced kidney damage, hypertension and cardiorenal syndrome kidney \ndamage, and metabolic syndrome and diabetes nephropathy. The compelling \npreclinical efficacy supports the prospect of advancing EET analogs to human \nclinical trials for kidney and cardiovascular diseases.", "Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into \nepoxyeicosatrienoic acids (EETs), which play important and diverse roles in the \ncardiovascular system. The anti-inflammatory, anti-apoptotic, pro-angiogenic, \nand anti-hypertensive properties of EETs in the cardiovascular system suggest a \nbeneficial role for EETs in diabetic nephropathy. This study investigated the \neffects of endothelial specific overexpression of CYP2J2 epoxygenase on diabetic \nnephropathy in streptozotocin-induced diabetic mice. Endothelial CYP2J2 \noverexpression attenuated renal damage as measured by urinary microalbumin and \nglomerulosclerosis. These effects were associated with inhibition of TGF-β/Smad \nsignaling in the kidney. Indeed, overexpression of CYP2J2 prevented \nTGF-β1-induced renal tubular epithelial-mesenchymal transition in vitro. These \nfindings highlight the beneficial roles of the CYP epoxygenase-EET system in the \npathogenesis of diabetic nephropathy.", "Inflammation and angiogenesis in the tumor microenvironment are increasingly \nimplicated in tumorigenesis. Endogenously produced lipid autacoids, locally \nacting small-molecule mediators, play a central role in inflammation and tissue \nhomeostasis. These lipid mediators, collectively referred to as eicosanoids, \nhave recently been implicated in cancer. Although eicosanoids, including \nprostaglandins and leukotrienes, are best known as products of arachidonic acid \nmetabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a \nsubstrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This \neicosanoid pathway consists of two main branches: ω-hydroxylases which converts \narachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which \nconverts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, \n8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular \ntone. The bioactive EETs are produced predominantly in the endothelium and are \nmainly metabolized by soluble epoxide hydrolase to less active \ndihydroxyeicosatrienoic acids. EET signaling was originally studied in \nconjunction with inflammatory and cardiovascular disease. Arachidonic acid and \nits metabolites have recently stimulated great interest in cancer biology. To \ndate, most research on eicosanoids in cancer has focused on the COX and LOX \npathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as \nEETs and HETEs, in cancer has received little attention. While CYP epoxygenases \nare expressed in human cancers and promote human cancer metastasis, the role of \nEETs (the direct products of CYP epoxygenases) in cancer remains poorly \ncharacterized. In this review, the emerging role of EET signaling in \nangiogenesis, inflammation, and cancer is discussed.", "Arachidonic acid metabolites contribute to the regulation of vascular tone and \ntherefore tissue blood flow. The vascular endothelium metabolizes arachidonic \nacid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The \nplacement of the epoxide group can occur on any of the double bonds of \narachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and \n14,15-EET. In the vasculature, EETs are key components of cellular signaling \ncascades that culminate in the activation of smooth muscle potassium channels to \ninduce membrane hyperpolarization and vascular relaxation. In some vasculatures \nsuch as bovine coronary arteries, EET regioisomers are equipotent in inducing \nrelaxations, while in other arteries, a specific EET regioisomer induces \nrelaxation while others do not. Therefore, the position of the double bonds \nand/or the epoxide group may alter vascular agonist activity. This observation \nsuggests that small alterations in the chemical structure of EETs can \nsignificantly impact vascular activity. To explore this hypothesis, we \nsynthesized a series of EET analogs and characterized their vasodilator agonist \nand antagonist activity in bovine coronary arteries. In this chapter, we first \nreview the mechanisms of EET-dependent relaxations in bovine coronary arteries \nto familiarize the reader with the role of EETs in these arteries. The second \ncomponent is a synopsis of the functional characterization of the 14,15-EET \nanalogs and the resulting description of structural components required for \nvascular dilator activity. Lastly, we discussed the characterization of three \n14,15-EET analogs with specific EET-antagonist activity and compared this to the \nactivity of similar 11,12-EET analogs. These studies have revealed that specific \nstructural components of the 14,15-EET molecule are critical for dilator \nactivity and that alteration of these components influences agonist activity and \nmay confer antagonist properties.", "Epoxyeicosatrienoic acids (EETs) are the epoxidation products of arachidonic \nacid catalyzed by cytochrome P450 (CYP) epoxygenases, which possess multiple \nbiological activities. In the present study, we aimed to explore the role and \neffects of CYP epoxygenases/EETs in wound healing in ob/ob mice. Full-thickness \nskin dorsal wounds were made on ob/ob mice and C57BL/6 control mice. The mRNA \nand protein expression of CYP epoxygenases were determined in granulation \ntissues of wounds. Effects of EETs on wound healing were evaluated. Inflammation \nand angiogenesis in wounds were also observed. Compared with C57BL/6 mice, the \nmRNA and protein expression of CYP2C65 and CYP2J6 in the granulation tissues in \nob/ob mice were significantly reduced. 11,12-EET treatment significantly \nimproved wound healing in ob/ob mice, whereas 14,15-EEZE, an EET antagonist, \nshowed the opposite effect. 11,12-EET treatment decreased neutrophil and \nmacrophage infiltration to the wound sites, resulting in reduced production of \ninflammatory cytokines, decreased MMP-9 expression, and increased collagen \naccumulation in the granulation tissues of ob/ob mice. In addition, 11,12-EET \nincreased angiogenesis in the granulation tissues of wounds in ob/ob mice. These \nfindings indicate that reduced expression of CYP epoxygenases may contribute to \nimpaired diabetic wound healing, and exogenous EETs may improve diabetic wound \nhealing by modulating inflammation and angiogenesis.", "Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by \ncytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic \nacids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic \neffects; EETs are vasodilatory and protect against ischemia/reperfusion injury, \nwhile ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. \nOther oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), \nhydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular \neffects. Post-ischemic vasodilation in the heart, known as coronary reactive \nhyperemia (CRH), protects against potential damage to the heart muscle caused by \nischemia. The relationship among CRH response to ischemia, in mice with altered \nlevels of CYP2J epoxygenases has not yet been investigated. Therefore, we \nevaluated the effect of endothelial overexpression of the human cytochrome P450 \nepoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. \nAdditionally, we evaluated the effect of pharmacologic inhibition of \nCYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that \nCRH would be enhanced in isolated mouse hearts with vascular endothelial \noverexpression of human CYP2J2 through modulation of oxylipin profiles. \nSimilarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, \nwhereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, \nTie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment \nduration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of \nω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 \nTr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 \nsignificantly changed oxylipin profiles, including increased EETs (P < 0.05), \nincreased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of \nCYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a \ndecrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < \n0.05). These data demonstrate that vascular endothelial overexpression of \nCYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP \nepoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.", "Epoxyeicosatrienoic acids (EETs), which are synthesized from arachidonic acid by \ncytochrome P450 epoxygenases, function primarily as autocrine and paracrine \neffectors in the cardiovascular system and kidney. They modulate ion transport \nand gene expression, producing vasorelaxation as well as anti-inflammatory and \npro-fibrinolytic effects. EETs are incorporated into the sn-2 position of \nphospholipids and are rapidly mobilized when a cell is treated with a Ca(2+) \nionophore, suggesting that they may play a role in phospholipid-mediated signal \ntransduction processes. Soluble epoxide hydrolase (sEH) converts EETs to \ndihydroxyeicosatrienoic acids (DHETs), and inhibition of sEH is a potential \napproach for enhancing the biological activity of EETs. EETs also undergo \nchain-elongation and beta-oxidation, and the accumulation of partial \nbeta-oxidation products increases when sEH is inhibited. Some functional effects \nof EETs occur through activation of either the guanine nucleotide binding \nprotein Galphas or the Src signal transduction pathways, suggesting that EETs \nact by binding to membrane receptors. However, other evidence indicates that the \nmodulation of gene expression occurs through an intracellular action of EETs. \nBecause of the diversity of biochemical and functional responses produced by \nEETs, it is doubtful that a single mechanism or signal transduction pathway can \naccount for all of their actions." ]	nan
62211b973a8413c65300006c	[ 33213893, 26845351, 34459951, 28620243, 24030712, 26908447 ]	train	Are G-quadruplexes(G4) possible drug targets for glioblastoma?	yesno	The 2H2-6M(4)-oxazole telomestatin derivative (6OTD) targets Glioma stem cells through G4 stabilization and promotion of DNA damage responses. Therefore, G4s are promising therapeutic targets for glioblastoma.	yes	[ "The G-quadruplex (G4) DNA, which has been developed as a potential anticancer \ntarget in drug screening and design, plays a crucial role in the oncogene \ntranscription and translation. Tanshinone IIA derivatives with a planar \nheterocycle structure may function as G4 stabilizers. We present an innovative \ncase of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 \nthat improve the selectivity and the binding affinity with G4 DNA and enhance \nthe target tumor inhibition. Cellular and in vivo experiments indicate that the \ntanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of \ntriple-negative breast cancer cells possibly through the stabilization of \nmultiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further \ninvestigation of the intermolecular interaction and the molecular docking \nindicates that tanshinone IIA derivatives have better selective binding \ncapability to various G4 DNAs than to double-stranded DNA. These findings \nprovide guidance in modifying the molecular structures of tanshinone IIA \nderivatives and reveal their potential to function as specific G4 stabilizers.", "Glioblastoma (GBM) is an invariably fatal brain tumor in which a small \nsubpopulation of self-renewable glioma stem cells (GSCs) contributes to tumor \npropagation and relapse. Targeting GSCs could therefore have a significant \nclinical impact for GBM. Telomestatin is a naturally-occurring compound that \npreferentially impairs GSC growth by perturbing transcription and inducing a DNA \ndamage response. Telomestatin stabilizes G-quadruplexes (G4s), which are \nguanine-rich four-strand nucleic acid structures observed in vitro and in vivo. \nHowever, the mechanism underlying the GSC-selective nature of the DNA damage \nresponse remains unknown. Here we demonstrate that GSCs are more susceptible to \ntelomestatin-induced telomere dysfunction and replication stress when compared \nwith GSC-derived non-stem glioma cells (NSGCs). Telomestatin induced \ndissociation of the telomere-capping protein TRF2 from telomeres, leading to \ntelomeric DNA damage in GSCs-but not in NSGCs. BIBR1532, a telomerase catalytic \ninhibitor, did not preferentially inhibit GSC growth, suggesting that \ntelomestatin promotes telomere dysfunction in a telomerase-independent manner. \nGSCs and NSGCs had comparable levels of G4s in their nuclei, and both responded \nto telomestatin with phosphorylation of RPA2 at Ser33-a hallmark of replication \nstress. However, activation of the checkpoint kinase Chk1, induction of a DNA \ndamage response, and subsequent growth inhibition occurred only in \ntelomestatin-treated GSCs. These observations suggest that telomestatin impairs \nGSC growth through removal of TRF2 from telomeres and potent activation of the \nreplication stress response pathway. Therefore, a novel G4-directed therapeutic \nstrategy could specifically target cancer stem cells in GBM.", "Author information:\n(1)Experimental Medicine Center, The Affiliated Hospital of Southwest Medical \nUniversity, Luzhou, 646000, Sichuan, China.\n(2)Department of Endocrinology and Metabolism, The Affiliated Hospital of \nSouthwest Medical University, Luzhou, 646000, Sichuan, China.\n(3)Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, and Sichuan \nClinical Research Center for Nephropathy, and Academician (Expert) Workstation \nof Sichuan Province, The Affiliated Hospital of Southwest Medical University, \nLuzhou, 646000, Sichuan, China.\n(4)State Key Laboratory of Crop Stress Biology for Arid Areas and College of \nLife Sciences, Northwest A&F University, Yangling, 712100, Shaanxi, China.\n(5)State Key Laboratory of Crop Stress Biology for Arid Areas and College of \nLife Sciences, Northwest A&F University, Yangling, 712100, Shaanxi, China. \nxxi01@ens-cachan.fr.\n(6)LBPA, Ecole Normale Supérieure Paris-Saclay, CNRS, Université Paris Saclay, \n61, Avenue du Président Wilson, 94235, Cachan, France. xxi01@ens-cachan.fr.\n(7)Experimental Medicine Center, The Affiliated Hospital of Southwest Medical \nUniversity, Luzhou, 646000, Sichuan, China. xywyll@swmu.edu.cn.\n(8)Department of Endocrinology and Metabolism, The Affiliated Hospital of \nSouthwest Medical University, Luzhou, 646000, Sichuan, China. \nxywyll@swmu.edu.cn.\n(9)Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, and Sichuan \nClinical Research Center for Nephropathy, and Academician (Expert) Workstation \nof Sichuan Province, The Affiliated Hospital of Southwest Medical University, \nLuzhou, 646000, Sichuan, China. xywyll@swmu.edu.cn.\n(#)Contributed equally", "G-quadruplex (G4) is a higher-order nucleic acid structure that is formed by \nguanine-rich sequences. G4 stabilization by small-molecule compounds called G4 \nligands often causes cytotoxicity, although the potential medicinal impact of \nthis effect has not been fully established. Here we demonstrate that a synthetic \nG4 ligand, Y2H2-6M(4)-oxazole telomestatin derivative (6OTD), limits the growth \nof intractable glioblastoma (grade IV glioma) and glioma stem cells (GSCs). \nExperiments involving a human cancer cell line panel and mouse xenografts \nrevealed that 6OTD exhibits antitumor activity against glioblastoma. 6OTD \ninhibited the growth of GSCs more potently than it did the growth of \ndifferentiated non-stem glioma cells (NSGCs). 6OTD caused DNA damage, G1 cell \ncycle arrest, and apoptosis in GSCs but not in NSGCs. These DNA damage foci \ntended to colocalize with telomeres, which contain repetitive G4-forming \nsequences. Compared with temozolomide, a clinical DNA-alkylating agent against \nglioma, 6OTD required lower concentrations to exert anti-cancer effects and \npreferentially affected GSCs and telomeres. 6OTD suppressed the intracranial \ngrowth of GSC-derived tumors in a mouse xenograft model. These observations \nindicate that 6OTD targets GSCs through G4 stabilization and promotion of DNA \ndamage responses. Therefore, G4s are promising therapeutic targets for \nglioblastoma.", "Guanine-rich oligonucleotides (GROs) are promising therapeutic candidate for \ncancer treatment and other biomedical application. We have introduced a \nG-quadruplex (G4) ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole \ndiiodide, to monitor the cellular uptake of naked GROs and map their \nintracellular localizations in living cells by using confocal microscopy. The \nGROs that form parallel G4 structures, such as PU22, T40214 and AS1411, are \ndetected mainly in the lysosome of CL1-0 lung cancer cells after incubation for \n2 h. On the contrary, the GROs that form non-parallel G4 structures, such as \nhuman telomeres (HT23) and thrombin binding aptamer (TBA), are rarely detected \nin the lysosome, but found mainly in the mitochondria. Moreover, the \nfluorescence resonant energy transfer studies of fluorophore-labeled GROs show \nthat the parallel G4 structures can be retained in CL1-0 cells, whereas the \nnon-parallel G4 structures are likely distorted in CL1-0 cells after cellular \nuptake. Of interest is that the distorted G4 structure of HT23 from the \nnon-parallel G4 structure can reform to a probable parallel G4 structure induced \nby a G4 ligand in CL1-0 living cells. These findings are valuable to the design \nand rationale behind the possible targeted drug delivery to specific cellular \norganelles using GROs.", "Interference with telomerase and telomere maintenance is emerging as an \nattractive target for anticancer therapies. Ligand-induced stabilization of \nG-quadruplex formation by the telomeric DNA 3'-overhang inhibits telomerase from \ncatalyzing telomeric DNA synthesis and from capping telomeric ends, making these \nligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the \nmost effective and specific ligand for telomeric G4. It is shown here that \nBRACO-19 suppresses proliferation and reduces telomerase activity in human \nglioblastoma cells, paralleled by the displacement of telomerase from nuclear to \ncytoplasm. Meanwhile, BRACO-19 triggers extensive DNA damage response at \ntelomere, which may result from uncapping and disassembly of telomeric T-loop \nstructure, characterized by the formation of anaphase bridge and telomere \nfusion, as well as the release of telomere-binding protein from telomere. The \nresulting dysfunctional telomere ultimately provokes p53 and p21-mediated cell \ncycle arrest, apoptosis and senescence. Notably, normal primary astrocytes do \nnot respond to the treatment of BRACO-19, suggesting the agent's good \nselectivity for cancer cells. These results reinforce the notion that \nG-quadruplex binding compounds can act as broad inhibitors of telomere-related \nprocesses and have potential as selective antineoplastic drugs for various \ntumors including malignant gliomas." ]	nan
6032187e1cb411341a000132	[ 31675472, 31776460, 31988111 ]	train	Are Gram positive bacteria able to release extracellular vesicles?	yesno	Yes, Gram-negative and Gram-positive bacteria release a variety of membrane vesicles through different formation routes.	yes	[ "Filifactor alocis, a gram-positive, obligate anaerobic rod, is an emerging \nperiodontal pathogen that is frequently isolated from patients with \nperiodontitis, peri-implantitis, and apical periodontitis. Recent studies have \nshown that extracellular vesicles (EVs) from gram-negative periodontal \npathogens, so-called outer membrane vesicles (OMVs), harbor various effector \nmolecules responsible for inducing host inflammatory responses. However, there \nare no reports of EVs from F. alocis. In this study, we purified and \ncharacterized the protein profiles of EVs from F. alocis and investigated their \nimmunostimulatory activity on human monocytic THP-1 and human oral keratinocyte \nHOK-16B cell lines. Highly pure EVs were obtained from F. alocis using density \ngradient ultracentrifugation. Nanoparticle tracking analysis and transmission \nelectron microscopy showed that F. alocis EVs were between 50 and 270 nm in \ndiameter. Proteome analysis identified 28 proteins, including lipoproteins, \nautolysins, F. alocis complement inhibitor (FACIN), transporter-related \nproteins, metabolism-related proteins, and ribosomal proteins. Human cytokine \narray analysis showed that F. alocis EVs remarkably induced the expression of \nCCL1, CCL2, MIP-1, CCL5, CXCL1, CXCL10, ICAM-1, IL-1β, IL-1ra, IL-6, IL-8, MIF, \nSerpinE, and TNF-α in THP-1 cells and CXCL1, G-CSF, GM-CSF, IL-6, and IL-8 in \nHOK-16B cells. The immunostimulatory activity of F. alocis EVs was similar to \nthat of the whole bacterial cells. Our findings provide new insight into the \nrole of EVs from gram-positive oral bacteria in periodontal diseases.", "Gram-negative and Gram-positive bacteria release a variety of membrane vesicles \nthrough different formation routes. Knowledge of the structure, molecular cargo \nand function of bacterial extracellular vesicles (BEVs) is primarily obtained \nfrom bacteria cultured in laboratory conditions. BEVs in human body fluids have \nbeen less thoroughly investigated most probably due to the methodological \nchallenges in separating BEVs from their matrix and host-derived eukaryotic \nextracellular vesicles (EEVs) such as exosomes and microvesicles. Here, we \npresent a step-by-step procedure to separate and characterize BEVs from human \nbody fluids. BEVs are separated through the orthogonal implementation of \nultrafiltration, size-exclusion chromatography (SEC) and density-gradient \ncentrifugation. Size separates BEVs from bacteria, flagella and cell debris in \nstool; and blood cells, high density lipoproteins (HDLs) and soluble proteins in \nblood. Density separates BEVs from fibers, protein aggregates and EEVs in stool; \nand low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), \nchylomicrons, protein aggregates and EEVs in blood. The procedure is label free, \nmaintains the integrity of BEVs and ensures reproducibility through the use of \nautomated liquid handlers. Post-separation BEVs are characterized using \northogonal biochemical endotoxin and Toll-like receptor-based reporter assays in \ncombination with proteomics, electron microscopy and nanoparticle tracking \nanalysis (NTA) to evaluate BEV quality, abundance, structure and molecular \ncargo. Separation and characterization of BEVs from body fluids can be done \nwithin 72 h, is compatible with EEV analysis and can be readily adopted by \nresearchers experienced in basic molecular biology and extracellular vesicle \nanalysis. We anticipate that this protocol will expand our knowledge on the \nbiological heterogeneity, molecular cargo and function of BEVs in human body \nfluids and steer the development of laboratory research tools and clinical \ndiagnostic kits.", "Release of extracellular vesicles (EVs) is a common feature among eukaryotes, \narchaea, and bacteria. However, the biogenesis and downstream biological effects \nof EVs released from gram-positive bacteria remain poorly characterized. Here, \nwe report that EVs purified from a community-associated methicillin-resistant \nStaphylococcus aureus strain were internalized into human macrophages in vitro \nand that this process was blocked by inhibition of the dynamin-dependent \nendocytic pathway. Human macrophages responded to S. aureus EVs by TLR2 \nsignaling and activation of NLRP3 inflammasomes through K+ efflux, leading to \nthe recruitment of ASC and activation of caspase-1. Cleavage of pro-interleukin \n(IL)-1β, pro-IL-18, and gasdermin-D by activated caspase-1 resulted in the \ncellular release of the mature cytokines IL-1β and IL-18 and induction of \npyroptosis. Consistent with this result, a dose-dependent cytokine response was \ndetected in the extracellular fluids of mice challenged intraperitoneally with \nS. aureus EVs. Pore-forming toxins associated with S. aureus EVs were critical \nfor NLRP3-dependent caspase-1 activation of human macrophages, but not for TLR2 \nsignaling. In contrast, EV-associated lipoproteins not only mediated TLR2 \nsignaling to initiate the priming step of NLRP3 activation but also modulated EV \nbiogenesis and the toxin content of EVs, resulting in alterations in IL-1β, \nIL-18, and caspase-1 activity. Collectively, our study describes mechanisms by \nwhich S. aureus EVs induce inflammasome activation and reveals an unexpected \nrole of staphylococcal lipoproteins in EV biogenesis. EVs may serve as a novel \nsecretory pathway for S. aureus to transport protected cargo in a concentrated \nform to host cells during infections to modulate cellular functions." ]	nan
5e64ed381af46fc130000015	[ 17543136, 12529926, 11001671, 17919656, 7875209, 26207883, 16305803, 26641849, 22117198, 25586702, 31729904, 10721489, 22351665, 9150551, 10924857 ]	train	Are ICAMS, Intracellular Adhesion Molecules, part of the immunoglobulin superfamily?	yesno	Intercellular adhesion molecule 3 (ICAM-3, also known as CD50), a human leukocyte-restricted immunoglobulin super-family (IgSF) member, has previously been implicated in apoptotic cell clearance,	yes	[ "The integrins are a superfamily of cell adhesion receptors that bind to \nextracellular matrix ligands, cell-surface ligands, and soluble ligands. They \nare transmembrane alphabeta heterodimers and at least 18 alpha and eight beta \nsubunits are known in humans, generating 24 heterodimers. Members of this family \nhave been found in mammals, chicken and zebrafish, as well as lower eukaryotes, \nincluding sponges, the nematode Caenorhabditis elegans (two alpha and one beta \nsubunits, generating two integrins) and the fruitfly Drosophila melanogaster \n(five alpha and one beta, generating five integrins). The alpha and beta \nsubunits have distinct domain structures, with extracellular domains from each \nsubunit contributing to the ligand-binding site of the heterodimer. The sequence \narginine-glycine-aspartic acid (RGD) was identified as a general \nintegrin-binding motif, but individual integrins are also specific for \nparticular protein ligands. Immunologically important integrin ligands are the \nintercellular adhesion molecules (ICAMs), immunoglobulin superfamily members \npresent on inflamed endothelium and antigen-presenting cells. On ligand binding, \nintegrins transduce signals into the cell interior; they can also receive \nintracellular signals that regulate their ligand-binding affinity. Here we \nprovide a brief overview that concentrates mostly on the organization, structure \nand function of mammalian integrins, which have been more extensively studied \nthan integrins in other organisms.", "Lymphocyte recruitment to the central nervous system (CNS) is a critical step in \nthe pathogenesis of diseases such as multiple sclerosis (MS), meningitis and \nposterior uveitis. The principle sequential stages that control lymphocyte \nemigration from the blood have been widely reported, but only recently has \nattention been directed towards the role of the vascular endothelium in actively \nsupporting transvascular migration. It has now been shown that adhesion \nmolecules, particularly those of the immunoglobulin super family (e.g. ICAM-1, \nVCAM-1 and PECAM-1), not only act as ligands for leucocyte receptors but can \nalso serve as signal transducers. Engagement of these receptors initiates \nendothelial signalling cascades that result in downstream effector mechanisms \nwhich in turn influence the progression of neuroinflammation. In particular, it \nhas been shown that ICAM-1-mediated signalling in brain endothelial cells is a \ncrucial regulatory step in the process of lymphocyte migration through the \nblood-brain barrier and as such represents an additional phase in the multistep \nparadigm of leucocyte recruitment. In this article we review current \nunderstanding of endothelial cell ICAM-1 signalling and discuss the importance \nof these findings in relation to leucocyte trafficking to the CNS.", "Intracellular adhesion molecule 1 (ICAM-1) is an adhesion-related molecule \nbelonging to the immunoglobulin superfamily. This molecule is found on the cell \nmembrane of endothelial cells. When activated ICAM-1 allows stable leukocyte \nadhesion to the endothelial surface. ICAM-1 is found not only in the membrane \nform but also circulating in serum. ICAM-1 (extracellular part of ICAM-1). This \nenables ICAM-1s to bind leukocyte integrin receptors such as LFA-1 (CDI1a/CD18) \nand Mac-1 (CDI1b/CD18) and therefore provide adaptive changes in the adhesion \nprocess between circulating cells and the endothelium.", "The conformational dynamics of the Inserted domain (I-domain) from the \nlymphocyte function-associated antigen-1 (LFA-1) was investigated by normal mode \nanalysis of multiple structures of the low, intermediate, and high affinity \nstates. LFA-1 is an integrin expressed on leukocytes and is of critical \nimportance in adhesion reactions, like antigen-specific responses, homing, and \ndiapedesis. The main ligand binding site of LFA-1 is the I-domain, which \nrecognizes intercellular adhesion molecules (ICAMs), members of the \nimmunoglobulin superfamily. From experimental crystal structures, a large-scale \nconformational change of, among others, the alpha7 helix of the I-domain has \nbeen observed leading to the proposal that these structural changes are linked \nto the conformational regulation of LFA-1. The results from the present \ncalculations show that structural changes of the alpha7 helix consistent with \nthose observed in the crystal structures are significantly sampled by the low \nfrequency modes. This was found to be particularly true for the low affinity \nstate of the I-domain, indicating that low frequency motions favor the \nconformational transition implicated in activation. However, beyond the simple \ndownward shift of the helix implied by the crystal structures, the calculations \nfurther show that there is a noticeable swinging-out motion of the helix. The \nconsequences of this motion are discussed in the context of integrin activation \nand inhibition. Moreover, significant changes in the atomic-level dynamics and \nin long-range correlated motions of the I-domain were found to occur upon \nbinding of the natural ligand ICAM. These changes were more local upon binding \nof an allosteric inhibitor. The present study opens the question of how changes \nin dynamics may contribute to the long-range transmission of signal upon ICAM \nbinding by the LFA-1 I-domain.", "Intercellular adhesion molecule-3 (ICAM-3, CD50), a member of the immunoglobulin \ngene superfamily, is a major ligand for the lymphocyte function-associated \nantigen 1 (LFA-1, CD18/CD11a) in the resting immune system and plays a role as a \nsignaling and costimulatory molecule on T lymphocytes. In this study we have \ngenerated a large panel of anti-ICAM-3 monoclonal antibodies (mAb) and show that \nthe biological effects of these antibodies are critically dependent on the \nepitope recognized. By using an adhesion assay employing COS cells expressing \nLFA-1 binding to recombinant chimeric ICAM-3-Fc proteins (which overcomes the \nconfounding effects of interleukocyte LFA-1/ICAM binding events), we have been \nable to examine the effects of these antibodies in blocking LFA-1/ICAM-3 \nadhesion. Our data suggests that only a small minority of ICAM-3 mAb, \nrecognizing a distinct epitope, are able to mimic the effects of LFA-1 binding \nto ICAM-3. Moreover these antibodies are functionally distinct as defined by \ntheir costimulatory activity and ability to elicit interleukin-2 production and \ncell proliferation in T lymphocytes.", "Endothelial cells represent an important vascular site of signaling and \ndevelopment of damage during ischemia, inflammation and other pathological \nconditions. Excessive reactive oxygen species production causes pathological \nactivation of endothelium including exposure of cell to adhesion molecules. \nIntercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 \n(VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members \nof the immunoglobulin super-family which are present on the surface of \nendothelial cells. These molecules represent important markers of endothelial \ninflammation. The present study was designed to investigate, with immunochemical \nand immunohistochemical techniques, the effect of treatment with (+/-)-alpha \nlipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in \nspontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by \nan increased oxidative stress status in the heart characterized by \nthiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation \nincrease. The higher oxidative stress also modifies adhesion molecules \nexpression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was \nincreased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly \ngreater in the renal endothelium of SHR. (+/-)-Alpha lipoic acid and (+)-alpha \nlipoic acid treatment significantly decreased TBARS levels, the nucleic acid \noxidation and prevented adhesion molecules expression in cardiac and renal \nvascular endothelium. These data suggest that endothelial molecules may be used \nfor studying the mechanisms of vascular injury on target organs of hypertension. \nThe effects observed after treatment with (+)-alpha lipoic acid could open new \nperspectives for countering heart and kidney microvascular injury which \nrepresent a common feature in hypertensive end-organs damage.", "Members of the immunoglobulin superfamily of endothelial adhesion molecules, \nvascular cell adhesion molecule (VCAM-1) and intercellular cell adhesion \nmolecule (ICAM- 1), strongly participate in leukocyte adhesion to the \nendothelium and play an important role in all stages of atherogenesis. The aim \nof this study was to detect and quantify the changes of endothelial expression \nof VCAM-1, and ICAM-1 in the vessel wall after the short-term administration of \nsimvastatin, atorvastatin, and micro dispersed derivatives of oxidised cellulose \n(MDOC) in apolipoprotein-E-deficient (apoE(-/-)) mice atherosclerotic model. \nHyperlipidemic apoE(-/-) mice (n = 32) received normal chow diet or diet \ncontaining simvastatin or atorvastatin 10 mg/kg/day or MDOC 50 mg/kg/day. Total \ncholesterol, VLDL, LDL, HDL and TAG were measured and the endothelial expression \nof VCAM-1 and ICAM-1 was visualized and quantified by means of \nimmunohistochemistry and stereology, respectively. Total cholesterol levels was \ninsignificantly lowered only in MDOC treated mice but not in mice treated with \nstatins. ICAM-1 endothelial expression was not affected by neither simvastatin \nnor MDOC treatment. However, significant diminution of VCAM-1 endothelial \nexpression was observed in both atorvastatin and MDOC treated mice. These \nresults provide new information of potential hypolipidemic substance MDOC and \nits potential anti-inflammatory effects. Furthermore, we have confirmed \nanti-inflammatory effects of atorvastatin independent of plasma cholesterol \nlowering. Thus, the results of this study show potential benefit of both MDOC \nand atorvastatin treatment in apoE(-/-) mouse model of atherosclerosis \nsuggesting their possible combination might be of interest.", "STUDY DESIGN: We investigated the association between ICAM-1, -2, -3 plasma \nlevels and ankylosing spondylitis (AS) disease activity.\nOBJECTIVE: In the present study, we aimed to investigate the association between \nICAM-1, -2, -3 plasma levels and AS disease activity in the Chinese Han \npopulation.\nSUMMARY OF BACKGROUND DATA: AS is a chronic inflammatory rheumatic disease that \neffects the sacroiliac joints and axial skeleton. The intercellular adhesion \nmolecules (ICAMs) are members of the immunoglobulin superfamily and have been \nidentified to play major roles in inflammation and immune responses.\nMETHODS: A total of 60 patients with AS and 60 healthy individuals were \nselected. The plasma levels of proinflammatory cytokines, including tumor \nnecrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and ICAM-1, -2, -3, were \nanalyzed by ELISA. Disease severity-related indexes, including the Bath \nankylosing spondylitis disease activity index (BASDAI), Bath ankylosing \nspondylitis functional index (BASFI), and ankylosing spondylitis disease \nactivity score (ASDAS), were assessed, along with the erythrocyte sedimentation \nrate (ESR) and C-reactive protein (CRP) level.\nRESULTS: Both ICAM-1 and ICAM-2 levels in plasma were markedly increased in AS \npatients compared with levels in the plasma of controls. There was no difference \nbetween controls and patients in term of ICAM-3 levels. Furthermore, in \npatients, correlation analysis showed that TNF-α and IL-6 production, as well as \nthe ESR and CRP levels, have positive relationships with ICAM-1 and ICAM-2 \nplasma levels; the BASDAI, BASFI, and ASDAS scores were also found to be \npositively correlated with ICAM-2. However, no significant correlations between \nICAM-1 levels and BASDAI, BASFI, or ASDAS were detected in our study.\nCONCLUSION: The current findings suggest that ICAM-2 may be a potential \nbiomarker reflecting disease activity and functional ability in AS patients.\nLEVEL OF EVIDENCE: 5.", "A wide range of molecules acting as apoptotic cell-associated ligands, \nphagocyte-associated receptors or soluble bridging molecules have been \nimplicated within the complex sequential processes that result in phagocytosis \nand degradation of apoptotic cells. Intercellular adhesion molecule 3 (ICAM-3, \nalso known as CD50), a human leukocyte-restricted immunoglobulin super-family \n(IgSF) member, has previously been implicated in apoptotic cell clearance, \nalthough its precise role in the clearance process is ill defined. The main \nobjective of this work is to further characterise the function of ICAM-3 in the \nremoval of apoptotic cells. Using a range of novel anti-ICAM-3 monoclonal \nantibodies (mAbs), including one (MA4) that blocks apoptotic cell clearance by \nmacrophages, alongside apoptotic human leukocytes that are normal or deficient \nfor ICAM-3, we demonstrate that ICAM-3 promotes a domain 1-2-dependent tethering \ninteraction with phagocytes. Furthermore, we demonstrate an apoptosis-associated \nreduction in ICAM-3 that results from release of ICAM-3 within microparticles \nthat potently attract macrophages to apoptotic cells. Taken together, these data \nsuggest that apoptotic cell-derived microparticles bearing ICAM-3 promote \nmacrophage chemoattraction to sites of leukocyte cell death and that ICAM-3 \nmediates subsequent cell corpse tethering to macrophages. The defined function \nof ICAM-3 in these processes and profound defect in chemotaxis noted to \nICAM-3-deficient microparticles suggest that ICAM-3 may be an important adhesion \nmolecule involved in chemotaxis to apoptotic human leukocytes.", "Intercellular adhesion molecules (ICAMs) belong to the immunoglobulin \nsuperfamily and participate in diverse cellular processes including \nhost-pathogen interactions. ICAM-1 is expressed on various cell types including \nmacrophages, whereas ICAM-4 is restricted to red blood cells. Here we report the \nidentification of an 11-kDa synthetic protein, M5, that binds to human ICAM-1 \nand ICAM-4, as shown by in vitro interaction studies, surface plasmon resonance \nand immunolocalization. M5 greatly inhibits the invasion of macrophages and \nerythrocytes by Mycobacterium tuberculosis and Plasmodium falciparum, \nrespectively. Pharmacological and siRNA-mediated inhibition of ICAM-1 expression \nalso results in reduced M. tuberculosis invasion of macrophages. ICAM-4 binds to \nP. falciparum merozoites, and the addition of recombinant ICAM-4 to parasite \ncultures blocks invasion of erythrocytes by newly released merozoites. Our \nresults indicate that ICAM-1 and ICAM-4 play roles in host cell invasion by M. \ntuberculosis and P. falciparum, respectively, either as receptors or as crucial \naccessory molecules.", "Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like \nsuperfamily of adhesion molecules that mediate leukocyte adhesion to vascular \nendothelium and are involved in several cardiovascular diseases, including \nischemia-reperfusion injury, myocardial infarction, and atherosclerosis. \nHowever, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac \nremodeling in mice remains unclear. Wild-type mice were administered an IgG \ncontrol or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG \nII (1,000 ng·kg-1·min-1) for up to 14 days. Cardiac contractile function and \nstructure were detected by echocardiography. Hypertrophy, fibrosis, and \ninflammation were assessed by histological examination. The infiltration of \nlymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was \nassessed by immunostaining. The mRNA expression of genes was evaluated by \nquantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We \nfound that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum \nfrom human patients with heart failure were significantly increased. Moreover, \nANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac \ncontractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ \nmacrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing \nantibody dose-dependently attenuated these effects. Moreover, our in vitro data \nfurther demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ \nmacrophage adhesion to endothelial cells and migration. In conclusion, these \nresults provide novel evidence that blocking ICAM-1 exerts a protective effect \nin ANG II-induced cardiac remodeling at least in part through the modulation of \nadhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of \nICAM-1 may represent a new therapeutic approach for hypertrophic heart \ndiseases.NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a \ncritical step in cardiovascular diseases. ICAM-1 is a member of \nimmunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to \nmediate leukocytes adhesion and migration. However, the significance of ICAM-1 \nin ANG II-induced cardiac remodeling remains unclear. This study reveals that \nblocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating \nadhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic \ntarget for hypertensive cardiac diseases.", "Cell adhesion molecules belonging to the integrin, cadherin and immunoglobulin \nsuperfamilies have been implicated in tumor progression in cutaneous melanoma. \nExpression of the alpha v beta 3 integrin first appears with the change from \nradial to vertical growth, a step which is associated with the development of \nmetastatic potential. VLA-4 expression is characteristic of advanced primary \ntumors and may mediate interaction of the tumor cells with VCAM-1 on vascular \nendothelium. Expression of these integrins is a marker of poor prognosis in \npatients and can confer invasive (alpha v beta 3) and metastatic (VLA-4) \nproperties to human melanoma cells injected into nude mice. Expression of the \nimmunoglobulin superfamily molecules MUC18/MCAM and ICAM-1 are associated with \nprimary tumors and metastases. MUC18/MCAM expression confers metastatic \npotential and increased tumorigenicity to human melanoma cells. Expression of \nICAM-1 has been shown to be a marker of poor prognosis in stage I tumors and \ninterfering with its expression inhibits experimental metastasis by melanomas in \nnude mice. E-cadherin is used by epidermal melanocytes to interact with \nneighboring keratinocytes. Changes in E-cadherin expression and cellular \nlocalization is first observed in the radial growth phase, the earliest stage in \nmelanoma development. Loss of E-cadherin function is associated with \nupregulation or induction of MUC18/MCAM and alpha v beta 3 in melanocytic cells \nin vitro and with alterations in the levels and cellular distribution of the \ntranscriptional regulator beta-catenin in melanomas in vivo. These observations \nsuggest that disturbances in E-cadherin function is not only important in \ncarcinomas but may also be a critical event in melanoma tumor progression.", "BACKGROUND: Members of the immunoglobulin superfamily of endothelial adhesion \nmolecules, vascular cell adhesion molecule (VCAM-1) and intercellular cell \nadhesion molecule (ICAM-1), participate in leukocyte adhesion to the endothelium \nand play an important role in all stages of atherosclerosis. The aim of the \nstudy was to examine the expression of VCAM-1 and ICAM-1 in the aorta of rats at \nthe early stages of atherosclerosis and the correlation with their plasma \nconcentrations.\nMATERIALS AND METHODS: Male rats (n=44), 10 weeks of age, were divided in 4 \ngroups. Groups A and C (n=12) were fed with rich cholesterol diet for 12 and 16 \nweeks, respectively. Group B (regression group, n=12) was fed for the first 12 \nweeks with rich cholesterol diet and for another 4 weeks with normal diet. Group \nD (control group, n=8) was fed with normal diet for 12 weeks. We measured the \nserum lipid profile, the concentration of soluble ICAM-1 and the \nimmunohistochemical expression of ICAM-1 and VCAM-1 in the endothelium, media \nand vasa vasorum of the aorta.\nRESULTS: There were significant differences (p<0.05) in the expression of ICAM-1 \nbetween group C (maximum time of rich cholesterol diet) and all other groups in \nthe 3 groups of the aorta studied. There was regression of the expression of \nICAM-1 in group B and significant differences (p<0.05) between group B and all \nthe other groups, except group D in the expression of ICAM-1. There were no \nsignificant differences in the expression of VCAM-1 between any groups. The \nserum concentration of soluble ICAM-1 positively correlated with the expression \nof the molecule in the vasa vasorum (r=0.35, p<0.05) and fibroblasts/smooth \nmuscular cells (r=0.34, p<0.05) of the aorta.\nCONCLUSION: A cholesterol diet plays a role in the expression of ICAM-1 but not \nin that of VCAM-1 in the rat aorta. The expression of ICAM-1 in the aorta \nregresses after the withdrawal of a cholesterol-rich diet. Soluble ICAM-1 is a \nreliable measure of ICAM-1 expression in the aorta, vasa vasorum and \nfibroblasts/smooth muscle cells.", "Cell adhesion molecules are glycoproteins expressed on the cell surface and play \nan important role in inflammatory as well as neoplastic diseases. There are four \nmain groups: the integrin family, the immunoglobulin superfamily, selectins, and \ncadherins. The integrin family has eight subfamilies, designated as beta 1 \nthrough beta 8. The most widely studied subfamilies are beta 1 (CD29, very late \nactivation [VLA] members), beta 2 (leukocyte integrins such as CD11a/CD18, \nCD11b/CD18, CD11c/CD18, and alpha d beta 2), beta 3 (CD61, cytoadhesions), and \nbeta 7 (alpha 4 beta 7 and alpha E beta 7). The immunoglobulin superfamily \nincludes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function \nantigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular \nadhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 \n(PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The \nselectin family includes E-selectin (CD62E), P-selectin (CD62P), and L-selectin \n(CD62L). Cadherins are major cell-cell adhesion molecules and include epithelial \n(E), placental (P), and neural (N) subclasses. The binding sites \n(ligands/receptors) are different for each of these cell adhesion molecules \n(e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell \nadhesion molecules and their ligands that may be involved in pathologic \nconditions and potential therapeutic strategies by modulating the expression of \nthese molecules will be discussed.", "The collective interaction between cells is, in part, mediated by different \nfamilies of adhesion molecules. Intercellular adhesion molecules (ICAMs) are \nstructurally related members of the immunoglobulin supergene family and are \nligands for the beta2 integrin molecules present on leukocytes. Of the five \nICAMs identified, ICAM-1 is the most extensively studied. Although ICAM-1 is \nexpressed constitutively at low levels on endothelial cells and on some \nlymphocytes and monocytes, its expression can be significantly increased in the \npresence of cytokines (TNFalpha, IL-1, IFNgamma) and reactive oxygen species. \nDepending upon cell type, ICAM-1 participates in trafficking of inflammatory \ncells, in cell:cell interactions during antigen presentation, in microbial \npathogenesis, and in signal transduction through outside-in signaling events. \nAgain, depending upon cell type examined, ICAM-1 engagement has been documented \nto activate specific kinases through phosphorylation, resulting in transcription \nfactor activation and increased cytokine production, increased cell membrane \nprotein expression, reactive oxygen species production, and cell proliferation." ]	nan
5c7836dad774d04240000002	[ 27102896, 19886822 ]	train	Are Mesenchymal stem cells (MSC) multipotent cells?	yesno	Yes, Mesenchymal stem cells (MSC) are multipotent cells.	yes	[ "INTRODUCTION: Current experimental research has proven the efficacy of \ntransplantation bone marrow-derived mesenchymal stem cells (MSC) in the \ntreatment of myocardial infarction (MI). The one of the main purposes of \nresearch was to evaluate the comparative data of the MSC transplantation with \n(5-azacytidine) and without commitment and to assess the post transplantation \neffects.\nMETHODS: The efficiency of intravenous cardiomyoplasty by infusion of MSC was \nevaluated in female Wistar-Kyoto rats with myocardial infarction model using \nechocardiography, morphological study, morphometry, immunohistostaining, data \nfrom in situ hybridization, and by measurement of blood serum levels of nitric \noxide, endothelin-1, vascular endothelial growth factor (VEGF), and fibroblast \ngrowth factor 2 (FGF2).\nRESULTS: The transplanted MSC were detected in all layers of the myocardium; MCS \nactively participate in the formation of blood vessels and connective tissue in \nthe scar zone. There was no observable differentiation of male MSC into \ncardiomyocytes in female rats with MI. However, MSC transplantation leads to \nsignificant improvement in vascularization in the area of MI, elevation blood \nserum levels of nitric oxide, VEGF, and FGF2. No significant differences were \nidentified morphologically between the two groups of animals after \ntransplantation with unmodified MSC or commited MSC (5-azaC).\nCONCLUSION: Intravenous transplantation of MSC without commitment in rats with \nMI improves the contractile function of the heart, the morphology of the \nmyocardium, and should be recommended for further clinical investigation as an \nalternative approach to deal with heart diseases.", "Mesenchymal stem cells (MSCs) can differentiate into multiple mesodermal cell \ntypes in vitro; however, their differentiation capacity is influenced by their \ntissue of origin. To what extent epigenetic information on promoters of \nlineage-specification genes in human progenitors influences transcriptional \nactivation and differentiation potential remains unclear. We produced bisulfite \nsequencing maps of DNA methylation in adipogenic, myogenic, and endothelial \npromoters in relation to gene expression and differentiation capacity, and \nunravel a similarity in DNA methylation profiles between MSCs isolated from \nhuman adipose tissue, bone marrow (BM), and muscle. This similarity is \nirrespective of promoter CpG content. Methylation patterns of MSCs are distinct \nfrom those of hematopoietic progenitor cells (HPCs), pluripotent human embryonic \nstem cells (hESCs), and multipotent hESC-derived mesenchymal cells (MCs). \nMoreover, in vitro MSC differentiation does not affect lineage-specific promoter \nmethylation states, arguing that these methylation patterns in differentiated \ncells are already established at the progenitor stage. Further, we find a \ncorrelation between lineage-specific promoter hypermethylation and lack of \ndifferentiation capacity toward that lineage, but no relationship between weak \npromoter methylation and capacity of transcriptional activation or \ndifferentiation. Thus, only part of the restriction in differentiation capacity \nof tissue-specific stem cells is programmed by promoter DNA methylation: \nhypermethylation seems to constitute a barrier to differentiation, however, no \nor weak methylation has no predictive value for differentiation potential." ]	nan
5522fadb7b523f2123000001	[ 23033986, 20015880, 16707600, 21302811, 20008221, 23022380, 24252593, 24140475, 23730497, 25493453, 24068942, 24301524, 17575125, 18184405, 21463127, 21263446, 18056171, 20967796, 24401270 ]	train	Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)?	yesno	Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL).	yes	[ "BACKGROUND: In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), \nactivating mutations of NOTCH1 are observed in more than 50% of cases, whereas \nthe t(7;9)(q34;q34) involving NOTCH1 at 9q34 and TRB@ at 7q34 is an extremely \nrare but recurrent translocation.\nPATIENT: A 41-year-old male with a large mediastinal mass, pleural effusion, and \nlymphadenopathy was diagnosed as having T-LBL. Lymphoma cells were positive for \nCD4, CD8, CD2, CD3, CD5, CD7, CD10, and TdT.\nRESULTS: G-banding and spectral karyotyping of pleural effusion cells showed \n47,XY,dup(1)(q21q32),t(7;9)(q34;q34),+20. Genomic polymerase chain reaction \n(PCR) revealed that the 5' end of TRB@ J1-5 was connected with the middle of \nNOTCH1 exon 25 (434 bp downstream from its 5' end) in a 'head-to-head' \nconfiguration on the der(9)t(7;9), although nine extra bases were inserted \nbetween the two genes. Reverse transcription-PCR confirmed expression of the \nTRB@/NOTCH1 fusion transcripts. Similarly, the 5' end of J1-5 was fused to the \nshortened exon 25 with nine extra bases. The NOTCH1 breakpoint in exon 25 was \nvery close to transcription start sites of deleted Notch1 in murine T-ALL.\nCONCLUSIONS: The TRB@/NOTCH1 fusion gene with a NOTCH1 breakpoint in exon 25, \nwhich has not previously been detected in four other reported cases with t(7;9), \ncould lead to aberrant expression of the truncated NOTCH1 by TRB@ enhancer \nelements. The resultant NOTCH1 receptor deleting most of the extracellular \ndomain may be implicated in the pathogenesis of T-LBL by ligand-independent, \nconstitutive activation of the NOTCH1 pathway, suggesting avenues for future \ntherapy with γ-secretase inhibitors.", "T-cell acute lymphoblastic leukemia (T-ALL) patients frequently display NOTCH1 \nactivating mutations and Notch can transcriptionally down-regulate the tumor \nsuppressor PTEN. However, it is not clear whether NOTCH1 mutations associate \nwith decreased PTEN expression in primary T-ALL. Here, we compared patients with \nor without NOTCH1 mutations and report that the former presented higher MYC \ntranscript levels and decreased PTEN mRNA expression. We recently showed that \nT-ALL cells frequently display CK2-mediated PTEN phosphorylation, resulting in \nPTEN protein stabilization and concomitant functional inactivation. Accordingly, \nthe T-ALL samples analyzed, irrespectively of their NOTCH1 mutational status, \nexpressed significantly higher PTEN protein levels than normal controls. To \nevaluate the integrated functional impact of Notch transcriptional and CK2 \npost-translational inactivation of PTEN, we treated T-ALL cells with both the \ngamma-secretase inhibitor DAPT and the CK2 inhibitors DRB/TBB. Our data suggest \nthat combined use of gamma-secretase and CK2 inhibitors may have therapeutic \npotential in T-ALL.", "PURPOSE: NOTCH signaling pathway is essential in T-cell development and NOTCH1 \nmutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). \nTo gain insight into its clinical significance, NOTCH1 mutation was investigated \nin 77 patients with T-ALL.\nEXPERIMENTAL DESIGN: Detection of NOTCH1 mutation was done using reverse \ntranscription-PCR amplification and direct sequencing, and thereby compared \naccording to the clinical/biological data of the patients.\nRESULTS: Thirty-two mutations were identified in 29 patients (with dual \nmutations in 3 cases), involving not only the heterodimerization and \nproline/glutamic acid/serine/threonine domains as previously reported but also \nthe transcription activation and ankyrin repeat domains revealed for the first \ntime. These mutations were significantly associated with elevated WBC count at \ndiagnosis and independently linked to short survival time. Interestingly, the \nstatistically significant difference of survival according to NOTCH1 mutations \nwas only observed in adult patients (>18 years) but not in pediatric patients (< \nor = 18 years), possibly due to the relatively good overall response of \nchildhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with \nHOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation \non prognosis was potentiated by HOX11L2 but was attenuated by HOX11.\nCONCLUSION: NOTCH1 mutation is an important prognostic marker in T-ALL and its \npredictive value could be even further increased if coevaluated with other \nT-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with \noncogenic transcriptional factors on T-ALL pathogenesis.", "Notch-1 is a transmembrane receptor protein that directs T-cell differentiation. \nGain-of-function mutations in Notch-1 have been reported in more than 50% of \nhuman T-cell acute lymphoblastic leukemia (T-ALL). The current study was \nundertaken to characterize mutations in the heterodimerization (HD) domain and \nproline, glutamic acid, serine, threonine-rich (PEST) domain of the Notch-1 \nreceptor. RNA was isolated from peripheral blood/bone marrow of 15 de novo T-ALL \nsubjects; the Notch-1 HD and PEST regions were amplified and sequenced. Overall \nsix patients (40%) had at least one Notch-1 mutation, 2/15 (13%) in the HD and \n4/15 (27%) in the PEST domain. None of the samples showed simultaneous mutations \nin HD and PEST domains. Mutations were seen in 4/10 adult patients (40%); in the \npediatric cohort 2/5 (40%) had mutations both of which were in the PEST domain. \nOf the different mutations, two have been previously reported and the other four \nare novel. A high incidence of Notch-1 mutations has been seen; unlike other \nstudies, a higher frequency of mutations was found in PEST domain. The current \nstudy also served to identify four novel mutants that add new insights into the \ngenetic heterogeneity of T-ALL. More ongoing larger studies are warranted to \nelucidate the molecular pathogenesis of T-ALL that arises in this part of the \nworld.", "The identification of activating mutations in NOTCH1 in over 50% of T-cell acute \nlymphoblastic leukemias (T-ALL) has generated major interest in the elucidation \nof the mechanisms of transformation downstream of oncogenic NOTCH and in the \ntargeting of the NOTCH signaling pathway in this disease. Small molecule \ngamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, \nyet the clinical development of GSIs has been held back by the development of \ngastrointestinal toxicity and their weak antileukemic effects against human \nT-ALL. However, new therapeutic strategies aiming to optimize the use of \nanti-NOTCH1 therapies for T-ALL, including combination therapies with \nmolecularly targeted drugs and glucocorticoids, have started to emerge as a \nresult of improved understanding of the molecular mechanisms that mediate the \neffects of GSIs in leukemic cells and the intestinal epithelium. This review \nfocuses on the molecular basis of NOTCH1-induced transformation, the mechanisms \nof action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in \nT-ALL.", "Activating mutations in NOTCH1, an essential regulator of T cell development, \nare frequently found in human T cell acute lymphoblastic leukemia (T-ALL). \nDespite important advances in our understanding of Notch signal transduction, \nthe regulation of Notch functions in the nucleus remains unclear. Using \nimmunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL \ncells and showed that, beyond the well-characterized core activation complex \n(ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the \ntranscription coactivator AF4p12, the PBAF nucleosome remodeling complex, and \nthe histone demethylases LSD1 and PHF8 acting through their demethylase activity \nto promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 \nfunctions as a corepressor when associated with CSL-repressor complex and as a \nNOTCH1 coactivator upon Notch activation. Our work provides new insights into \nthe molecular mechanisms that govern Notch transcriptional activity and \nrepresents glimpse into NOTCH1 interaction landscape, which will help in \ndeciphering mechanisms of NOTCH1 functions and regulation.", "The Notch signaling pathway plays a critical role in maintaining the balance \nbetween cell proliferation, differentiation and apoptosis, and is a highly \nconserved signaling pathway that regulates normal development in a context- and \ndose-dependent manner. Dysregulation of Notch signaling has been suggested to be \nkey events in a variety of hematological malignancies. Notch1 signaling appears \nto be the central oncogenic trigger in T cell acute lymphoblastic leukemia \n(T-ALL), in which the majority of human malignancies have acquired mutations \nthat lead to constitutive activation of Notch1 signaling. However, emerging \nevidence unexpectedly demonstrates that Notch signaling can function as a potent \ntumor suppressor in other forms of leukemia. This minireview will summarize \nrecent advances related to the roles of activated Notch signaling in human \nlymphocytic leukemia, myeloid leukemia, stem cells and stromal microenvironment, \nand we will discuss the perspectives of Notch signaling as a potential \ntherapeutic target as well.", "T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk \nstratified disease associated with frequent relapse, chemotherapy resistance, \nand a poorer prognostic outlook than B-precursor ALL. Many of the challenges in \ntreating T-ALL reflect the lack of prognostic cytogenetic or molecular \nabnormalities on which to base therapy, including targeted therapy. Notch1 \nactivating mutations were identified in more than 50% of T-ALL cases and can be \ntherapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can \nactivate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type \nphosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 \ntranscriptionally represses PTEN, an effect reversible by GSIs. Notch1 also \npromotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of \nPTEN is common in primary T-ALLs due to mutation or posttranslational \ninactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, \nGSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might \nregulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in \nPTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase \nphosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central \nrole of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by \nNotch1 and potential therapeutic interventions, with emphasis on GSI-resistant \nT-ALL.", "T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by \naberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of \nactivating NOTCH1 mutations highlights the critical role of NOTCH signaling in \nthe pathogenesis of this disease and has prompted the development of therapeutic \napproaches targeting the NOTCH signaling pathway. Small molecule gamma secretase \ninhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical \ntesting for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are \nstrongly synergistic and may overcome the gastrointestinal toxicity associated \nwith systemic inhibition of the NOTCH pathway. In addition, emerging new \nanti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 \nantibodies and stapled peptides targeting the NOTCH transcriptional complex in \nthe nucleus.", "The NOTCH1 signaling pathway is essential for hematopoiesis and a critical \nregulatory step for T-cell proliferation and maturation. The E3 ubiquitin ligase \nFBXW7 controls NOTCH1 protein stability. Mutations in NOTCH1/FBXW7 activate \nNOTCH signaling and are of prognostic significance in patients with T-cell acute \nlymphoblastic leukemia (T-ALL). In this study we analyzed NOTCH1 and FBXW7 \nmutations in 50 South Indian T-ALL patients treated by a modified ALL BFM 95 \nregimen. The hot spot exons (HD-N, HD-C, TAD, and PEST) of NOTCH1 and exons 9 of \nthe 10 of FBXW7 were polymerase chain reaction amplified and sequenced. In \ntotal, 20 of the 50 (40%) T-ALL patients revealed heterozygous mutations in the \nNOTCH1 domains, and a predominance of missense mutations in HD-N (70%) and PEST \n(15%) domains. FBXW7 mutations were detected in 5 of the 50 (10%) T-ALL \npatients. T-ALL patients with NOTCH1/FBXW7 mutations expressed higher protein \nlevel of NOTCH1 compared with patients without NOTCH1/FBXW7 mutations. Six of \nthe mutations detected in NOTCH1 were not reported previously. When tested in a \nDual Luciferase Renilla reporter assay some of these conferred increased NOTCH \nactivity, suggesting that these are activating mutations. Importantly, 13 of the \n20 (65%) NOTCH1/FBXW7-mutated T-ALL patients showed a good prednisone response \n(P=0.01) and a better clinical outcome compared with NOTCH1/FBXW7 nonmutated \npatients (P=0.03). These data suggest that NOTCH1/FBXW7 mutations are present in \nT-ALL patients from Southern India and may be useful biomarkers to predict \nprognosis in T-ALL.", "Growth factor independent 1 (Gfi1) is a transcriptional repressor originally \nidentified as a gene activated in T-cell leukemias induced by \nMoloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that \nis frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 \nis an important factor in the initiation and maintenance of lymphoid leukemias \nand its deficiency significantly impedes Notch dependent initiation of T-ALL in \nanimal models. Here, we show that immature hematopoietic cells require Gfi1 to \ncompetently integrate Notch-activated signaling. Notch1 activation coupled with \nGfi1 deficiency early in T-lineage specification leads to a dramatic loss of \nT-cells, whereas activation in later stages leaves development unaffected. In \nGfi1 deficient multipotent precursors, Notch activation induces lethality and is \ncell autonomous. Further, without Gfi1, multipotent progenitors do not maintain \nNotch1-activated global expression profiles typical for T-lineage precursors. In \nagreement with this, we find that both lymphoid-primed multipotent progenitors \n(LMPP) and early T lineage progenitors (ETP) do not properly form or function in \nGfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) \nprogenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. \nOur data indicate that Gfi1 is required for hematopoietic precursors to \nwithstand Notch1 activation and to maintain Notch1 dependent transcriptional \nprogramming to determine early T-lymphoid lineage identity.", "The Notch signaling pathway has been recognized as a key factor for the \npathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high \nincidence of activating mutations of Notch1. Notch inhibition could serve as a \nnew treatment strategy for T-ALL; however, the attempts to perturb Notch \nsignaling pathways have been unsuccessful so far. In this study, we found that \nproteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive \nactivation of Notch1 to a similar extent as myeloma cells. The proteasome \ninhibitor bortezomib repressed the transcription of Notch1 and downstream \neffectors including Hes1, GATA3, RUNX3 and nuclear factor-κB (NF-κB) (p65 and \np50), coincided with downregulation of the major transactivator Sp1 and its \ndissociation from Notch1 promoter. Overexpression of the Notch1 intracellular \ndomain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against \nT-ALL cells. Drug combination studies revealed that bortezomib showed \nsynergistic or additive effects with key drugs for the treatment of T-ALL such \nas dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily \nabolished by NICD overexpression. The synergy of bortezomib and DEX was \nconfirmed in vivo using a murine xenograft model. Our findings provide a \nmolecular basis and rationale for the inclusion of proteasome inhibitors in \ntreatment strategies for T-ALL.", "Notch signaling is of crucial importance in normal T-cell development and Notch \n1 is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading \nto aberrantly high Notch signaling. In this report, we determine whether T-ALL \nmutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, \nAgo, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is \nmutated in leukemic cells from more than 30% of patients with pediatric T-ALL \nand derived cell lines. Most hCDC4 mutations found were missense substitutions \nat critical arginine residues (Arg(465), Arg(479), and Arg(505)) localized in \nthe substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL \ncells containing hCDC4 mutations exhibited an increased Notch1 protein \nhalf-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent \nproteolysis of Notch1. Furthermore, restoration of wild-type but not mutant \nhCdc4 in HCT 116 hCDC4-negative cells led to an increased Notch1 ubiquitylation \nand decreased Notch1 signaling. These results show that hCdc4 mutations \ninterfere with normal Notch1 regulation in vivo. Finally, we found that \nmutations in hCDC4 and NOTCH1 can occur in the same cancers and that patients \ncarrying hCDC4 and/or NOTCH1 mutations have a favorable overall survival. \nCollectively, these data show that mutation of hCDC4 is a frequent event in \nT-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 \nmight synergize in contributing to the development of pediatric T-ALL \nleukemogenesis.", "NOTCH proteins (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) play crucial roles in \nembryonic development. Also, mounting evidence indicates that NOTCH contributes \nto the pathogenesis of hematopoietic and solid malignancies. Recent studies \nreported a high incidence of gain-of-function mutations of the NOTCH1 gene in \nT-cell acute lymphoblastic leukemias (ALL). To see whether NOTCH1 mutation \noccurs in other malignancies, we analyzed NOTCH1 for the detection of somatic \nmutations in 334 malignancies, including 48 lung, 48 breast, 48 colorectal and \n48 gastric carcinomas, and 142 acute leukemias (105 acute myelogenous leukemias, \n32 B-ALLs and 4 T-ALLs) by single-strand conformation polymorphism assay. Also, \nto see whether other NOTCH genes harbor somatic mutations, we analyzed NOTCH2, \nNOTCH3 and NOTCH4 genes in the same tissue samples. Overall, we detected three \nNOTCH mutations in the cancers, which consisted of one NOTCH1 mutation in the \nT-ALLs (25.0%), one NOTCH2 mutation in the breast carcinomas (2.1%), and one \nNOTCH3 mutation in the colorectal carcinomas (2.0%). There was no NOTCH mutation \nin other malignancies analyzed. Our data indicate that NOTCH1 is mutated in \nT-ALL, but not in other common human cancers, and that NOTCH2, NOTCH3 and NOTH4 \ngenes are rarely mutated in common human cancers. Despite the importance of \nNOTCH activation in many types of human cancers, mutation of NOTCH genes, except \nfor NOTCH1 mutation in T-ALL, may not play an important role in the \ntumorigenesis of common cancers.", "Activating mutations in NOTCH1 consitute the most prominent genetic abnormality \nin T-cell acute lymphoblastic leukemia (T-ALL). However, most T-ALL cell lines \nwith NOTCH1 mutations are resistant to treatment with γ-secretase inhibitors \n(GSIs). The spotlight is now shifting to the phosphatidylinositide 3-kinase \n(PI3K)/phosphatase and tensin homolog deleted on chromosome ten \n(PTEN)/AKT/mammalian target of rapamycin (mTOR) pathway as another key potential \ntarget. These two signaling routes are deregulated in many types of cancer. In \nthis review we discuss these two pathways with respect to their signaling \nmechanisms, functions during T-cell development, and their mutual roles in the \ndevelopment of T-ALL.", "Activation of the Notch pathway occurs commonly in T acute lymphoblastic \nleukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the \nregulation of cell proliferation and survival. Deregulated Notch3 signalling has \nalso been shown to promote leukemogenesis in transgenic mice, but the targets of \nNotch3 in human T-ALL cells remain poorly characterized. Here, we show that \nNotch3 controls levels of mitogen-activated protein kinase (MAPK) phosphatase 1 \n(MKP-1). In a model of T-ALL cell dormancy, both Notch3 activation and MKP-1 \nexpression were upregulated in aggressive compared with dormant tumors, and this \ninversely correlated with the levels of phosphorylated p38 and extracellular \nsignal-regulated kinase1/2 (ERK1/2) MAPKs, two canonical MKP-1 targets. We \ndemonstrate that MKP-1 protein levels are regulated by Notch3 in T-ALL cell \nlines because its silencing by RNA interference or treatment with γ-secretase \ninhibitors induced strong MKP-1 reduction whereas activation of Notch3 \nsignalling had the opposite effect. Furthermore, MKP-1 has an important role in \nT-ALL cell survival because its attenuation by short hairpin RNA significantly \nincreased cell death under stress conditions. This protective function has a key \nrole in vivo, as MKP-1-deficient cells showed impaired tumorigenicity. These \nresults elucidate a novel mechanism downstream of Notch3 that controls the \nsurvival of T-ALL cells.", "PURPOSE: Activating Notch-1 mutations are frequent in T-cell acute lymphoblastic \nleukemia (T-ALL), occurring in >50% of patients. In murine models of T-ALL, \nNotch-1 activation can both directly initiate leukemia and cooperate secondarily \nto other primary events. Whether acquisition of Notch-1 mutations is an early \ninitiating event or a secondary event in the pathogenesis of human T-ALL is \nunclear.\nEXPERIMENTAL DESIGN: We used denaturing high-performance liquid chromatography, \nsequencing, and fragment analysis to analyze Notch-1 mutational status and \nmutant level in 62 patients at presentation as well as 16 matched \npresentation-relapse samples.\nRESULTS: We detected Notch-1 mutations in 47 patients (76%). Seven of these were \nlow-level mutations (quantified at < or =10%), despite high blast counts, \nsuggesting that they were acquired as a secondary event in a subclone. Of 16 \nmatched presentation-relapse samples studied, 7 were wild-type at both \npresentation and relapse. Five of nine mutant-positive patients at presentation \nrelapsed with the same mutation(s) at the same high level. Four patients had \nevidence of a change in mutant at relapse. One lost a PEST mutation and became \nwild-type. Two others lost mutations at relapse but acquired different \nmutations, despite unchanged T-cell receptor rearrangements, suggesting that the \nlatter event predated the acquisition of the Notch-1 mutation. One relapsed with \na secondary T-cell leukemia and different Notch mutation.\nCONCLUSIONS: These results suggest that Notch-1 mutations can sometimes be \nacquired as secondary events in leukemogenesis and must be used cautiously as \nsolitary minimal residual disease markers.", "Notch receptors participate in a highly conserved signalling pathway that \nregulates normal development and tissue homeostasis in a context- and \ndose-dependent manner. Deregulated Notch signalling has been implicated in many \ndiseases, but the clearest example of a pathogenic role is found in T-cell \nlymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and \nmurine tumours have acquired mutations that lead to aberrant increases in Notch1 \nsignalling. Remarkably, it appears that the selective pressure for Notch \nmutations is virtually unique among cancers to T-LL, presumably reflecting a \nspecial context-dependent role for Notch in normal T-cell progenitors. \nNevertheless, there are some recent reports suggesting that Notch signalling has \nsubtle, yet important roles in other forms of haematological malignancy as well. \nHere, we review the role of Notch signalling in various blood cancers, focusing \non T-LL with an eye towards targeted therapeutics.", "T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is \nfrequently associated with activating mutations in NOTCH1 and dysregulation of \nMYC. Here, we performed 2 complementary screens to identify FDA-approved drugs \nand drug-like small molecules with activity against T-ALL. We developed a \nzebrafish system to screen small molecules for toxic activity toward \nMYC-overexpressing thymocytes and used a human T-ALL cell line to screen for \nsmall molecules that synergize with Notch inhibitors. We identified the \nantipsychotic drug perphenazine in both screens due to its ability to induce \napoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity \nchromatography coupled with mass spectrometry, we identified protein phosphatase \n2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine \nexhibited rapid dephosphorylation of multiple PP2A substrates and subsequent \napoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated \nperphenazine activity, indicating that PP2A mediates the drug's antileukemic \nactivity. Finally, human T-ALLs treated with perphenazine exhibited suppressed \ncell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our \nfindings provide a mechanistic explanation for the recurring identification of \nphenothiazines as a class of drugs with anticancer effects. Furthermore, these \ndata suggest that pharmacologic PP2A activation in T-ALL and other cancers \ndriven by hyperphosphorylated PP2A substrates has therapeutic potential." ]	['http://www.disease-ontology.org/api/metadata/DOID:5603']
571e3e2abb137a4b0c000008	[ 23886114, 18509604, 17973861, 24459177, 23750830, 22982575, 22232210, 25204339, 15535988, 24523126, 21395542, 23695864, 24151358 ]	train	Are OATP1B1 and OATP1B3 associated with bilirubin transport?	yesno	Yes, OATP1B1 and OATP1B3 are involved in the transport of bilirubin.	yes	[ "1. Transient benign unconjugated hyperbilirubinemia has been observed \nclinically with several drugs including indinavir, cyclosporine, and rifamycin \nSV. Genome-wide association studies have shown significant association of \nOATP1B1 and UGT1A1 with elevations of unconjugated bilirubin, and OATP1B1 \ninhibition data correlated with clinical unconjugated hyperbilirubinemia for \nseveral compounds. 2. In this study, inhibition of OATP1B3 and UGT1A1, in \naddition to OATP1B1, was explored to determine whether one measure offers value \nover the other as a potential prospective tool to predict unconjugated \nhyperbilirubinemia. OATP1B1 and OATP1B3-mediated transport of bilirubin was \nconfirmed and inhibition was determined for atazanavir, rifampicin, indinavir, \namprenavir, cyclosporine, rifamycin SV and saquinavir. To investigate the \nintrinsic inhibition by the drugs, both in vivo Fi (fraction of intrinsic \ninhibition) and R-value (estimated maximum in vivo inhibition) for OATP1B1, \nOATP1B3 and UGT1A1 were calculated. 3. The results indicated that in vivo Fi \nvalues >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are \nassociated with previously reported clinical cases of drug-induced unconjugated \nhyperbilirubinemia. 4. In conclusion, inhibition of OATP1B1 and/or OATP1B3 \nalong with predicted human pharmacokinetic data could be used pre-clinically to \npredict potential drug-induced benign unconjugated hyperbilirubinemia in the \nclinic.", "PURPOSE: Transport of the hepatobiliary scintigraphy agent Tc-99m mebrofenin \n(MEB) was characterized and simulation studies were conducted to examine the \neffects of altered hepatic transport on MEB pharmacokinetics in humans.\nMETHODS: MEB transport was investigated in Xenopus laevis oocytes expressing \nOATP1B1 or OATP1B3, and in membrane vesicles prepared from HEK293 cells \ntransfected with MRP2 or MRP3. A pharmacokinetic model was developed based on \nblood, urine and bile concentration-time profiles obtained in healthy humans, \nand the effect of changes in hepatic uptake and/or excretion associated with \ndisease states (hyperbilirubinemia and cholestasis) on MEB disposition was \nsimulated.\nRESULTS: MEB (80 pM) transport by OATP1B1 and OATP1B3 was inhibited by \nrifampicin (50 microM) to 10% and 4% of control, respectively. MEB (0.4 nM) \ntransport by MRP2 was inhibited to 12% of control by MK571 (50 microM); \nMRP3-mediated transport was inhibited to 5% of control by \nestradiol-17-beta-glucuronide (100 microM). A two-compartment model described \nMEB (2.5 mCi) systemic disposition in humans (systemic clearance = 16.2 +/- 2.7 \nml min(-1) kg(-1)); biliary excretion was the predominant route of hepatic \nelimination (efflux rate constants ratio canalicular/sinusoidal = 3.4 +/- 0.8). \nBased on simulations, altered hepatic transport markedly influenced MEB systemic \nand hepatic exposure.\nCONCLUSIONS: MEB may be a useful probe to assess how altered hepatic function at \nthe transport level modulates hepatobiliary drug disposition.", "1. Elevated serum bilirubin levels are caused mainly by liver diseases, \nhaematolysis, genetic defects and drug intake. Unconjugated bilirubin (UCB) is \ntaken up into hepatocytes by human organic anion transporting polypeptide 1B1 \n(OATP1B1; encoded for by the SLCO1B1 gene). The present study was performed to \ndetermine the association between SLCO1B1 gene polymorphisms and serum bilirubin \nlevels in vivo. Moreover, the effects of administration of low-dose rifampicin \non serum bilirubin levels in different SLCO1B1 genotypes was examined. 2. Serum \nbilirubin levels were examined in 42 healthy volunteers who had been analysed \nfor SLCO1B1 genotype (seven, 13, 14 and eight with SLCO1B1 genotypes 1a/1a, \n1b/1b, 1b/15 and 15/15, respectively). Among them, 24 subjects (seven, \nseven, eight and two with SLCO1B1 genotypes 1a/1a, 1b/1b, 1b/15 and \n15/15, respectively) were selected to participate in an open-label, two-phase \nclinical trial. Each was given 450 mg rifampicin orally once daily at 2000 hours \nfor 5 consecutive days. Serum bilirubin concentrations at 0800 hours on the 1st \nand 6th days were compared between the different SLCO1B1 genotypes. 3. In the 42 \nvolunteers, the mean (+/-SD) serum UCB in both SLCO1B11b/15 and 15/15 groups \nwas significantly higher than that in the SLCO1B11b/1b group (11.07 +/- 2.31, \n13.01 +/- 3.87 and 8.21 +/- 2.68 micromol/L, respectively; P = 0.009 and P < \n0.001). Total bilirum (T.BIL) in both the SLCO1B11b/15 and 15/15 groups was \nsignificantly higher than that in the SLCO1B11b/1b group (16.69 +/- 4.09, \n20.71 +/- 5.12 and 13.06 +/- 5.12 micromol/L, respectively; P = 0.029 and P < \n0.001). The direct bilirubin (D.BIL) in the SLCO1B115/15 group was \nsignificantly higher than that in the SLCO1B11b/1b group (7.69 +/- 1.81 vs \n4.85 +/- 1.81 micromol/L, respectively; P = 0.001). Rifampicin significantly \nincreased UCB, T.BIL and D.BIL concentrations in 24 healthy volunteers (17.68 \n+/- 5.96 vs 13.95 +/- 4.44 micromol/L (P = 0.040), 5.72 +/- 2.01 vs 4.35 +/- \n1.50 micromol/L (P = 0.028) and 12.00 +/- 4.26 vs 9.61 +/- 3.15 micromol/L (P = \n0.035), respectively). However, the extent of the increase in serum bilirubin \ncaused by 450 mg rifampicin for 5 days was not affected by SLCO1B1 genotype. 4. \nGenetic polymorphism in SLCO1B1 is a major determinant of interindividual \nvariability in the serum bilirubin level. SLCO1B115 carriers had higher \nbaseline serum UCB, T.BIL and D.BIL levels compared with subjects with the \nSLCO1B11a/1a and SLCO1B11b/1b genotypes. SLCO1B115/15 homozygotes are more \nsusceptible to hyperbilirubinaemia. Serum bilirubin levels could be increased by \nlow-dose rifampicin administration, but the extent of the increase was not \nassociated with SLCO1B1 genotype.", "Increased concentrations of bilirubin glucuronides in blood plasma indicate \nhepatocellular dysfunction. Elucidation of the transport processes of bilirubin \nconjugates across the basolateral (sinusoidal) and the canalicular plasma \nmembrane domains of hepatocytes has decisively contributed to our current \nunderstanding of the molecular basis of conjugated hyperbilirubinemia in human \nliver diseases. Under normal conditions, unconjugated bilirubin is taken up into \nhepatocytes by transporters of the organic anion-transporting polypeptide (OATP) \nfamily, followed by conjugation with glucuronic acid, and ATP-dependent \ntransport into bile. This efflux across the canalicular membrane is mediated by \nmultidrug resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein \ntransporting with high affinity and efficiency monoglucuronosyl bilirubin and \nbisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in human \nDubin-Johnson syndrome. Under pathophysiological conditions such as cholestatic \nliver injury and MRP2 inhibition, the basolateral efflux pump multidrug \nresistance protein 3 (MRP3 or ABCC3) is responsible for the occurrence of \nconjugated hyperbilirubinemia. MRP3 is a glycoprotein with a similar molecular \nmass as MRP2, with 48% amino acid identity, and with overlapping substrate \nspecificity. Human MRP3 is the only basolateral efflux pump shown to transport \nbilirubin glucuronides. In human and rat hepatocytes, MRP3/Mrp3 is strongly \nupregulated under conditions of cholestasis and MRP2 deficiency. This is in line \nwith the concept that basolateral efflux pumps of the hepatocyte compensate for \nimpaired canalicular efflux of compounds into bile and contribute to balance the \nrate of uptake or synthesis of compounds in hepatocytes with the capacity for \nefflux into bile.", "Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the \nbody. Bilirubin elimination is a multifaceted process consisting of uptake of \nbilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the \nhepatocytes, it is extensively glucuronidated by UGT1A1. Eventually, the \nglucuronide metabolite is excreted into the bile via MRP2. UGT1A1 inhibition has \nbeen previously shown to be linked with hyperbilirubinemia. However, because \ndrug transporters also contribute to bilirubin elimination, the purpose of this \nwork was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and \nBSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs \ninvestigated in this study were atazanavir and indinavir, which are associated \nwith hyperbilirubinemia and elevations in serum transaminase; ritonavir and \nnelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, \ntroglitazone, and trovafloxacin, which are associated with severe idiosyncratic \nhepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to \nlimited solubility and poor ionization of bilirubin and its glucuronide, the \nformation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 \nactivity, while the transport of pitavastatin, CDCF, and taurocholate were used \nas surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, \nand BSEP, respectively. It was assumed that any inhibition of the surrogate \nprobe substrates by test drugs is indicative of the potential impact of test \ndrugs to modulate the function of proteins involved in bilirubin disposition. In \nvitro inhibition was determined by calculating IC50. Moreover, Cmax and \nCmax,free were integrated with IC50 values to calculate R and Rfree, \nrespectively, which represents the ratio of probe drug glucuronidation/transport \nin the absence and presence of test drugs. Analysis of the data showed that \nRfree demonstrated the best correlation to hyperbilirubinemia. Specifically, \nRfree was above the 1.1 target threshold against UGT1A1, OATP1B1, and BSEP for \natazanavir and indinavir. In contrast, Rfree was below this threshold for \nritonavir and nelfinavir as well as for bromfenac, troglitazone, and \ntrovafloxacin. For all test drugs examined, only minor inhibition against \nOATP1B3 and MRP2 were observed. These data suggest that the proposed surrogate \nprobe substrates to evaluate the in vitro inhibition of UGT1A1, OATP1B1, and \nBSEP may be suitable to assess bilirubin disposition. For protease inhibitors, \ninclusion of OATP1B1 and BSEP inhibition may improve the predictability of \nhyperbilirubinemia.", "Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted \nby the liver into bile. Failure of this system can lead to a buildup of \nconjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis \nof bilirubin excretion and hyperbilirubinemia syndromes is largely understood, \nbut that of Rotor syndrome, an autosomal recessive disorder characterized by \nconjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic \nuptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 \nRotor-syndrome families and found that Rotor syndrome was linked to mutations \npredicted to cause complete and simultaneous deficiencies of the organic anion \ntransporting polypeptides OATP1B1 and OATP1B3. These important \ndetoxification-limiting proteins mediate uptake and clearance of countless drugs \nand drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 \npolymorphisms have previously been linked to drug hypersensitivities. Using mice \ndeficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we \nfound that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b \ntransporters mediate their hepatic re uptake. Transgenic expression of human \nOATP1B1 or OATP1B3 restored the function of this detoxification-enhancing \nliver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this \nshuttle may allow flexible transfer of bilirubin conjugates (and probably also \ndrug conjugates) formed in upstream hepatocytes to downstream hepatocytes, \nthereby preventing local saturation of further detoxification processes and \nhepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin \nglucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains \nRotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may \nconfer substantial drug toxicity risks.", "Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted \nby the liver into bile. Failure of this system can lead to a buildup of \nconjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis \nof bilirubin excretion and hyperbilirubinemia syndromes is largely understood, \nbut that of Rotor syndrome, an autosomal recessive disorder characterized by \nconjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic \nuptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 \nRotor-syndrome families and found that Rotor syndrome was linked to mutations \npredicted to cause complete and simultaneous deficiencies of the organic anion \ntransporting polypeptides OATP1B1 and OATP1B3. These important \ndetoxification-limiting proteins mediate uptake and clearance of countless drugs \nand drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 \npolymorphisms have previously been linked to drug hypersensitivities. Using mice \ndeficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we \nfound that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b \ntransporters mediate their hepatic reuptake. Transgenic expression of human \nOATP1B1 or OATP1B3 restored the function of this detoxification-enhancing \nliver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this \nshuttle may allow flexible transfer of bilirubin conjugates (and probably also \ndrug conjugates) formed in upstream hepatocytes to downstream hepatocytes, \nthereby preventing local saturation of further detoxification processes and \nhepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin \nglucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains \nRotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may \nconfer substantial drug toxicity risks.", "Faldaprevir, an investigational agent for hepatitis C virus treatment, is well \ntolerated but associated with rapidly reversible, dose-dependent, clinically \nbenign, unconjugated hyperbilirubinemia. Multidisciplinary preclinical and \nclinical studies were used to characterize mechanisms underlying this \nhyperbilirubinemia. In vitro, faldaprevir inhibited key processes involved in \nbilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 \nµM), which conjugates bilirubin, and hepatic uptake and efflux transporters, \norganic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 \n0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), \nwhich transport bilirubin and its conjugates. In rat and human hepatocytes, \nuptake and biliary excretion of [(3)H]bilirubin and/or its glucuronides \ndecreased on coincubation with faldaprevir. In monkeys, faldaprevir (≥20 mg/kg \nper day) caused reversible unconjugated hyperbilirubinemia, without hemolysis or \nhepatotoxicity. In clinical studies, faldaprevir-mediated hyperbilirubinemia was \npredominantly unconjugated, and levels of unconjugated bilirubin correlated with \nthe UGT1A128 genotype. The reversible and dose-dependent nature of the clinical \nhyperbilirubinemia was consistent with competitive inhibition of bilirubin \nclearance by faldaprevir, and was not associated with liver toxicity or other \nadverse events. Overall, the reversible, unconjugated hyperbilirubinemia \nassociated with faldaprevir may predominantly result from inhibition of \nbilirubin conjugation by UGT1A1, with inhibition of hepatic uptake of bilirubin \nalso potentially playing a role. Since OATP1B1/1B3 are known to be involved in \nhepatic uptake of circulating bilirubin glucuronides, inhibition of OATP1B1/1B3 \nand MRP2 may underlie isolated increases in conjugated bilirubin. As such, \nfaldaprevir-mediated hyperbilirubinemia is not associated with any liver injury \nor toxicity, and is considered to result from decreased bilirubin elimination \ndue to a drug-bilirubin interaction.", "OATP1B1 (a.k.a. OATP-C, OATP2, LST-1, or SLC21A6) is a liver-specific organic \nanion uptake transporter and has been shown to be a higher affinity bilirubin \nuptake transporter than OATP1B3. Using human embryonic kidney (HEK 293) cells \nstably transfected with OATP1B1, we have studied the effects of indinavir, \nsaquinavir, cyclosporin A, and rifamycin SV on human OATP1B1 transport function. \nThese drugs are potent inhibitors of OATP1B1 transport activity in vitro. We \nfurther provide evidence that the calculated fraction of OATP1B1 inhibited at \nthe clinical exposure level correlated very well with the observed \nhyperbilirubinemia outcome for these drugs in humans. Our data support the \nhypothesis that inhibition of OATP1B1 is an important mechanism for drug-induced \nunconjugated hyperbilirubinemia. Inhibition of OATPs may be an important \nmechanism in drug-drug and drug-endogenous substance interactions.", "New molecular entities (NMEs) are evaluated using a rigorous set of in vitro and \nin vivo studies to assess their safety and suitability for testing in humans. \nRegulatory health authorities require that therapeutic and supratherapeutic \ndoses be administered, by the intended route of administration, to two \nnonclinical species prior to human testing (ICH Expert Working Group. The \ninternational conference on harmonization of technical requirements for \nregistration of pharmaceuticals for human use (ICH); Multidisciplinary \nguidelines; Nonclinical safety studies (M3). \nhttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf \n, 2009). The purpose of these studies is to identify potential target organ \ntoxicity and to determine if the effects are reversible. Liver is a potential \nsite for toxicity caused by orally administered NMEs due to high exposure during \nfirst pass after oral administration. A range of clinical chemistry analytes are \nroutinely measured in both nonclinical and clinical studies to evaluate and \nmonitor for hepatotoxicity. While bilirubin itself circulates within a wide \nrange of concentrations in many animal species and humans, without causing \nadverse effects and possibly providing benefits (Sedlak and Snyder. Pediatrics \n113(6):1776-1782, 2004), bilirubin is one of the few readily monitored \ncirculating biomarkers that can provide insight into liver function. Therefore, \nany changes in plasma or urine bilirubin levels must be carefully evaluated. \nChanges in bilirubin may occur as a result of adaptive nontoxic changes or \nsevere toxicity. Examples of adaptive nontoxic changes in liver function, which \nmay elevate direct (conjugated) and/or indirect (unconjugated) bilirubin above \nbaseline levels, include reversible inhibition of UGT1A1-mediated bilirubin \nmetabolism and OATP1B1-, OATP1B3-, or MRP2-mediated transport (Keogh. Adv \nPharmacol 63:1-42, 2012). Alternatively, hepatocellular necrosis, \nhypoalbuminuria, or cholestasis may also lead to elevation of bilirubin; in some \ncases, these effects may be irreversible (FDA/CDER. Guidance for industry \ndrug-induced liver injury: premarketing clinical evaluation. \nhttp://www.fda.gov/downloads/Drugs/…/Guidances/UCM174090.pdf , 2012).This \nchapter aims to demonstrate application of enzyme kinetic principles in \nunderstanding the risk of bilirubin elevation through inhibition of multiple \nprocesses-involving both enzymes and transporters. In the sections that follow, \nwe first provide a brief summary of bilirubin formation and disposition. Two \ncase examples are then provided to illustrate the enzyme kinetic studies needed \nfor risk assessment and for identifying the mechanisms of bilirubin elevation. \nCaveats of methods and data interpretation are discussed in these case studies. \nThe data presented in this chapter is unpublished at the time of compilation of \nthis book. It has been incorporated in this chapter to provide a sense of \ncomplexities in enzyme kinetics to the reader.", "Eleven members of the human organic anion transporter (OATP) family (grouped \ninto six families) facilitate the Na(+)- independent transmembrane transport of \nvarious endo- and xenobiotics (bile acids, bilirubin, steroid hormone \nconjugates, thyroid hormones, prostaglandins, clinically used drugs, and \ntoxins). OATPs are 12-transmembrane glycoproteins (643-722 amino acids) and \ncontain many conserved structural features, for example, eleven cysteines in the \nlarge extracellular loop 5. They are important for proper transport, for which \ntranslocation of substrates through a central, positively-charged pore in a \nrocker-switch-type mechanism has been proposed. Although OATPs are expressed in \nvarious cells and tissues, some members show a more restricted pattern \n(well-studied OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in \ntestis). In cancer, the distribution pattern is no longer maintained, and OATPs, \nlike OATP1B3, become upregulated in malignant tissues (colon, breast, prostate). \nStudies in cell lines and animal models further revealed that the expression of \nOATPs is regulated in a cell- and tissue-specific way by cytokines and \nactivation of nuclear receptors (LXR, FXR, PXR, CAR, HNF4). Also epigenetic \nmechanisms and postranslational modifications influence their expression and \nfunction. Therefore, changes in the expression of OATPs under pathological \nconditions will influence transport processes causing an altered accumulation of \nOATP substrates in cells of excretory organs (intestine, liver, kidney) and on \nvarious blood/organ barriers (such as brain, testis, placenta). For drugs, this \nmay result in increased toxicity and adverse drug reactions. Therefore, it is \nimportant to improve the knowledge on the regulation and function of individual \nOATPs, and to apply it for therapeutic considerations.", "Silibinin has been reported to be a promising compound for hepatitis C treatment \nof nonresponders to standard treatment. Although administered silibinin is well \ntolerated, increased serum bilirubin levels have been observed during high-dose \ni.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in \nhumans, however, has not been identified so far. The aim of this study was to \ninvestigate the effect of silibinin on hepatocellular uptake and efflux \ntransport systems for organic anions to elucidate the cause of silibinin-induced \nhyperbilirubinemia. Therefore, the effect of silibinin on transport activity of \nthe hepatocellular uptake transporters organic anion-transporting polypeptides \n(OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na(+)-taurocholate \ncotransporting polypeptide (NTCP) and of the efflux transporters multidrug \nresistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was \nstudied. The effect of silibinin on OATPs and NTCP function was studied in \nstable transfected Chinese hamster ovary cells using the radiolabeled model \nsubstrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and \ntaurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured \nin vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters \nusing either estradiol-17β-glucuronide or taurocholate as substrates. OATP1B1, \nOATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited \nby (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In \ncontrast, the bile acid transporters NTCP and BSEP were not affected by \nsilibinin. We concluded that silibinin-induced hyperbilirubinemia may be caused \nby an inhibition of the bilirubin-transporting OATPs and the efflux-transporter \nMRP2.", "Bilirubin, a major end product of heme breakdown, is an important constituent of \nbile, responsible for its characteristic colour. Over recent decades, our \nunderstanding of bilirubin metabolism has expanded along with the processes of \nelimination of other endogenous and exogenous anionic substrates, mediated by \nthe action of multiple transport systems at the sinusoidal and canalicular \nmembrane of hepatocytes. Several inherited disorders characterised by impaired \nbilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert \nsyndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various \ndegrees of hyperbilirubinemia of either the predominantly unconjugated or \npredominantly conjugated type. Moreover, disrupted regulation of hepatobiliary \ntransport systems can explain jaundice in many acquired liver disorders. In this \nreview, we discuss the recent data on liver bilirubin handling based on the \ndiscovery of the molecular basis of Rotor syndrome. The data show that a \nsubstantial fraction of bilirubin conjugates is primarily secreted by MRP3 at \nthe sinusoidal membrane into the blood, from where they are subsequently \nreuptaken by sinusoidal membrane-bound organic anion transporting polypeptides \nOATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of \nbilirubin conjugated in splanchnic organs, such as the intestine and kidney, and \nfor a number of endogenous compounds, xenobiotics and drugs. Absence of one or \nboth OATP1B proteins thus may have serious impact on toxicity of commonly used \ndrugs cleared by this system such as statins, sartans, methotrexate or \nrifampicin. The liver-blood cycling of conjugated bilirubin is impaired in \ncholestatic and parenchymal liver diseases and this impairment most likely \ncontributes to jaundice accompanying these disorders." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D001663', 'http://amigo.geneontology.org/amigo/term/GO:0015723', 'http://www.biosemantics.org/jochem#4274830']
6031002d1cb411341a000129	[ 32522499, 31187503 ]	train	Are PDXK mutations linked to polyneuropathy?	yesno	Yes, PDXK mutations are linked to polyneuropathy.	yes	[ "Author information:\n(1)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), \nInstitute of Genetics, and Center for Rare Diseases Cologne, University of \nCologne, Cologne, Germany.\n(2)Molecular and Clinical Sciences Institute, St. George's University of London, \nCranmer Terrace, London SW17 0RE, UK; Department of Neuromuscular Diseases, UCL \nInstitute of Neurology, Queen Square, London, WC1N 3BG, UK.\n(3)Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen \nSquare, London, WC1N 3BG, UK; Department of Neurology and Neurosurgery, \nInstitute of Emergency Medicine, Toma Ciorbă 1, 2052 Chisinau, Republic of \nMoldova.\n(4)Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, \nUniversity College London, London WC1E 6BT, UK.\n(5)Neurology Dept., Ghaem Hospital, Medical School, Mashhad University of \nMedical Sciences, Mashhad, Iran.\n(6)Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad \n009851, Iran.\n(7)Molecular and Clinical Sciences Institute, St. George's University of London, \nCranmer Terrace, London SW17 0RE, UK; Department of Molecular Genetics, Next \nGeneration Genetic Polyclinic, Mashhad 009851, Iran.\n(8)Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.\n(9)Institute of Human Genetics, Center for Molecular Medicine Cologne (CMMC), \nInstitute of Genetics, and Center for Rare Diseases Cologne, University of \nCologne, Cologne, Germany. Electronic address: mert.karakaya@uk-koeln.de.", "Author information:\n(1)Department of Neuromuscular Diseases, University College London Queen Square \nInstitute of Neurology, London, United Kingdom.\n(2)Department of Neurology and Neurosurgery, Institute of Emergency Medicine, \nChisinau, Moldova.\n(3)Genetics and Genomic Medicine, University College London Great Ormond Street \nInstitute of Child Health, London, United Kingdom.\n(4)Department of Medicine (Neurology), University of Ottawa, Ottawa, Ontario, \nCanada.\n(5)Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.\n(6)Children's Hospital of Eastern Ontario Research Institute, University of \nOttawa, Ottawa, Ontario, Canada.\n(7)Department of Clinical and Experimental Epilepsy, University College London \nQueen Square Institute of Neurology, London, United Kingdom.\n(8)Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.\n(9)Cyprus School of Molecular Medicine, Nicosia, Cyprus.\n(10)Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, \nLondon, United Kingdom.\n(11)Randall Centre of Cell and Molecular Biophysics, School of Basic and Medical \nBiosciences, King's College London, London, United Kingdom.\n(12)Department of Neurology, Neurological Institute, Taipei Veterans General \nHospital, Taipei, Taiwan.\n(13)National Yang-Ming University School of Medicine, Taipei, Taiwan.\n(14)Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.\n(15)Department of Neurology and Psychiatry, Assiut University Hospital, Faculty \nof Medicine, Asyut, Egypt.\n(16)Reta Lila Weston Research Laboratories, University College London Queen \nSquare Institute of Neurology, London, United Kingdom.\n(17)Department of Information and Communications Engineering, University of \nMurcia, Murcia, Spain.\n(18)Department of Medical & Molecular Genetics, King's College London, Guy's \nHospital, London, United Kingdom.\n(19)Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, \nOntario, Canada.\n(20)Neuro-ophthalmology Department, National Hospital for Neurology and \nNeurosurgery, London, United Kingdom.\n(21)Clinical Neurophysiology Department, National Hospital for Neurology and \nNeurosurgery, London, United Kingdom.\n(22)Department of Neurodegenerative Disease, University College London Queen \nSquare Institute of Neurology, London, United Kingdom.\n(23)UK Dementia Research Institute at University College London, London, United \nKingdom.\n(24)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, \nMölndal, Sweden.\n(25)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and \nPhysiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.\n(26)Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, \nLondon, United Kingdom.\n(27)Department of Cell Biology, Yale School of Medicine, New Haven, CT." ]	nan
5709e947cf1c32585100001d	[ 15703275, 18216854 ]	train	Are Sidekick proteins members of the immunoglobulin superfamily?	yesno	Yes, sidekick are cell adhesion molecules of the immunoglobulin superfamily.	yes	[ "Sidekick-1, a cell adhesion molecule of the immunoglobulin superfamily, is \nup-regulated in glomerular podocytes in the collapsing glomerulopathy of \nHIV-associated nephropathy (HIVAN). Sidekick-1 and its ortholog sidekick-2 have \nalso been shown to function as neuronal targeting molecules, guiding developing \nneurons to specific synapses. In the current work, we overexpress mouse \nsidekick-1 and -2 in HEK 293 T cells in order to characterize their binding \nspecificities. Cells transiently transfected with either sidekick-1 or -2 cDNA \nformed separate aggregates when mixed together, demonstrating that sidekicks are \nhomophilic adhesion molecules. The transfection of the short splice variant \n(lacking the first two Ig domains) or a construct encoding sidekick-1 with the \nsecond Ig domain deleted both resulted in nearly abolished adhesion. A \nbeta-sheet strand peptide containing the sequence QLVILA corresponding to an \namino acid sequence in the second Ig domain of sidekick-1 showed specific \ninteraction with the recombinant first Ig domain-His protein of sidekick-1. \nCells expressing a mutant sidekick-1 where the binding sequence QLVILA is \ndeleted failed to mediate significant adhesion. Furthermore, cells transfected \nwith a chimeric sidekick, where the first two Ig domains of sidekick-2 are \nreplaced with the corresponding two Ig domains of sidekick-1, form aggregates \nwith sidekick-1-transfected cells. The reverse chimera, where the first two Ig \ndomains of sidekick-2 are substituted onto sidekick-1, was similarly able to \nform aggregates with sidekick-2-transfected cells. These results establish that \nthe first and second Ig domains of sidekick-1 and -2 are necessary and \nsufficient to mediate and target homophilic adhesion, and the QLVILA sequence is \ncritical to the interaction. Understanding these functional domains has \nwidespread implications in normal development and HIVAN pathogenesis.", "Synaptic circuits in the retina transform visual input gathered by \nphotoreceptors into messages that retinal ganglion cells (RGCs) send to the \nbrain. Processes of retinal interneurons (amacrine and bipolar cells) form \nsynapses on dendrites of RGCs in the inner plexiform layer (IPL). The IPL is \ndivided into at least 10 parallel sublaminae; subsets of interneurons and RGCs \narborize and form synapses in just one or a few of them. These lamina-specific \ncircuits determine the visual features to which RGC subtypes respond. Here we \nshow that four closely related immunoglobulin superfamily (IgSF) adhesion \nmolecules--Dscam (Down's syndrome cell adhesion molecule), DscamL (refs 6-9), \nSidekick-1 and Sidekick-2 (ref. 10)--are expressed in chick by non-overlapping \nsubsets of interneurons and RGCs that form synapses in distinct IPL sublaminae. \nMoreover, each protein is concentrated within the appropriate sublaminae and \neach mediates homophilic adhesion. Loss- and gain-of-function studies in vivo \nindicate that these IgSF members participate in determining the IPL sublaminae \nin which synaptic partners arborize and connect. Thus, vertebrate Dscams, like \nDrosophila Dscams, play roles in neural connectivity. Together, our results on \nDscams and Sidekicks suggest the existence of an IgSF code for laminar \nspecificity in retina and, by implication, in other parts of the central nervous \nsystem." ]	nan
5e67bc121af46fc13000001c	[ 24926928, 27593814 ]	train	Are Spinal Intradural Primary Malignant Peripheral Nerve Sheath Tumors(MPNST) rare in neurofibromatosis patients?	yesno	Spinal intradural primary malignant peripheral nerve sheath tumors (MPNST) are rare in patients without neurofibromatosis.	no	[ "Primary malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare in \npatients without a history of neurofibromatosis; only 18 cases have been \nreported in the English-language literature to this point. The authors report \ntheir experience with 1 new case of a primary MPNST. A 33-year-old woman \npresented with low-back pain radiating to the right calf that progressed over 1 \nyear. Magnetic resonance imaging of the spine revealed an intradural \nextramedullary lesion at the T12-L1 level. The patient was diagnosed with \nprimary MPNST, underwent two surgical excisions and radiation therapy, and \ndeveloped leptomeningeal metastases as well as brain metastases. The patient \nrevisited the emergency room with sudden loss of consciousness. A brain CT scan \ndisplayed bilateral lateral ventricle enlargement, for which a \nventriculoperitoneal shunt was inserted. These symptoms have not been described \nin any previous report. Primary spinal MPNST is an exceedingly rare entity, and \nthe overall prognosis is very poor. To the authors' knowledge, no standard of \ncare for primary spinal MPNSTs has yet been established. All 19 cases of primary \nspinal MPNSTs are reviewed, and the authors discuss their clinical, \nradiological, and therapeutic features and outcomes.", "Spinal intradural primary malignant peripheral nerve sheath tumors (MPNST) are \nrare in patients without neurofibromatosis. Here we represent a 3-year-old girl \nof primary intradural spinal malignant peripheral nerve sheath tumor. The tumor \nwas removed partially and MPNST was diagnosed in the histopathological \nexamination. Her condition deteriorated due to acute hydrocephalus in the \nfollowing days. In this article, we discuss the clinical presentation, imaging, \ntreatment, and prognosis of our patient and the other 22 patients of primary \nintradural MPNST, found in the literature. The Kaplan?Meier method was applied \nfor univariate analysis and Cox proportional hazards model for multivariate \nanalysis. This analysis showed that age, was an important factor predicting \nshort-term survival of patients with MPNST." ]	nan
58ee1cafeda5a57672000014	[ 25409831, 26748519, 25367294, 26518482, 26431028, 26030525, 25959774 ]	train	Are TAD boundaries in Drosophila depleted in highly-expressed genes?	yesno	Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes.	no	[ "Eukaryotic chromosomes replicate in a temporal order known as the \nreplication-timing program. In mammals, replication timing is cell-type-specific \nwith at least half the genome switching replication timing during development, \nprimarily in units of 400-800 kilobases ('replication domains'), whose positions \nare preserved in different cell types, conserved between species, and appear to \nconfine long-range effects of chromosome rearrangements. Early and late \nreplication correlate, respectively, with open and closed three-dimensional \nchromatin compartments identified by high-resolution chromosome conformation \ncapture (Hi-C), and, to a lesser extent, late replication correlates with \nlamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure \nwithin chromatin compartments called topologically associating domains (TADs) \nthat are largely conserved in their positions between cell types and are similar \nin size to replication domains. However, TADs can be further sub-stratified into \nsmaller domains, challenging the significance of structures at any particular \nscale. Moreover, attempts to reconcile TADs and LADs to replication-timing data \nhave not revealed a common, underlying domain structure. Here we localize \nboundaries of replication domains to the early-replicating border of \nreplication-timing transitions and map their positions in 18 human and 13 mouse \ncell types. We demonstrate that, collectively, replication domain boundaries \nshare a near one-to-one correlation with TAD boundaries, whereas within a cell \ntype, adjacent TADs that replicate at similar times obscure replication domain \nboundaries, largely accounting for the previously reported lack of alignment. \nMoreover, cell-type-specific replication timing of TADs partitions the genome \ninto two large-scale sub-nuclear compartments revealing that replication-timing \ntransitions are indistinguishable from late-replicating regions in chromatin \ncomposition and lamina association and accounting for the reduced correlation of \nreplication timing to LADs and heterochromatin. Our results reconcile \ncell-type-specific sub-nuclear compartmentalization and replication timing with \ndevelopmentally stable structural domains and offer a unified model for \nlarge-scale chromosome structure and function.", "Three-dimensional genome structure plays an important role in gene regulation. \nGlobally, chromosomes are organized into active and inactive compartments while, \nat the gene level, looping interactions connect promoters to regulatory \nelements. Topologically associating domains (TADs), typically several hundred \nkilobases in size, form an intermediate level of organization. Major questions \ninclude how TADs are formed and how they are related to looping interactions \nbetween genes and regulatory elements. Here we performed a focused 5C analysis \nof a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We \nfind that the same TAD boundaries are present in all cell types, indicating that \nTADs represent a universal chromosome architecture. Furthermore, we find that \nthese TAD boundaries are present irrespective of the expression and looping of \ngenes located between them. In contrast, looping interactions between promoters \nand regulatory elements are cell-type specific and occur mostly within TADs. \nThis is exemplified by the CFTR promoter that in different cell types interacts \nwith distinct sets of distal cell-type-specific regulatory elements that are all \nlocated within the same TAD. Finally, we find that long-range associations \nbetween loci located in different TADs are also detected, but these display much \nlower interaction frequencies than looping interactions within TADs. \nInterestingly, interactions between TADs are also highly cell-type-specific and \noften involve loci clustered around TAD boundaries. These data point to key \nroles of invariant TAD boundaries in constraining as well as mediating \ncell-type-specific long-range interactions and gene regulation.", "The spatial arrangement of interphase chromosomes in the nucleus is important \nfor gene expression and genome function in animals and in plants. The recently \ndeveloped Hi-C technology is an efficacious method to investigate genome \npacking. Here we present a detailed Hi-C map of the three-dimensional genome \norganization of the plant Arabidopsis thaliana. We find that local chromatin \npacking differs from the patterns seen in animals, with kilobasepair-sized \nsegments that have much higher intrachromosome interaction rates than \nneighboring regions, representing a dominant local structural feature of genome \nconformation in A. thaliana. These regions, which appear as positive strips on \ntwo-dimensional representations of chromatin interaction, are enriched in \nepigenetic marks H3K27me3, H3.1, and H3.3. We also identify more than 400 \ninsulator-like regions. Furthermore, although topologically associating domains \n(TADs), which are prominent in animals, are not an obvious feature of A. \nthaliana genome packing, we found more than 1000 regions that have properties of \nTAD boundaries, and a similar number of regions analogous to the interior of \nTADs. The insulator-like, TAD-boundary-like, and TAD-interior-like regions are \neach enriched for distinct epigenetic marks and are each correlated with \ndifferent gene expression levels. We conclude that epigenetic modifications, \ngene density, and transcriptional activity combine to shape the local packing of \nthe A. thaliana nuclear genome.", "Recent advances enabled by the Hi-C technique have unraveled many principles of \nchromosomal folding that were subsequently linked to disease and gene \nregulation. In particular, Hi-C revealed that chromosomes of animals are \norganized into topologically associating domains (TADs), evolutionary conserved \ncompact chromatin domains that influence gene expression. Mechanisms that \nunderlie partitioning of the genome into TADs remain poorly understood. To \nexplore principles of TAD folding in Drosophila melanogaster, we performed Hi-C \nand poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, \nDmBG3-c2, and OSC). Contrary to previous studies, we find that regions between \nTADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly \nenriched with the insulator protein dCTCF, while another insulator protein \nSu(Hw) is preferentially present within TADs. However, Drosophila inter-TADs \nharbor active chromatin and constitutively transcribed (housekeeping) genes. \nAccordingly, we find that binding of insulator proteins dCTCF and Su(Hw) \npredicts TAD boundaries much worse than active chromatin marks do. \nInterestingly, inter-TADs correspond to decompacted inter-bands of polytene \nchromosomes, whereas TADs mostly correspond to densely packed bands. \nCollectively, our results suggest that TADs are condensed chromatin domains \ndepleted in active chromatin marks, separated by regions of active chromatin. We \npropose the mechanism of TAD self-assembly based on the ability of nucleosomes \nfrom inactive chromatin to aggregate, and lack of this ability in acetylated \nnucleosomal arrays. Finally, we test this hypothesis by polymer simulations and \nfind that TAD partitioning may be explained by different modes of \ninter-nucleosomal interactions for active and inactive chromatin.", "Dosage compensation mechanisms provide a paradigm to study the contribution of \nchromosomal conformation toward targeting and spreading of epigenetic regulators \nover a specific chromosome. By using Hi-C and 4C analyses, we show that \nhigh-affinity sites (HAS), landing platforms of the male-specific lethal (MSL) \ncomplex, are enriched around topologically associating domain (TAD) boundaries \non the X chromosome and harbor more long-range contacts in a sex-independent \nmanner. Ectopically expressed roX1 and roX2 RNAs target HAS on the X chromosome \nin trans and, via spatial proximity, induce spreading of the MSL complex in cis, \nleading to increased expression of neighboring autosomal genes. We show that the \nMSL complex regulates nucleosome positioning at HAS, therefore acting locally \nrather than influencing the overall chromosomal architecture. We propose that \nthe sex-independent, three-dimensional conformation of the X chromosome poises \nit for exploitation by the MSL complex, thereby facilitating spreading in males.", "The three-dimensional organization of a genome plays a critical role in \nregulating gene expression, yet little is known about the machinery and \nmechanisms that determine higher-order chromosome structure. Here we perform \ngenome-wide chromosome conformation capture analysis, fluorescent in situ \nhybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) \nmaps of the Caenorhabditis elegans genome and to dissect X chromosome dosage \ncompensation, which balances gene expression between XX hermaphrodites and XO \nmales. The dosage compensation complex (DCC), a condensin complex, binds to both \nhermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex \nsites) to reduce chromosome-wide gene expression by half. Most DCC condensin \nsubunits also act in other condensin complexes to control the compaction and \nresolution of all mitotic and meiotic chromosomes. By comparing chromosome \nstructure in wild-type and DCC-defective embryos, we show that the DCC remodels \nhermaphrodite X chromosomes into a sex-specific spatial conformation distinct \nfrom autosomes. Dosage-compensated X chromosomes consist of self-interacting \ndomains (∼1 Mb) resembling mammalian topologically associating domains (TADs). \nTADs on X chromosomes have stronger boundaries and more regular spacing than on \nautosomes. Many TAD boundaries on X chromosomes coincide with the \nhighest-affinity rex sites and become diminished or lost in DCC-defective \nmutants, thereby converting the topology of X to a conformation resembling \nautosomes. rex sites engage in DCC-dependent long-range interactions, with the \nmost frequent interactions occurring between rex sites at DCC-dependent TAD \nboundaries. These results imply that the DCC reshapes the topology of X \nchromosomes by forming new TAD boundaries and reinforcing weak boundaries \nthrough interactions between its highest-affinity binding sites. As this model \npredicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary \nusing CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a \ndistinct higher-order structure onto X chromosomes while regulating gene \nexpression chromosome-wide.", "Author information:\n(1)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 \nBerlin, Germany; Institute for Medical and Human Genetics, Charité \nUniversitätsmedizin Berlin, 13353 Berlin, Germany.\n(2)Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, \n13353 Berlin, Germany.\n(3)Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133 \nRome, Italy.\n(4)Institute of Human Genetics Biozentrum, Julius Maximilian University of \nWürzburg, 97070 Würzburg, Germany.\n(5)Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, \n34093 Istanbul, Turkey.\n(6)Department of Pediatrics, School of Medicine, University of Utah, Salt Lake \nCity, UT 84108, USA.\n(7)Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital \nUniversitario La Paz, 28046 Madrid, Spain; U753 Centro de Investigación \nBiomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, \n28046 Madrid, Spain.\n(8)Service de Génétique, C.H.U. de Poitiers, 86021 Poitiers, France.\n(9)Department Developmental Genetics, Max Planck Institute for Molecular \nGenetics, 14195 Berlin, Germany.\n(10)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 \nBerlin, Germany.\n(11)Department of Computational Molecular Biology, Max Planck Institute for \nMolecular Genetics, 14195 Berlin, Germany.\n(12)Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, \nBerkeley, CA 94720, USA.\n(13)Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 \nBerlin, Germany.\n(14)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 \nBerlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), \nCharité Universitätsmedizin Berlin, 13353 Berlin, Germany.\n(15)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 \nBerlin, Germany; Institute for Medical and Human Genetics, Charité \nUniversitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for \nRegenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, \nGermany.\n(16)Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, \nBerkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, \nWalnut Creek, CA 94598, USA; School of Natural Sciences, University of \nCalifornia, Merced, CA 95343, USA.\n(17)Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 \nBerlin, Germany; Institute for Medical and Human Genetics, Charité \nUniversitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for \nRegenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, \nGermany. Electronic address: mundlos@molgen.mpg.de." ]	nan
602c2ade1cb411341a000124	[ 29594035 ]	train	Are TAMs good anticancer therapeutic targets?	yesno	Therapeutic strategies to target TAMs to complement conventional therapies has yielded promising results.	yes	[ "Macrophages are a major component of the tumor microenvironment and orchestrate \nvarious aspects of immunity. Within tumors, macrophages can reversibly alter \ntheir endotype in response to environmental cues, including hypoxia and stimuli \nderived from other immune cells, as well as the extracellular matrix. Depending \non their activation status, macrophages can exert dual influences on \ntumorigenesis by either antagonizing the cytotoxic activity immune cells or by \nenhancing antitumor responses. In most solid cancers, increased infiltration \nwith tumor-associated macrophages (TAMs) has long been associated with poor \npatient prognosis, highlighting their value as potential diagnostic and \nprognostic biomarkers in cancer. A number of macrophage-centered approaches to \nanticancer therapy have been investigated, and include strategies to block their \ntumor-promoting activities or exploit their antitumor effector functions. \nIntegrating therapeutic strategies to target TAMs to complement conventional \ntherapies has yielded promising results in preclinical trials and warrants \nfurther investigation to determine its translational benefit in human cancer \npatients. In this review, we discuss the molecular mechanisms underlying the \npro-tumorigenic programming of macrophages and provide a comprehensive update of \nmacrophage-targeted therapies for the treatment of solid cancers." ]	nan
603285861cb411341a000141	[ 31462144, 31799626, 31712269, 33075123, 31865463 ]	train	Are Toll-like receptors (TLRs) induced by microbes?	yesno	Yes, Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form.	yes	[ "Host-directed therapies are gaining considerable impetus because of the \nemergence of drug-resistant strains of pathogens due to antibiotic therapy. \nTherefore, there is an urgent need to exploit alternative and novel strategies \ndirected at host molecules to successfully restrict infections. The C-type \nlectin receptor CLEC4E and Toll-like receptor TLR4 expressed by host cells are \namong the first line of defense in encountering pathogens. Therefore, we \nexploited signaling of macrophages through CLEC4E in association with TLR4 \nagonists (C4.T4) to control the growth of Mycobacterium tuberculosis (Mtb). We \nobserved significant improvement in host immunity and reduced bacterial load in \nthe lungs of Mtb-infected mice and guinea pigs treated with C4.T4 agonists. \nFurther, intracellular killing of Mtb was achieved with a 10-fold lower dose of \nisoniazid or rifampicin in conjunction with C4.T4 than the drugs alone. C4.T4 \nactivated MYD88, PtdIns3K, STAT1 and RELA/NFKB, increased lysosome biogenesis, \ndecreased Il10 and Il4 gene expression and enhanced macroautophagy/autophagy. \nMacrophages from autophagy-deficient (atg5 knockout or Becn1 knockdown) mice \nshowed elevated survival of Mtb. The present findings also unveiled the novel \nrole of CLEC4E in inducing autophagy through MYD88, which is required for \ncontrol of Mtb growth. This study suggests a unique immunotherapeutic approach \ninvolving CLEC4E in conjunction with TLR4 to restrict the survival of Mtb \nthrough autophagy.\nABBREVIATIONS: 3MA: 3 methyladenine; AO: acridine orange; Atg5: autophagy \nrelated 5; AVOs: acidic vesicular organelles; BECN1: beclin 1, autophagy \nrelated; BMDMs: bone marrow derived macrophages; bw: body weight; C4.T4: \nagonists of CLEC4E (C4/TDB) and TLR4 (T4/ultra-pure-LPS); CFU: colony forming \nunit; CLEC4E/Mincle: C-type lectin domain family 4, member e; CLR: c-type lectin \nreceptor; INH: isoniazid; LAMP1: lysosomal-associated membrane protein 1; \nMφC4.T4: Mtb-infected C4.T4 stimulated macrophages; MAP1LC3/LC3: \nmicrotubule-associated protein 1 light chain 3; MDC: monodansylcadaverine; MTOR: \nmechanistic target of rapamycin kinase; MYD88: myeloid differentiation primary \nresponse 88; NFKB: nuclear factor of kappa light polypeptide gene enhance in B \ncells; NLR: NOD (nucleotide-binding oligomerization domain)-like receptors; PFA: \nparaformaldehyde; PPD: purified protein derivative; PtdIns3K: class III \nphosphatidylinositol 3-kinase; RELA: v-rel reticuloendotheliosis viral oncogene \nhomolog A (avian); RIF: rifampicin; RLR: retinoic acid-inducible gene-I-like \nreceptors; TDB: trehalose-6,6´-dibehenate; TLR4: toll-like receptor 4; \nUltra-pure-LPS: ultra-pure lipopolysaccharide-EK; V-ATPase: vacuolar-type H+ \nATPase.", "During viral infection, viral nucleic acids are detected by virus sensor \nproteins including toll-like receptor 3 or retinoic acid-inducible gene I-like \nreceptors (RLRs) in mammalian cells. Activation of these virus sensor proteins \ninduces type-I interferon production and represses viral replication. Recently, \nwe reported that an RLR family member, laboratory of genetics and physiology 2 \n(LGP2), modulates RNA silencing by interacting with an RNA silencing enhancer, \nTAR-RNA binding protein (TRBP). However, the biological implications remained \nunclear. Here, we show that LGP2 enhances apoptosis by upregulating apoptosis \nregulatory genes during viral infection. Sendai virus (SeV) infection increased \nLGP2 expression approximately 900 times compared to that in non-virus-infected \ncells. Then, the induced LGP2 interacted with TRBP, resulting in the inhibition \nof maturation of the TRBP-bound microRNA (miRNA) and its subsequent RNA \nsilencing activity. Gene expression profiling revealed that apoptosis regulatory \ngenes were upregulated during SeV infection: caspases-2, -8, -3 and -7, four \ncysteine proteases with key roles in apoptosis, were upregulated directly or \nindirectly through the repression of a typical TRBP-bound miRNA, miR-106b. Our \nfindings may shed light on the mechanism of apoptosis, induced by the TRBP-bound \nmiRNAs through the interaction of TRBP with LGP2, as an antiviral defense system \nin mammalian cells.", "Helicobacter pylori colonizes the stomach in about half of the world's \npopulation. H. pylori strains containing the cag pathogenicity island (cag PAI) \nare associated with a higher risk of gastric adenocarcinoma or peptic ulcer \ndisease than cag PAI-negative strains. The cag PAI encodes a type IV secretion \nsystem (T4SS) that mediates delivery of the CagA effector protein as well as \nnonprotein bacterial constituents into gastric epithelial cells. H. \npylori-induced nuclear factor kappa-light-chain-enhancer of activated B cells \n(NF-κB) activation and interleukin-8 (IL-8) secretion are attributed to \nT4SS-dependent delivery of lipopolysaccharide metabolites and peptidoglycan into \nhost cells, and Toll-like receptor 9 (TLR9) activation is attributed to delivery \nof bacterial DNA. In this study, we analyzed the bacterial energetic \nrequirements associated with these cellular alterations. Mutant strains lacking \nCagα, Cagβ, or CagE (putative ATPases corresponding to VirB11, VirD4, and VirB4 \nin prototypical T4SSs) were capable of T4SS core complex assembly but defective \nin CagA translocation into host cells. Thus, the three Cag ATPases are not \nfunctionally redundant. Cagα and CagE were required for H. pylori-induced NF-κB \nactivation, IL-8 secretion, and TLR9 activation, but Cagβ was dispensable for \nthese responses. We identified putative ATP-binding motifs (Walker-A and \nWalker-B) in each of the ATPases and generated mutant strains in which these \nmotifs were altered. Each of the Walker box mutant strains exhibited properties \nidentical to those of the corresponding deletion mutant strains. These data \nsuggest that Cag T4SS-dependent delivery of nonprotein bacterial constituents \ninto host cells occurs through mechanisms different from those used for \nrecruitment and delivery of CagA into host cells.", "Author information:\n(1)Department of Pathology, University of Cambridge, Cambridge, UK.\n(2)Centre for Trophoblast Research, Departments of Physiology and Neuroscience, \nUniversity of Cambridge, Cambridge, UK.\n(3)Singapore Immunology Network, Agency for Science, Technology and Research, \nSingapore, Singapore.\n(4)School of Biological Sciences, Nanyang Technological University, Singapore, \nSingapore.\n(5)Key Laboratory for Regenerative Medicine of Ministry of Education, Institute \nof Hematology, School of Medicine, Jinan University, Guangzhou, China.\n(6)State Key Laboratory of Proteomics, Academy of Military Medical Sciences, \nAcademy of Military Sciences, Beijing, China.\n(7)State Key Laboratory of Experimental Hematology, Institute of Hematology and \nBlood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China.\n(8)Shanghai Institute of Immunology, Shanghai JiaoTong University School of \nMedicine, Shanghai, China.\n(9)Translational Immunology Institute, SingHealth Duke-NUS Academic Medical \nCentre, Singapore, Singapore.\n(10)Department of Genetics, University of Cambridge, Cambridge, UK.", "Recent advances in small-bowel endoscopy such as capsule endoscopy have shown \nthat non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small \nintestine, with the prevalence rate of mucosal breaks of around 50% in chronic \nusers. A significant proportion of patients with NSAIDs-induced enteropathy are \nasymptomatic, but some patients develop symptomatic or complicated ulcers that \nneed therapeutic intervention. Both inhibition of prostaglandins due to the \ninhibition of cyclooxygenases and mitochondrial dysfunction secondary to the \ntopical effect of NSAIDs play a crucial role in the early process of injury. As \na result, the intestinal barrier function is impaired, which allows \nenterobacteria to invade the mucosa. Gram-negative bacteria and endogenous \nmolecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 \nto induce excessive expression of cytokines such as tumor necrosis factor-α and \nto activate NLRP3 inflammasome, a multiprotein complex that processes \npro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the \nmucosa, resulting in intestinal ulceration. Currently, misoprostol is the only \ndrug that has a proven beneficial effect on bleeding small intestinal ulcers \ninduced by NSAIDs or low-dose aspirin, but its protection is insufficient. \nTherefore, the efficacy of the combination of misoprostol with other drugs, \nespecially those targeting the innate immune system, should be assessed in the \nnext step." ]	nan
621ed10f3a8413c653000062	[ 16393984, 19816193, 18205702, 23635849, 21386770, 22749847, 17234458, 17368474, 23983771, 16020508, 24754976, 16809644, 24483245, 20843956, 18032693, 21655351, 27109178, 22899644, 34495808, 19005268, 23531479, 17407195, 17826781, 25113439, 17848162, 20384869, 19543397, 15778406, 24095986, 21597299, 18580479 ]	train	Are Tregs CD4(+)CD25(+) regulatory T cells a positive regulator of the immune response?	yesno	CD4(+)CD25(+) regulatory T cells (Tregs) are negative regulators of the immune system that induce and maintain immune tolerance.	no	[ "CD4+ T cells naturally expressing CD25 molecules (natural T regulatory cells \n(Tregs)) have a role in maintaining self tolerance and in regulating responses \nto infectious agents, transplantation Ags, and tumor Ags. CD4+ Tregs induced \nfrom CD4+CD25- precursors (induced Tregs) also regulate immune responses in the \nperiphery. However, which of these Tregs is a major impediment in generating \nantitumor CTL responses is not clear. We show that although the CD4+CD25+ \nsubsets isolated from peripheral blood-derived lymphocytes do suppress the \nproliferation of CD4+CD25- effector T cells, they do not suppress the activation \nand expansion of the self but melanoma-associated, melanoma Ag-reactive T cell 1 \n(MART-1)27-35-specific CD8+ T cells stimulated by the respective peptide-loaded \nmatured dendritic cells in vitro. The CD4+CD25- counterparts, in contrast, lead \nto the generation of CD25+ glucocorticoid-inducible TNFR+-Forkhead/winged helix \ntranscription factor+ populations and efficiently suppress the activation and \nexpansion of the MART-127-35 epitope-specific CTLs. Our data suggest that when \nCTL precursors are optimally stimulated, natural Tregs are not a formidable \nconstraint toward generating a robust antitumor CTL response, but induced Tregs \ncould be.", "The immunosuppressive effects of CD4+ CD25 high regulatory T cells (Tregs) \ninterfere with antitumor immune responses in cancer patients. Here, we present a \nnovel class of engineered human interleukin (IL)-2 analogs that antagonizes the \nIL-2 receptor, for inhibiting regulatory T cell suppression. These antagonists \nhave been engineered for high affinity to the alpha subunit of the IL-2 receptor \nand very low affinity to either the beta or gamma subunit, resulting in a \nsignaling-deficient IL-2 analog that sequesters the IL-2 receptor alpha subunit \nfrom wild type IL-2. Two variants, \"V91R\" and \"Q126T\" with residue substitutions \nthat disrupt the beta and gamma subunit binding interfaces, respectively, have \nbeen characterized in both a T cell line and in human primary Tregs. These \nmutants retain their high affinity binding to IL-2 receptor alpha subunit, but \ndo not activate STAT5 phosphorylation or stimulate T cell growth. The 2 mutants \ncompetitively antagonize wild-type IL-2 signaling through the IL-2 receptor with \nsimilar efficacy, with inhibition constants of 183 pM for V91R and 216 pM for \nQ126T. Here, we present a novel approach to CD25-mediated Treg inhibition, with \nthe use of an engineered human IL-2 analog that antagonizes the IL-2 receptor.", "CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells \nwhose role is the suppression and regulation of immune responses to self and \nnon-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs \nin both autoimmune and infectious disease has continued to expand. This review \nexamines the recent advances on the role CD4+ CD25+ Tregs may be playing in \nvarious diseases regarding progression or protection. In addition, advances made \nin the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, \ntechniques and antibodies are discussed. Ultimately, an overall understanding of \nthe exact mechanism which CD4+ CD25+ Tregs implement during disease progression \nwill enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically \nbeneficial manner.", "It is well established that CD4CD25 regulatory T cells (Tregs) downregulate \ninflammatory immune responses and help to maintain immune homeostasis. Recent \nreports have shown that ligation of germline encoded pattern recognition \nreceptors such as Toll-like receptors can stimulate Tregs and therefore \nimplicate Tregs in the pathophysiology of sepsis and other inflammatory \ndiseases. In this report, we show that injection of lipopolysaccharide (LPS) \nleads to expansion of CD4CD25FoxP3 Tregs, suggesting that these cells may play \nan important role in immune regulation in LPS-induced acute inflammation. \nIndeed, genetic or immunological inhibition of Treg function using mice lacking \nfunctional Tregs (CD25 KO mice) or anti-CD25 monoclonal antibody (anti-CD25 \nmAb), respectively, led to acute death in an otherwise nonlethal LPS challenge. \nThis was accompanied by exaggerated production of proinflammatory cytokines. \nStrikingly, adoptive transfer of CD4CD25 Tregs to CD25 KO mice before LPS \nchallenge rescues mice from death. Unlike LPS, depletion of Tregs followed by \nconcanavalin A (Con A) challenge does not result in mortality, suggesting that \nTreg depletion does not globally influence all models of acute inflammation. We \nauthenticate our findings by showing that depletion of Tregs leads to mortality \nin a nonlethal Escherichia coli challenge accompanied by elevated serum levels \nof proinflammatory cytokines. Collectively, our results indicate that in \naddition to regulation of LPS-induced acute inflammation, Tregs help to improve \nbacterial clearance and promote survival in an acute model of bacterial \ninfection.", "BACKGROUND: Because CD4CD25Foxp3 regulatory T cells (Tregs) are essential for \nthe maintenance of self-tolerance, significant interest surrounds the \ndevelopmental cues for thymic-derived natural Tregs (nTregs) and \nperiphery-generated adaptive Tregs (aTregs). In the transplant setting, the \nallograft may play a role in the generation of alloantigen-specific Tregs, but \nthis role remains undefined. We examined whether the immune response to a \ntransplant allograft results in the peripheral generation of aTregs.\nMETHODS: To identify generation of aTregs, purified graft-reactive CD4CD25 T \ncells were adoptively transferred to mice-bearing skin allograft. To demonstrate \nthat aTregs are necessary for tolerance, DBA/2 skin was transplanted onto \nC57BL/6-RAG-1-deficient recipients adoptively transferred with purified sorted \nCD4CD25 T cells; half of the recipients undergo tolerance induction treatment.\nRESULTS: By tracking adoptively transferred cells, we show that purified \ngraft-reactive CD4CD25 T lymphocytes up-regulate Foxp3 in mice receiving skin \nallografts in the absence of any treatment. Interestingly, cotransfer of \nantigen-specific nTregs suppresses the up-regulation of Foxp3 by inhibiting the \nproliferation of allograft-responsive T cells. In vitro data are consistent with \nour in vivo data-Foxp3 cells are generated on antigen activation, and this \ngeneration is suppressed on coculture with antigen-specific nTregs. Finally, \nblocking aTreg generation in grafted, rapamycin-treated mice disrupts \nalloantigen-specific tolerance induction. In contrast, blocking aTreg generation \nin grafted mice treated with nondepleting anti-CD4 plus anti-CD40L antibodies \ndoes not disrupt graft tolerance.\nCONCLUSIONS: We conclude that graft alloantigen stimulates the de novo \ngeneration of aTregs, and this generation may represent a necessary step in some \nbut not all protocols of tolerance induction.", "Accumulating evidence has demonstrated that naturally occurring CD4(+)CD25(+) \nregulatory T cells (Tregs) are critical for maintenance of immunological \ntolerance and have been shown to be important in regulating the immune responses \nin many diseases. Curcumin, a phytochemical obtained from the rhizome of the \nplant Curcuma longa, has achieved the potential therapeutic interest to numerous \nimmune-related disorders. However, the effect and mechanism of curcumin on Tregs \nremain largely elusive. In the present study, curcumin inhibition of the \nsuppressive activity of CD4(+)CD25(+) regulatory T cells appears to be dependent \non three categories: inhibiting cell-cell contact by down-regulation of CTLA-4, \nsuppressing inhibitory cytokine secretion and decreasing the ability to consume \nIL-2 and/or suppress IL-2 production. In addition, Foxp3 expression was also \nreduced on Tregs after curcumin stimulation. Moreover, we found that nuclear \ntranslocation of p65 and c-Rel, which is critical for Foxp3 and CD25 \nexpressions, was markedly decreased in Tregs with curcumin stimulation. Based on \nthe role of curcumin in the suppressive activity of Tregs, it may be feasible to \nuse curcumin as an immunotherapy for Treg-related diseases, such as tumors and \nsepsis.", "CD4(+)CD25(+) regulatory T cells (Treg) play a central role in the prevention of \nautoimmunity and in the control of immune responses by down-regulating the \nfunction of effector CD4(+) or CD8(+) T cells. The role of Treg in Mycobacterium \ntuberculosis infection and persistence is inadequately documented. Therefore, \nthe current study was designed to determine whether CD4(+)CD25(+)FoxP3(+) \nregulatory T cells may modulate immunity against human tuberculosis (TB). Our \nresults indicate that the number of CD4(+)CD25(+)FoxP3(+) Treg increases in the \nblood or at the site of infection in active TB patients. The frequency of \nCD4(+)CD25(+)FoxP3(+) Treg in pleural fluid inversely correlates with local \nMTB-specific immunity (p<0.002). These CD4(+)CD25(+)FoxP3(+) T lymphocytes \nisolated from the blood and pleural fluid are capable of suppressing \nMTB-specific IFN-gamma and IL-10 production in TB patients. Therefore, \nCD4(+)CD25(+)FoxP3(+) Treg expanded in TB patients suppress M. tuberculosis \nimmunity and may therefore contribute to the pathogenesis of human TB.", "CD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key role as \nsuppressors of immune mediated reactions. The analysis of Treg function in \npatients with autoimmune, allergic or oncogenic diseases has emerged over the \npast years. In the present study we describe a CFSE based protocol to measure \nTreg mediated suppression of CD4(+) T cells. Measuring Treg suppressive capacity \ntowards proliferation of anti-CD3 Ab stimulated CD4(+)CD25(-) T cells in \ncoculture experiments by means of a CFSE based and a classical [(3)H]thymidine \nincorporation assay gave similar results, provided that CD4(+)CD25(+) T cells \nwere anergic. However, when CD4(+)CD25(+) T cells proliferated upon mitogenic \nstimulation, data obtained by the CFSE assay allowed the detection of a \nsignificant Treg suppression whereas this was clearly underestimated using the \n[(3)H]thymidine assay. In addition, an indirect CFSE based method was developed \nto analyze antigen specific responses of total CD4(+) T cells and Treg depleted \nCD4(+) T cells (i.e. CD4(+)CD25(-) T cells). Our results indicate that, in \nhealthy individuals, CD4(+) T cell responses against the multiple sclerosis (MS) \nauto-antigens, myelin basic protein (MBP) and myelin oligodendrocyte \nglycoprotein (MOG), were increased in Treg depleted CD4(+) T cells as compared \nto total CD4(+) T cells. Our initial data suggest that Tregs in MS patients show \nan impaired suppression of myelin reactive T cells when compared to healthy \ncontrols. Moreover, this experimental setup permits the measurement of cytokine \nproduction of the antigen proliferated CFSE(low) T cells by additional flow \ncytometric analyses. In conclusion, the described CFSE based Treg suppression \nassay is a valuable tool to study suppressor T cells in (auto)immune disorders.", "Stroke is a common, debilitating trauma that has an incompletely elucidated \npathophysiology and lacks an effective therapy. FoxP3(+)CD25(+)CD4(+) regulatory \nT cells (Tregs) suppress a variety of normal physiological and pathological \nimmune responses via several pathways, such as inhibitory cytokine secretion, \ndirect cytolysis induction, and antigen-presenting cell functional modulation. \nFoxP3(+)CD25(+)CD4(+) Tregs are involved in a variety of central nervous system \ndiseases and injuries, including axonal injury, neurodegenerative diseases, and \nstroke. Specifically, FoxP3(+)CD25(+)CD4(+) Tregs exert neuroprotective effects \nin acute experimental stroke models. These beneficial effects, however, are \ndifficult to elucidate. In this review, we summarized evidence of \nFoxP3(+)CD25(+)CD4(+) Tregs as potentially important immunomodulators in stroke \npathogenesis and highlight further investigations for possible immunotherapeutic \nstrategies by modulating the quantity and/or functional effects of \nFoxP3(+)CD25(+)CD4(+) Tregs in stroke patients.", "CD4+CD25+ regulatory T cells (Tregs) are essential negative regulators of immune \nresponses. Here, we examined the signaling properties of human Tregs, using \nCD4+CD25+ Treg and CD4+CD25- control (Tcont) cell lines generated from cord \nblood. Treg cell lines were markedly hyporesponsive to stimulation with \ndendritic cells and with anti-CD3/CD28-coated beads. Hyporesponsiveness was \nreversed by exogenous interleukin-2 (IL-2). T-cell receptor \n(TCR)-CD3/CD28-mediated activation of Rap1 and Akt was retained in Tregs, but \nactivation of Ras, mitogenactivated protein kinase 1/2 (MEK1/2), and \nextracellular signal-regulated kinase 1/2 (Erk1/2) was impaired. Tregs were \nblocked from cell cycle progression due to decrease of cyclin E and cyclin A and \nincrease of p27kip1 (p27kip cyclin dependent kinase inhibitor). IL-2 induced \nsustained increase of cyclin E and cyclin A and prevented up-regulation of \np27kip1. Tregs had high susceptibility to apoptosis that was reversed by IL-2, \nwhich correlated with activation of Erk1/2, up-regulation of Bcl-x(L) (B-cell \nCLL/lymphoma 2-like nuclear gene encoding mitochondrial protein, transcript \nvariant 2), and phosphorylation of Bad (Bcl2 antagonist of cell death) at \nSer112. Thus, Tregs share biochemical characteristics of anergy, including \nabortive activation of Ras-MEK-Erk, increased activation of Rap1, and increased \nexpression of p27kip1. In addition, our results indicate that \nTCR-CD3/CD28-mediated and IL-2 receptor-mediated signals converge at the level \nof MEK-Erk kinases to regulate Treg survival and expansion and suggest that \nmanipulation of the MEK-Erk axis may represent a novel strategy for Treg \nexpansion for immunotherapy.", "Ischemia reperfusion injury (IRI) is critical in the pathogenesis of acute renal \nfailure and graft rejection. Regulatory T cells (Tregs) suppress excessive \nimmune responses in IRI. We investigated the role of CD4(+)CD25(high)CD127(low) \nTregs in the early phase of renal IRI pathogenesis in a mouse model. \nCD4(+)CD25(high)CD127(low) Tregs in the kidney, tubular necrosis scores, and \nrenal function were measured 24 or 72 h after reperfusion. PC61, an anti-CD25 \nmonoclonal antibody, was used to deplete Tregs before renal ischemia to confirm \nthe effect of these Tregs. CD4(+)CD25(high)CD127(low) Tregs were expanded 24 and \n72 h after reperfusion. Depletion of CD4(+)CD25(high)CD127(low) Tregs was \nassociated with worsening of renal function and histology, particularly at 72 h \nafter reperfusion. These results indicated that expansion of \nCD4(+)CD25(high)CD127(low) Tregs in the early phase of renal IRI may participate \nin tissue repair. These data reveal new insights into the pathogenesis of \nischemic acute renal failure and a novel therapeutic approach.", "The immune system has evolved numerous mechanisms of peripheral T cell \nimmunoregulation, including a network of regulatory T (Treg) cells, to modulate \nand down-regulate immune responses at various times and locations and in various \ninflammatory circumstances. Amongst these, naturally occurring CD4(+)CD25(+) \nTreg cells (nTreg) represent a major lymphocyte population engaged in the \ndominant control of self-reactive T responses and maintaining tolerance in \nseveral models of autoimmunity. CD4(+)CD25(+) Treg cells differentiate in the \nnormal thymus as a functionally distinct subpopulation of T cells bearing a \nbroad T cell receptor repertoire, endowing these cells with the capacity to \nrecognize a wide range of self and nonself antigen specificities. The generation \nof CD4(+)CD25(+) Treg cells in the immune system is genetically controlled, \ninfluenced by antigen recognition, and various signals, in particular, cytokines \nsuch as interleukin-2 and transforming growth factor-beta1, control their \nactivation, expansion, and suppressive effector activity. Functional abrogation \nof these cells in vivo or genetic defects that affect their development or \nfunction unequivocally promote the development of autoimmune and other \ninflammatory diseases in animals and humans. Recent progress has shed light on \nour understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg \ncell-mediated immune regulation. This article discusses the relative \ncontribution of CD4(+)CD25(+) nTreg cells in the induction of immunologic \nself-tolerance and provides a comprehensive overview of recent finding regarding \nthe functional properties and effector mechanism of these cells, as revealed \nfrom various in vitro and in vivo models.", "Balanced mucosal immunity in the gut is critical for host homeostasis and \ndefense. Th17 cells are a subset of IL-17-producing CD4+ T cells, which play a \ncrucial role in clearing pathogens during host defense reactions and in inducing \ntissue inflammation in autoimmune diseases. CD4+CD25+ Foxp3+ regulatory T cells \n(Tregs) are recognized as one of the major regulatory factors in immune \ntolerance and inflammatory responses. Since both Tregs and Th17 cells pertain to \nthe gut immune system, their inter-regulation and balance represent a novel \nmechanism for maintaining the intestinal immune and inflammatory homeostasis. \nAccordingly, the imbalance and dysregulation of Tregs and Th17 cells in the \nintestine is closely associated with intestinal autoimmune disorders like the \ninflammatory bowel diseases. In this review, we discuss the characteristics of \ngut Tregs and Th17 cells and their role in gut diseases.", "α7 Nicotinic acetylcholine receptor (α7 nAChR) has been found in several \nnon-neuronal cells and is described as an important regulator of cellular \nfunction. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are \nessential for the active suppression of autoimmunity. The present study \ninvestigated whether naturally occurring Tregs expressed α7 nAChR and \ninvestigated the functionary role of this receptor in controlling suppressive \nactivity of these cells. We found that CD4(+)CD25(+) Tregs from naive C57BL/6J \nmice positively expressed α7 nAChR, and its activation by nicotine enhanced the \nsuppressive capacity of Tregs. Nicotine stimulation up-regulated the expression \nof cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix \ntranscription factor p3 (Foxp3) on Tregs but had no effect on the production of \ninterleukin (IL)-10 and transforming growth factor-β1 by Tregs. In the \nsupernatants of CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell cocultures, we observed \na decrease in the concentration of IL-2 in nicotine-stimulated groups, but \nnicotine stimulation had no effect on the ratio of IL-4/interferon (IFN)-γ, \nwhich partially represented T-cell polarization. The above-mentioned effects of \nnicotine were reversed by a selective α7 nAChR antagonist, α-bungarotoxin. In \naddition, the ratio of IL-4/IFN-γ was increased by treatment with \nα-bungarotoxin. We conclude that nicotine might increase Treg-mediated immune \nsuppression of lymphocytes via α7 nAChR. The effect is related to the \nup-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion \nin CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell coculture supernatants. α7 nAChR \nseems to be a critical regulator for immunosuppressive function of CD4(+)CD25(+) \nTregs.", "CD4(+)CD25(+) regulatory T cells (Tregs) are potent modulators of immune \nresponses. The transcriptional program distinguishing Tregs from the \nCD4(+)CD25(-) Th cells is unclear. NFAT, a key transcription factor, is reported \nto interact with forkhead box p3, allowing inhibitory and activating signals in \nT cells. In the current study, we hypothesize that distinctive NFAT regulation \nin Tregs as compared with Th cells, may contribute to specific functions of \nthese cells. Tregs express basal levels of cytoplasmic NFATc1 and NFATc2. In \ncontrast to Th cells, anti-CD3-mediated T cell activation did not induce nuclear \ntranslocation of NFATc1 or NFATc2 in Tregs. This effect was associated with \naltered regulation for NFAT in Tregs that included reduced calcium flux, \ndiminished calcineurin activation, and increased activity of glycogen synthase \nkinase-3beta, a negative regulatory kinase for NFAT in Tregs relative to Th \ncells. These data suggested that NFAT inhibition in Th cells may induce \nregulatory function. Indeed, pharmacologically mediated NFAT inhibition induced \nTh cells to function as Tregs, an effect that was mediated by induction of \nmembrane-bound TGF-beta on Th cells. Collectively, these data suggest that \nmaintaining NFAT at basal levels is a part of the transcriptional program \nrequired for Tregs.", "CD25(High) CD4+ regulatory T cells (Treg cells) have been described as key \nplayers in immune regulation, preventing infection-induced immune pathology and \nlimiting collateral tissue damage caused by vigorous anti-parasite immune \nresponse. In this review, we summarize data obtained by the investigation of \nTreg cells in different clinical forms of Chagas' disease. Ex vivo \nimmunophenotyping of whole blood, as well as after stimulation with Trypanosoma \ncruzi antigens, demonstrated that individuals in the indeterminate (IND) \nclinical form of the disease have a higher frequency of Treg cells, suggesting \nthat an expansion of those cells could be beneficial, possibly by limiting \nstrong cytotoxic activity and tissue damage. Additional analysis demonstrated an \nactivated status of Treg cells based on low expression of CD62L and high \nexpression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. \ncruzi antigenic stimulation. Moreover, there was an increase in the frequency of \nthe population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND \ngroup, whereas in the cardiac (CARD) group, there was an increase in the \npercentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4. These data \nsuggest that IL-10 produced by Treg cells is effective in controlling disease \ndevelopment in IND patients. However, in CARD patients, the same regulatory \nmechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient \nto control the progression of the disease. These data suggest that Treg cells \nmay play an important role in controlling the immune response in Chagas' disease \nand the balance between regulatory and effector T cells may be important for the \nprogression and development of the disease. Additional detailed analysis of the \nmechanisms on how these cells are activated and exert their function will \ncertainly give insights for the rational design of procedure to achieve the \nappropriate balance between protection and pathology during parasite infections.", "Publisher: AMAÇ: Multipl miyelom (MM) plazmositlerin ve bunların öncü \nhücrelerinin habis proliferasyonu ile kendini gösteren bir hastalıktır. T \ndüzenleyici (regülatör) hücreler (Treg) immünsüpresyonda ve otoimmün sistemin \ndenetiminde rol oynarlar. Ayrıca tümör hücrelerine karşı oluşan immün yanıttaki \nrolleri de güncel bir araştırma konusudur. Treg hücreleri MM’da otolog çevre \nkanı kök hücre nakli (APBSCT) ile ilişkili olarak daha önce araştırılmamıştır. \nBu çalışmanın amacı, CD4+ CD25+ FoxP3+ Treg hücreleri ile, CD200 ve PD–1 ‘in \nAPBSCT yapılmış ve yapılmamış MM hastalarındaki düzeylerini karşılaştırmaktır. \nYÖNTEMLER: Yaşları 41 ile 78 arasında 28 MM hastasından CD4+ CD25+ FoxP3+ Treg \nhücreleri ile, CD200 ve PD–1 (CD279) analizi için çevre kanı örnekleri alındı. \nMononükleer hücreler dansite gradient santrifüj yöntemi ile ayrıldı. Dört renkli \nakış sitometri ile uygulandı. Ardışık kapılamalar (gating) ile Treg hücreleri \nCD4+ CD25+ FoxP3+ T hücreleri olarak tanımlandı. Sonuçlar Mann Whitney U \nnonparametrik testi ve Compare Means testleri ile analiz edildi. P değerleri \n<0.05 olanlar istatistiksel açıdan anlamlı kabul edildi.\nBULGULAR: Bu çalışma 28 MM hastası (10 kadın, 18 erkek) içermektedir. Otolog \nçevresel kan kök hücre nakli 11 hastaya uygulanmıştır. CD4+ Treg hücreler CD4+ \nCD25+ FoxP3+ olarak saptanmış olup APBSCT alan hastalarda daha yüksek \nbulunmuştur (p=0.042). CD200 ve PD-1 iki grup arasında istatistiksel anlamlı bir \nsonuç göstermemiştir (sırasıyla; p=0.711 ve p=0.404). APBSCT yapılan ve \nyapılmayan gruplar arasında CD200, PD-1 ve CD4+CD25+FOXP3+ düzeyleri \nkarşılaştırıldığında istatistiksel anlamlı bir sonuç bulunmamıştır (p>0.05). \nSONUÇ: Bu çalışmada Treg hücreleri APBSCT yapılmış hastalarda daha yüksek \ndüzeyde bulunmuştur. Treg hücrelerinin bireyin kendi hücrelerine karşı periferik \ntoleransın indüklenmesinde ve korunmasında çok önemli rolü olduğu bilinmektedir. \nBuna ek olarak, Treg hücreleri tümör antijenlerine karşı oluşturulacak immün \nyanıtı baskılayabilmektedir. Ne var ki, çalışmamızda APBSCT veya Treg hücre \ndüzeyleri CD200 ve PD-1 ekspresyonları ile korelasyon göstermemiştir. Prognoz \nile ilişkileri daha fazla sayıda olgu grupları içeren çalışmalarla \naydınlatılabilir.", "A sustained neuroinflammatory response is the hallmark of many neurodegenerative \ndiseases, including Parkinson's disease, Alzheimer's disease, amyotrophic \nlateral sclerosis, multiple sclerosis, and HIV-associated neurodegeneration. A \nspecific subset of T cells, currently recognized as FOXP3(+) CD25(+) CD4(+) \nregulatory T cells (Tregs), are pivotal in suppressing autoimmunity and \nmaintaining immune homeostasis by mediating self-tolerance at the periphery as \nshown in autoimmune diseases and cancers. A growing body of evidence shows that \nTregs are not only important for maintaining immune balance at the periphery but \nalso contribute to self-tolerance and immune privilege in the central nervous \nsystem. In this article, we first review the current status of knowledge \nconcerning the development and the suppressive function of Tregs. We then \ndiscuss the evidence supporting a dysfunction of Tregs in several \nneurodegenerative diseases. Interestingly, a dysfunction of Tregs is mainly \nobserved in the early stages of several neurodegenerative diseases, but not in \ntheir chronic stages, pointing to a causative role of inflammation in the \npathogenesis of neurodegenerative diseases. Furthermore, we provide an overview \nof a number of molecules, such as hormones, neuropeptides, neurotransmitters, or \nion channels, that affect the dysfunction of Tregs in neurodegenerative \ndiseases. We also emphasize the effects of the intestinal microbiome on the \ninduction and function of Tregs and the need to study the crosstalk between the \nenteric nervous system and Tregs in neurodegenerative diseases. Finally, we \npoint out the need for a systems biology approach in the analysis of the \nenormous complexity regulating the function of Tregs and their potential role in \nneurodegenerative diseases.", "Not all T cells are effector cells of the anti-tumor immune system. One of the \nsubpopulations of CD4+ T cells that express CD25+ and the transcription factor \nFOXP3, known as Regulator T cells (TReg), plays an essential role in maintaining \ntolerance and immune homeostasis preventing autoimmune diseases, minimalize \nchronic inflammatory diseases by enlisting various immunoregulatory mechanisms. \nThe balance between effector T cells (Teff) and regulator T cells is crucial in \ndetermining the outcome of an immune response. Regarding tumors, activation or \nexpansion of TReg cells reduces anti-tumor immunity. TReg cells inhibit the \nactivation of CD4+ and CD8+ T cells and suppress anti-tumor activity in the \ntumor microenvironment. In addition, TReg cells also promote tumor angiogenesis \nboth directly and indirectly to ensure oxygen and nutrient transport to the \ntumor. There is accumulating evidence showing a positive result that removing or \nsuppressing TReg cells increases anti-tumor immune response. However, depletion \nof TReg cells will cause autoimmunity. One strategy to improve or restore tumor \nimmunity is targeted therapy on the dominant effector TReg cells in tumor \ntissue. Various molecules such as CTLA-4, CD4, CD25, GITR, PD-1, OX40, ICOS are \nin clinical trials to assess their role in attenuating TReg cells' function.", "OBJECTIVE: Expansion of regulatory T (Treg) cells has been described in \nchronically HIV-infected individuals. We investigated whether HIV-suppressive \nTreg could be detected during primary HIV infection (PHI).\nMETHODS: Seventeen patients diagnosed early after PHI (median: 13 days; 1-55) \nwere studied. Median CD4 cell count was 480 cells/microl (33-1306) and plasma \nHIV RNA levels ranged between 3.3 and 5.7 log10 copies/ml. Suppressive capacity \nof blood purified CD4CD25 was evaluated in a coculture assay. Fox-p3, IL-2 and \nIL-10 were quantified by reverse transcriptase (RT)-PCR and intracellular \nstaining of ex vivo and activated CD4+CD25 T cells.\nRESULTS: The frequency of CD4CD127CD25 T cells among CD4 T cells was lower in \npatients with PHI compared with chronic patients (n = 19). They exhibited a \nphenotype of memory T cells and expressed constitutively FoxP3. Similar to \nchronic patients, Treg from patients with PHI inhibited the proliferation of \npurified tuberculin (PPD) and HIV p24 activated CD4CD25 T cells. CD4CD25 T cells \nfrom patients with PHI responded specifically to p24 stimulation by expressing \nIL-10. In untreated patients with PHI, the frequency as well as HIV-specific \nactivity of Treg decreased during a 24-month follow-up. A positive correlation \nbetween percentages of Treg and both CD4 cell counts and the magnitude of \np24-specific suppressive activity at diagnosis of PHI was found.\nCONCLUSION: Our data showed that HIV drives Treg, as PHI and these cells persist \nthroughout the course of the infection. A correlation between the frequency of \nTreg and CD4 T-cell counts suggest that these cells may impact on the immune \nactivation set point at PHI diagnosis.", "OBJECTIVES: CD4CD25 regulatory T cells (Tregs) play a key role in the prevention \nof various inflammatory and autoimmune disorders by suppressing immune \nresponses. The beneficial effect of statins on myocardial ischemia-reperfusion \ninjury (IRI) depends in part on their immunomodulatory and anti-inflammatory \nmechanisms. We aimed to determine whether Tregs contribute to statin-induced \ncardioprotection against myocardial IRI.\nMETHODS: Thirty-two rats were divided into four groups: sham, \nischemia-reperfusion (IR), rosuvastatin (RSV)/IR, and mevalonic acid \n(MVA)+RSV/IR. Myocardial IR was induced by a 30-min coronary occlusion, followed \nby a 48-h reperfusion. RSV (5 mg/kg) was administered intravenously 18 h before \nIR. The rats were killed after 48-h reperfusion. Serum cardiac troponin I (cTnI) \nwas measured by ELISA, infiltration of inflammatory cells in myocardium by \nhematoxylin and eosin staining, expression of FoxP3 protein by western blotting, \naccumulation of Tregs in myocardium by immunohistochemical examination, and \ninfarct size by TTC staining.\nRESULTS: Significant elevation in serum cTnI, enlarged infarct size, and marked \ninfiltration of inflammatory cells in myocardium were observed in the IR group. \nThe administration of RSV significantly reduced the serum cTnI level, attenuated \nthe accumulation of inflammatory cells, decreased infarct size, and increased \nthe FoxP3 expression and Treg accumulation in myocardium compared with the IR \ngroup. The combination of RSV and MVA pretreatment partially abolished the \nanti-inflammatory and infarct size-limiting effects and completely reversed Treg \naccumulation in myocardium induced by RSV. The accumulation of inflammatory \ncells was negatively correlated with FoxP3 expression and Treg accumulation in \nthe ischemic myocardium.\nCONCLUSION: RSV pretreatment was associated with more Treg accumulation, less \ninflammatory response, and myocardial injury, suggesting that such \ncardioprotection against IRI was partially mediated by Treg-negative modulation \nof inflammation response, probably through the HMG-CoA reductase pathway.", "Naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells (CD25(+) Tregs) \nconstitute a specialized population of T cells that is essential for the \nmaintenance of peripheral self-tolerance. The immune regulatory function of \nCD25(+) Tregs depends upon their activation. We found that anti-CD4 antibodies \nactivate the suppressive function of human CD25(+) Tregs in a dose-dependent \nmanner. We demonstrate that CD4-activated CD25(+) Tregs suppress the \nproliferation of CD4(+) and CD8(+) T cells, their IL-2 and IFN-gamma production \nas well as the capacity of CD8(+) T cells to re-express CD25. By contrast, \nanti-CD4 stimulation did not induce suppressive activity in conventional CD4(+) \nT cells. These results identify CD4 as a trigger for the suppressive function of \nCD25(+) Tregs and suggest a possible CD4-mediated exploitation of these cells.", "Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are \nin widespread use due to their LDL reducing properties and concomitant \nimprovement of clinical outcome in patients with and without preexisting \natherosclerosis. Considerable evidence suggests that immune mediated mechanisms \nplay a dominant role in the beneficial effects of statins. Naturally occurring \nCD4(+)CD25(+) regulatory T cells (Tregs) have a key role in the prevention of \nvarious inflammatory and autoimmune disorders by suppressing immune responses. \nWe tested the hypothesis that statins influence the circulating number and the \nfunctional properties of Tregs. We studied the effects of in vivo and in vitro \nstatin treatment of human and murine mononuclear cells on the number of Tregs \nand the expression level of their master transcription regulator, Foxp3. \nAtorvastatin, but not mevastatin nor pravastatin, treatment of human peripheral \nblood mononuclear cells (PBMCs) increased the number of CD4(+)CD25(high) cells, \nand CD4(+)CD25(+)Foxp3(+) cells. These Tregs, induced by atorvastatin, expressed \nhigh levels of Foxp3, which correlated with an increased regulatory potential. \nFurthermore, co-culture studies revealed that atorvastatin induced \nCD4(+)CD25(+)Foxp3(+) Tregs were derived from peripheral CD4(+)CD25(-)Foxp3(-) \ncells. Simvastatin and pravastatin treatment in hyperlipidemic subjects \nincreased the number of Tregs. In C57BL/6 mice however, no effect of statins on \nTregs was evident. In conclusion, statins appear to significantly influence the \nperipheral pool of Tregs in humans. This finding may shed light on the \nmechanisms governing the plaque stabilizing properties of statins.", "BACKGROUND: Alteration of regulatory T cells (Tregs) may contribute to \nineffective suppression of proinflammatory cytokines in type 1 diabetes.\nAIM: We determined the percentage of Tregs expressing CD62L or tumor necrosis \nfactor receptor type 2 (TNFR2) in 70 young type 1 diabetic patients compared \nwith 30 controls and assessed their relation to inflammation, glycemic control \nand micro-vascular complications.\nMETHODS: High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), \ntumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) were assessed \nwith flow cytometric analysis of Tregs, Tregs expressing CD62L or TNFR2.\nRESULTS: The percentage of CD4(+)CD25(high) T cells and \nCD4(+)CD25(high)CD62L(high) cells were significantly decreased while \nCD4(+)CD25(high)TNFR2(+) T cells were elevated in patients with micro-vascular \ncomplications than those without and controls (p<0.001). ROC curve revealed that \nthe cutoff values of Tregs, Tregs expressing CD62L and Tregs expressing TNFR2 \n(7.46%, 24.2% and 91.9%, respectively) could detect micro-vascular \ncomplications. Significant negative correlations were observed between Tregs \nexpressing CD62L and disease duration, FBG, HbA1c, urinary albumin excretion and \nhs-CRP, whereas, positive correlations were found between Tregs expressing TNFR2 \nand these variables (p<0.05). TNF-α was significantly increased while IL-10 was \ndecreased among patients with micro-vascular complications than those without \n(p<0.05).\nCONCLUSIONS: Alteration in the frequency of Tregs and Tregs expressing CD62L or \nTNFR2 in type 1 diabetes is associated with increased inflammation, poor \nglycemic control and risk of micro-vascular complications.", "Regulatory CD4(+) CD25(+) T (Treg) cells with the ability to suppress host \nimmune responses against self- or non-self antigens play important roles in the \nprocesses of autoimmunity, transplant rejection, infectious diseases and \ncancers. The proper regulation of CD4(+) CD25(+) Treg cells is thus critical for \noptimal immune responses. Toll-like receptor (TLR)-mediated recognition of \nspecific structures of invading pathogens initiates innate as well as adaptive \nimmune responses via antigen-presenting cells (APCs). Interestingly, new \nevidence suggests that TLR signalling may directly or indirectly regulate the \nimmunosuppressive function of CD4(+) CD25(+) Treg cells in immune responses. TLR \nsignalling may shift the balance between CD4(+) T-helper cells and Treg cells, \nand subsequently influence the outcome of the immune response. This \nimmunomodulation pathway may therefore have potential applications in the \ntreatment of graft rejection, autoimmune diseases, infection diseases and \ncancers.", "CD4(+)CD25(+) regulatory T cells (Tregs) are critical for the peripheral immune \ntolerance. Understanding the signals for the generation of Tregs is important \nfor the clinical immunotherapy, but only limited progress has been made on \nobtaining enough peripheral Tregs. The aim of this study was to evaluate the \nrole of trichosanthin (Tk) extracted from Chinese medicinal herb Trichosanthes \nkirilowi on the function of Tregs in vitro and in vivo. We reported here that Tk \nis needed for the expansion of freshly isolated CD4(+)CD25(+)Tregs (nTregs) into \nTk-expanded CD4(+)CD25(+)Tregs (Tk-Tregs) through up-regulating CD25 and Foxp3 \nexpression. The dose-response analyses indicated that 100 ng/ml Tk was the most \nappropriate dose. The result of real-time PCR showed that Tk-Tregs expressed \n1.5-fold higher levels of Foxp3 than those observed in nTregs. Tk-Tregs markedly \nsuppressed activation of effector T cells at a suppressor/responder ratio of \n1:1, 1:2, 1:4, 1:8 or 1:16, and their effect was dose dependent. Moreover, \nTk-Tregs secreted more immunosuppressive cytokines interleukin (IL)-10 and \ntransforming growth factor (TGF)-beta1 after stimulating with antigen and \nantigen-presenting cells (APC). Transwell experiments showed that not only \ncell-to-cell contact but also soluble cytokines were involved in suppressive \nmechanism of Tk-Tregs. And Tk-Tregs were more efficient in suppressing CD25(-)T \ncell response to specific antigen than to irrelative antigen. Most importantly, \nit was revealed for the first time that Tk-Tregs could prolong the survival \nduration of mice with acute graft-versus-host disease (aGVHD). In conclusion, \nthe study suggests a possible therapeutic potential of Tk-Tregs for clinical \ntreatment on aGVHD.", "BACKGROUND: Regulatory T cells (Tregs) are essential in the control of \ntolerance. Evidence implicates Tregs in human autoimmune conditions. Here we \ninvestigated their role in systemic sclerosis (SSc).\nMETHODS/PRINCIPAL FINDINGS: Patients were subdivided as having limited cutaneous \nSSc (lcSSc, n = 20) or diffuse cutaneous SSc (dcSSc, n = 48). Further \nsubdivision was made between early dcSSc (n = 24) and late dcSSc (n = 24) based \nupon the duration of disease. 26 controls were studied for comparison. CD3+ \ncells were isolated using FACS and subsequently studied for the expression of \nCD4, CD8, CD25, FoxP3, CD127, CD62L, GITR, CD69 using flow cytometry. T cell \nsuppression assays were performed using sorted CD4CD25(high)CD127(-) and \nCD4CD25(low)CD127(high) and CD3(+) cells. Suppressive function was correlated \nwith CD69 surface expression and TGFbeta secretion/expression. The frequency of \nCD4(+)CD25(+) and CD25(high)FoxP3(high)CD127(neg) T cells was highly increased \nin all SSc subgroups. Although the expression of CD25 and GITR was comparable \nbetween groups, expression of CD62L and CD69 was dramatically lower in SSc \npatients, which correlated with a diminished suppressive function. Co-incubation \nof Tregs from healthy donors with plasma from SSc patients fully abrogated \nsuppressive activity. Activation of Tregs from healthy donors or SSc patients \nwith PHA significantly up regulated CD69 expression that could be inhibited by \nSSc plasma.\nCONCLUSIONS/SIGNIFICANCE: These results indicate that soluble factors in SSc \nplasma inhibit Treg function specifically that is associated with altered Treg \nCD69 and TGFbeta expression. These data suggest that a defective Treg function \nmay underlie the immune dysfunction in systemic sclerosis.", "Immune activation during chronic HIV infection is a strong clinical predictor of \ndeath and may mediate CD4(+) T cell depletion. Regulatory T cells (Tregs) are \nCD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune \nresponses. We asked whether loss of Tregs during HIV infection mediates immune \nactivation in a cross-sectional study of 81 HIV-positive Ugandan volunteers. We \nfound that Treg number is strongly correlated with both CD4(+) and CD8(+) T cell \nactivation. In multivariate modeling, this relationship between Treg depletion \nand CD4(+) T cell activation was stronger than any other clinical factor \nexamined, including viral load and absolute CD4 count. Tregs appear to decline \nat different rates compared with other CD4(+) T cells, resulting in an increased \nregulator to helper ratio in many patients with advanced disease. We hypothesize \nthat this skewing may contribute to T cell effector dysfunction. Our findings \nsuggest Tregs are a major contributor to the immune activation observed during \nchronic HIV infection.", "CD4(+)CD25(+) regulatory T cells (Tregs) are negative regulators of the immune \nsystem that induce and maintain immune tolerance. Exosomes are natural products \nreleased from many sources and play a role in antigen presentation, \nimmunoregulation, and signal transduction. In order to determine whether \nexosomes can be released from Tregs and participate in transplantation \ntolerance, we isolated and purified Tregs-derived exosomes and established a rat \nmodel of kidney transplantation. We then transferred the autologous exosomes \ninto recipients to observe the effect of transplantation tolerance in vivo and \nin vitro. From in vivo study, serum analysis and histology showed that the \nfunction of exosomes can postpone allograft rejection and prolong the survival \ntime of transplanted kidney. From in vitro study, exosomes possessed the \ncapacity to suppress T cells proliferation. Taken together, these results \nsuggest that the Tregs-derived exosomes have a suppressive role on acute \nrejection and inhibit T cells proliferation, especially exosomes derived from \ndonor-type Tregs, which imply that the Tregs-derived exosomes are one of far-end \nregulation mechanisms of Tregs. Thus, exosomes released from Tregs could be \nconsidered as a possible immunosuppressive reagent for the treatment of \ntransplant rejection.", "BACKGROUND: Evidence indicating that CD4+CD25+ regulatory T (Treg) cells play a \ncrucial role in the maintenance of peripheral T cell tolerance to allergens has \nbeen accumulated. To explore the functional role of Treg cells in patients with \nJapanese cedar pollinosis, we performed an in vitro investigation of the \nregulation of immune responses to allergens by Treg cells.\nMETHODS: CD4+ and CD4+CD25- T cells obtained from 12 patients with Japanese \ncedar pollinosis were stimulated with Cry j 1 protein and Cry j 1-derived \npeptide. On day 6, T cells were tested for allergen-specific reactivity using a \nCFSE-based proliferation assay and cytokine ELISA assays. The frequency of Cry j \n1-specific interleukin (IL)-10-producing Treg cells was assessed by ELISPOT \nassays.\nRESULTS: The proportion of proliferated cells induced by allergen stimulation \nwas similar in both CD4+ and CD4+CD25- cell cultures. The production of \ninterferon (IFN)-γ, but not that of IL-5 was significantly enhanced in CD4+CD25- \ncell cultures compared to that in CD4+ cell cultures. Interestingly, the \nproduction of IL-10 was decreased in CD4+CD25- cell cultures. Moreover, Cry j \n1-specific IL-10-producing Treg cells were detected in pollen-allergic patients.\nCONCLUSION: Our findings suggest that in pollen-allergic patients, Treg cells \npredominantly suppresses Th1 responses rather than Th2 responses, where \nallergen-specific IL-10-producing Treg cells may also be responsible for the \ndownregulation of allergen-specific immune responses.", "BACKGROUND: Cellular rejection of xenografts is predominantly mediated by CD4 T \ncells. Little is known of the effectiveness of CD4CD25 T regulatory (Treg) cells \nat suppressing this strong T-cell mediated immune response. In this study, we \nevaluated the activity of fresh Treg cells and expanded Treg cells to suppress \nthe xeno immune response in vitro.\nMETHODS: Human Treg cells were preferentially expanded by CD3/CD28 expand beads, \ninterleukin (IL)-2, and rapamycin. Human CD4CD25 T cells were stimulated with \nirradiated porcine peripheral blood mononuclear cells in the presence or absence \nof fresh or expanded human Treg cells for 5 days before proliferation assay. In \na separate experiment, the porcine xenoantigen-stimulated CD4CD25 T cells were \nseparated from Treg cells by transwells and assessed for cytotoxicity of porcine \nperipheral blood mononuclear cells target cells. Cytokine-producing cells and \ncytokine release in the cocultures were examined by enzyme-linked immunosorbent \nspot and enzyme-linked immonosorbent assay, respectively.\nRESULTS: Human Treg were expanded up to 3,500-fold after 14 days in culture. The \naddition of fresh Treg suppressed the T-cell mediated xenoimmune response. \nCompared with fresh Treg cells, expanded Treg cells were more potent at \nsuppressing CD4CD25 T-cell-mediated antiporcine xenogeneic responses. This \nsuppression required cell contact. However, the enhanced suppression by expanded \nTreg cells was associated with increased secretion of IL-4 and IL-10 when \ncompared with their nonexpanded Treg counterparts.\nCONCLUSION: This study shows that expanded human Treg cells were capable of \nsuppressing antiporcine xenogeneic responses in vitro and involve both contact \ndependent and cytokine mediated mechanisms." ]	nan
58a71bb960087bc10a00002d	[ 18957701, 25340765, 24349264, 22987666, 16998490, 21092253 ]	train	Are Ultra-conserved elements (UCEs) enriched in segmental duplications?	yesno	ULEs are located in intergenic or intronic regions and are depleted from segmental duplications. In addition, here we show that these elements are preferentially found in pathogenic deletions (enrichment ratio 3.6 vs. 0.5 in duplications), and that this association is not related with a higher content of genes.	no	[ "Ultraconserved elements (UCEs) are sequences that are identical between \nreference genomes of distantly related species. As they are under negative \nselection and enriched near or in specific classes of genes, one explanation for \ntheir ultraconservation may be their involvement in important functions. Indeed, \nmany UCEs can drive tissue-specific gene expression. We have demonstrated that \nnonexonic UCEs are depleted among segmental duplications (SDs) and copy number \nvariants (CNVs) and proposed that their ultraconservation may reflect a \nmechanism of copy counting via comparison. Here, we report that nonexonic UCEs \nare also depleted among 10 of 11 recent genomewide data sets of human CNVs, \nincluding 3 obtained with strategies permitting greater precision in determining \nthe extents of CNVs. We further present observations suggesting that nonexonic \nUCEs per se may contribute to this depletion and that their apparent dosage \nsensitivity was in effect when they became fixed in the last common ancestor of \nmammals, birds, and reptiles, consistent with dosage sensitivity contributing to \nultraconservation. Finally, in searching for the mechanism(s) underlying the \nfunction of nonexonic UCEs, we have found that they are enriched in TAATTA, \nwhich is also the recognition sequence for the homeodomain DNA-binding module, \nand bounded by a change in A + T frequency.", "Ultraconserved elements (UCEs) are strongly depleted from segmental duplications \nand copy number variations (CNVs) in the human genome, suggesting that deletion \nor duplication of a UCE can be deleterious to the mammalian cell. Here we \naddress the process by which CNVs become depleted of UCEs. We begin by showing \nthat depletion for UCEs characterizes the most recent large-scale human CNV \ndatasets and then find that even newly formed de novo CNVs, which have passed \nthrough meiosis at most once, are significantly depleted for UCEs. In striking \ncontrast, CNVs arising specifically in cancer cells are, as a rule, not depleted \nfor UCEs and can even become significantly enriched. This observation raises the \npossibility that CNVs that arise somatically and are relatively newly formed are \nless likely to have established a CNV profile that is depleted for UCEs. \nAlternatively, lack of depletion for UCEs from cancer CNVs may reflect the \ndiseased state. In support of this latter explanation, somatic CNVs that are not \nassociated with disease are depleted for UCEs. Finally, we show that it is \npossible to observe the CNVs of induced pluripotent stem (iPS) cells become \ndepleted of UCEs over time, suggesting that depletion may be established through \nselection against UCE-disrupting CNVs without the requirement for meiotic \ndivisions.", "Metazoan genomes contain many ultra-conserved elements (UCEs), long sequences \nidentical between distant species. In this study we identified UCEs in \ndrosophilid and vertebrate species with a similar level of phylogenetic \ndivergence measured at protein-coding regions, and demonstrated that both the \nlength and number of UCEs are larger in vertebrates. The proportion of \nnon-exonic UCEs declines in distant drosophilids whilst an opposite trend was \nobserved in vertebrates. We generated a set of 2,126 Sophophora UCEs by merging \nelements identified in several drosophila species and compared these to the \neutherian UCEs identified in placental mammals. In contrast to vertebrates, the \nSophophora UCEs are depleted around transcription start sites. Analysis of \n52,954 P-element, piggyBac and Minos insertions in the D. melanogaster genome \nrevealed depletion of the P-element and piggyBac insertions in and around the \nSophophora UCEs. We examined eleven fly strains with transposon insertions into \nthe intergenic UCEs and identified associated phenotypes in five strains. Four \ninsertions behave as recessive lethals, and in one case we observed a \nsuppression of the marker gene within the transgene, presumably by silenced \nchromatin around the integration site. To confirm the lethality is caused by \nintegration of transposons we performed a phenotype rescue experiment for two \nstocks and demonstrated that the excision of the transposons from the intergenic \nUCEs restores viability. Sequencing of DNA after the transposon excision in one \nfly strain with the restored viability revealed a 47 bp insertion at the \noriginal transposon integration site suggesting that the nature of the mutation \nis important for the appearance of the phenotype. Our results suggest that the \nUCEs in flies and vertebrates have both common and distinct features, and \ndemonstrate that a significant proportion of intergenic drosophila UCEs are \nsensitive to disruption.", "Ultraconserved elements (UCEs), stretches of DNA that are identical between \ndistantly related species, are enigmatic genomic features whose function is not \nwell understood. First identified and characterized in mammals, UCEs have been \nproposed to play important roles in gene regulation, RNA processing, and \nmaintaining genome integrity. However, because all of these functions can \ntolerate some sequence variation, their ultraconserved and ultraselected nature \nis not explained. We investigated whether there are highly conserved DNA \nelements without genic function in distantly related plant genomes. We compared \nthe genomes of Arabidopsis thaliana and Vitis vinifera; species that diverged \n∼115 million years ago (Mya). We identified 36 highly conserved elements with at \nleast 85% similarity that are longer than 55 bp. Interestingly, these elements \nexhibit properties similar to mammalian UCEs, such that we named them UCE-like \nelements (ULEs). ULEs are located in intergenic or intronic regions and are \ndepleted from segmental duplications. Like UCEs, ULEs are under strong purifying \nselection, suggesting a functional role for these elements. As their mammalian \ncounterparts, ULEs show a sharp drop of A+T content at their borders and are \nenriched close to genes encoding transcription factors and genes involved in \ndevelopment, the latter showing preferential expression in undifferentiated \ntissues. By comparing the genomes of Brachypodium distachyon and Oryza sativa, \nspecies that diverged ∼50 Mya, we identified a different set of ULEs with \nsimilar properties in monocots. The identification of ULEs in plant genomes \noffers new opportunities to study their possible roles in genome function, \nintegrity, and regulation.", "An earlier search in the human, mouse and rat genomes for sequences that are \n100% conserved in orthologous segments and > or = 200 bp in length identified \n481 distinct sequences. These human-mouse-rat sequences, which represent \nultraconserved elements (UCEs), are believed to be important for functions \ninvolving DNA binding, RNA processing and the regulation of transcription and \ndevelopment. In vivo and additional computational studies of UCEs and other \nhighly conserved sequences are consistent with these functional associations, \nwith some observations indicating enhancer-like activity for these elements. \nHere, we show that UCEs are significantly depleted among segmental duplications \nand copy number variants. Notably, of the UCEs that are found in segmental \nduplications or copy number variants, the majority overlap exons, indicating, \nalong with other findings presented, that UCEs overlapping exons represent a \ndistinct subset.", "BACKGROUND: The ultraconserved elements (UCEs) are defined as stretches of at \nleast 200 base pairs of human DNA that match identically with corresponding \nregions in the mouse and rat genomes, albeit their real significance remains an \nintriguing issue. These elements are most often located either overlapping exons \nin genes involved in RNA processing or in introns or nearby genes involved in \nthe regulation of transcription and development. Interestingly, human UCEs have \nbeen reported to be strongly depleted among segmental duplications and benign \ncopy number variants (CNVs). However no comprehensive survey of a putative \nenrichment of these elements among pathogenic dose variants has yet been \nreported.\nRESULTS: A survey for UCEs was performed among the 26 cryptic genomic \nrearrangements detected in our series of 200 patients with idiopathic \nneurodevelopmental disorders associated to congenital anomalies. A total of 29 \nelements, out of the 481 described UCEs, were contained in 13 of the 26 \npathogenic gains or losses detected in our series, what represents a highly \nsignificant enrichment of ultraconserved elements. In addition, here we show \nthat these elements are preferentially found in pathogenic deletions (enrichment \nratio 3.6 vs. 0.5 in duplications), and that this association is not related \nwith a higher content of genes. In contrast, pathogenic CNVs lacking UCEs showed \nalmost a threefold higher content in genes.\nCONCLUSIONS: We propose that these elements may be interpreted as hallmarks for \ndose-sensitive genes, particularly for those genes whose gain or loss may be \ndirectly implied in neurodevelopmental disorders. Therefore, their presence in \ngenomic imbalances of unknown effect might be suggestive of a clinically \nrelevant condition." ]	nan
56e5aeec0c19e5451d000002	[ 24980705, 25073090, 25220136, 25009261, 24574382, 25064589, 25010002, 25066614, 25350397 ]	train	Are adenylyl cyclases always transmembrane proteins?	yesno	Adenylyl cyclases exists both as transmembrane and soluble proteins.	no	[ "Recently published findings indicate that a knockout (KO) of soluble adenylyl \ncyclase (sAC, also known as AC-10) gene expression in mice leads to defective \nglucoregulation that is characterized by reduced pancreatic insulin secretion \nand reduced intraperitoneal glucose tolerance. Summarized here are current \nconcepts regarding the molecular basis for this phenotype, with special emphasis \non the potential role of sAC as a determinant of glucose-stimulated insulin \nsecretion. Highlighted is new evidence that in pancreatic beta cells, oxidative \nglucose metabolism stimulates mitochondrial CO₂production that in turn generates \nbicarbonate ion (HCO(3)(-)). Since HCO(3)(-) binds to and directly stimulates \nthe activity of sAC, we propose that glucose-stimulated cAMP production in beta \ncells is mediated not simply by transmembrane adenylyl cyclases (TMACs), but \nalso by sAC. Based on evidence that sAC is expressed in mitochondria, there \nexists the possibility that beta-cell glucose metabolism is linked to \nmitochondrial cAMP production with consequent facilitation of oxidative \nphosphorylation. Since sAC is also expressed in the cytoplasm, sAC catalyzed \ncAMP production may activate cAMP sensors such as PKA and Epac2 to control ion \nchannel function, intracellular Ca²⁺ handling, and Ca²⁺-dependent exocytosis. \nThus, we propose that the existence of sAC in beta cells provides a new and \nunexpected explanation for previously reported actions of glucose metabolism to \nstimulate cAMP production. It seems possible that alterations of sAC activity \nmight be of importance when evaluating new strategies for the treatment of type \n2 diabetes (T2DM), or when evaluating why glucose metabolism fails to stimulate \ninsulin secretion in patients diagnosed with T2DM. This article is part of a \nSpecial Issue entitled: The role of soluble adenylyl cyclase in health and \ndisease.", "Adenylyl cyclase (AC) is a key enzyme that synthesizes cyclic AMP (cAMP) at the \nonset of the signaling pathway to activate sperm motility. Here, we showed that \nboth transmembrane AC (tmAC) and soluble AC (sAC) are distinctly involved in the \nregulation of sperm motility in the ascidian Ciona intestinalis. A tmAC \ninhibitor blocked both cAMP synthesis and the activation of sperm motility \ninduced by the egg factor sperm activating and attracting factor (SAAF), as well \nas those induced by theophylline, an inhibitor of phoshodiesterase. It also \nsignificantly inhibited cAMP-dependent phosphorylation of a set of proteins at \nmotility activation. On the other hand, a sAC inhibitor does not affect on \nSAAF-induced transient increase of cAMP, motility activation or protein \nphosphorylation, but it reduced swimming velocity to half in \ntheophylline-induced sperm. A sAC inhibitor KH-7 induced circular swimming \ntrajectory with smaller diameter and significantly suppressed chemotaxis of \nsperm to SAAF. These results suggest that tmAC is involved in the basic \nmechanism for motility activation through cAMP-dependent protein \nphosphorylation, whereas sAC plays distinct roles in increase of flagellar beat \nfrequency and in the Ca2+-dependent chemotactic movement of sperm.", "BACKGROUND AND PURPOSE: H2 O2 is widely understood to regulate intracellular \nsignalling. In airway epithelia, H2 O2 stimulates anion secretion primarily by \nactivating an autocrine PGE2 signalling pathway via EP4 and EP1 receptors to \ninitiate cytic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) secretion. \nThis study investigated signalling downstream of the receptors activated by H2 \nO2 .\nEXPERIMENTAL APPROACH: Anion secretion by differentiated bronchial epithelial \ncells was measured in Ussing chambers during stimulation with H2 O2 , an EP4 \nreceptor agonist or β2 -adrenoceptor agonist in the presence and absence of \ninhibitors of ACs and downstream effectors. Intracellular calcium ([Ca(2+) ]I ) \nchanges were followed by microscopy using fura-2-loaded cells and PKA activation \nfollowed by FRET microscopy.\nKEY RESULTS: Transmembrane adenylyl cyclase (tmAC) and soluble AC (sAC) were \nboth necessary for H2 O2 and EP4 receptor-mediated CFTR activation in bronchial \nepithelia. H2 O2 and EP4 receptor agonist stimulated tmAC to increase exchange \nprotein activated by cAMP (Epac) activity that drives PLC activation to raise \n[Ca(2+) ]i via Ca(2+) store release (and not entry). Increased [Ca(2+) ]i led to \nsAC activation and further increases in CFTR activity. Stimulation of sAC did \nnot depend on changes in [HCO3 (-) ]. Ca(2+) -activated apical KCa 1.1 channels \nand cAMP-activated basolateral KV 7.1 channels contributed to H2 O2 -stimulated \nanion currents. A similar Epac-mediated pathway was seen following β2 \n-adrenoceptor or forskolin stimulation.\nCONCLUSIONS AND IMPLICATIONS: H2 O2 initiated a complex signalling cascade that \nused direct stimulation of tmACs by Gαs followed by Epac-mediated Ca(2+) \ncrosstalk to activate sAC. The Epac-mediated Ca(2+) signal constituted a \npositive feedback loop that amplified CFTR anion secretion following stimulation \nof tmAC by a variety of stimuli.", "Neurons in the CNS do not regenerate following injury; regeneration is blocked \nby inhibitory proteins in myelin, such as myelin-associated glycoprotein (MAG). \nElevating neuronal levels of the second messenger cAMP overcomes this blocked \naxonal outgrowth. One way to elevate cAMP is pretreating neurons with \nneurotrophins, such as brain-derived neurotrophic factor (BDNF). However, \npleiotropic effects and poor bioavailability make exogenous administration of \nneurotrophins in vivo problematic; therefore, alternative targets must be \nconsidered. In neurons, two families of adenylyl cyclases synthesize cAMP, \ntransmembrane adenylyl cyclases (tmACs), and soluble adenylyl cyclase (sAC). \nHere, we demonstrate that sAC is the essential source of cAMP for BDNF to \novercome MAG-dependent inhibition of neurite outgrowth. Elevating sAC in rat and \nmouse neurons is sufficient to induce neurite outgrowth on myelin in vitro and \npromotes regeneration in vivo. These results suggest that stimulators of sAC \nmight represent a novel therapeutic strategy to promote axonal growth and \nregeneration.", "Soluble adenylyl cyclase (sAC) is a recently recognized source of the signaling \nmolecule cyclic AMP (cAMP) that is genetically and biochemically distinct from \nthe classic G-protein-regulated transmembrane adenylyl cyclases (tmACs). \nMammalian sAC is distributed throughout the cytoplasm and it may be present in \nthe nucleus and inside mitochondria. sAC activity is directly stimulated by \nHCO3(-), and sAC has been confirmed to be a HCO3(-) sensor in a variety of \nmammalian cell types. In addition, sAC can functionally associate with carbonic \nanhydrases to act as a de facto sensor of pH and CO2. The two catalytic domains \nof sAC are related to HCO3(-)-regulated adenylyl cyclases from cyanobacteria, \nsuggesting the cAMP pathway is an evolutionarily conserved mechanism for sensing \nCO2 levels and/or acid/base conditions. Reports of sAC in aquatic animals are \nstill limited but are rapidly accumulating. In shark gills, sAC senses blood \nalkalosis and triggers compensatory H(+) absorption. In the intestine of bony \nfishes, sAC modulates NaCl and water absorption. And in sea urchin sperm, sAC \nmay participate in the initiation of flagellar movement and in the acrosome \nreaction. Bioinformatics and RT-PCR results reveal that sAC orthologs are \npresent in most animal phyla. This review summarizes the current knowledge on \nthe physiological roles of sAC in aquatic animals and suggests additional \nfunctions in which sAC may be involved.", "Axon regeneration in the mature central nervous system is limited by extrinsic \ninhibitory signals and a postnatal decline in neurons' intrinsic growth \ncapacity. Neuronal levels of the second messenger cAMP are important in \nregulating both intrinsic growth capacity and neurons' responses to extrinsic \nfactors. Approaches which increase intracellular cAMP in neurons enhance neurite \noutgrowth and facilitate regeneration after injury. Thus, understanding the \nfactors which affect cAMP in neurons is of potential therapeutic importance. \nRecently, soluble adenylyl cyclase (sAC, ADCY10), the ubiquitous, \nnon-transmembrane adenylyl cyclase, was found to play a key role in neuronal \nsurvival and axon growth. sAC is activated by bicarbonate and cations and may \ntranslate physiologic signals from metabolism and electrical activity into a \nneuron's decision to survive or regenerate. Here we critically review the \nliterature surrounding sAC and cAMP signaling in neurons to further elucidate \nthe potential role of sAC signaling in neurite outgrowth and regeneration. This \narticle is part of a Special Issue entitled: The role of soluble adenylyl \ncyclase in health and disease.", "cAMP signaling is an evolutionarily conserved intracellular communication system \ncontrolling numerous cellular functions. Until recently, transmembrane adenylyl \ncyclase (tmAC) was considered the major source for cAMP in the cell, and the \nrole of cAMP signaling was therefore attributed exclusively to the activity of \nthis family of enzymes. However, increasing evidence demonstrates the role of an \nalternative, intracellular source of cAMP produced by type 10 soluble adenylyl \ncyclase (sAC). In contrast to tmAC, sAC produces cAMP in various intracellular \nmicrodomains close to specific cAMP targets, e.g., in nucleus and mitochondria. \nOngoing research demonstrates involvement of sAC in diverse physiological and \npathological processes. The present review is focused on the role of cAMP \nsignaling, particularly that of sAC, in cell death and growth. Although the \ncontributions of sAC to the regulation of these cellular functions have only \nrecently been discovered, current data suggest that sAC plays key roles in \nmitochondrial bioenergetics and the mitochondrial apoptosis pathway, as well as \ncell proliferation and development. Furthermore, recent reports suggest the \nimportance of sAC in several pathologies associated with apoptosis as well as in \noncogenesis. This article is part of a Special Issue entitled: The role of \nsoluble adenylyl cyclase in health and disease.", "Cyclic adenosine 3',5'-monophosphate (cAMP), the first second messenger to be \ndescribed, plays a central role in cell signaling in a wide variety of cell \ntypes. Over the last decades, a wide body of literature addressed the different \nroles of cAMP in cell physiology, mainly in response to neurotransmitters and \nhormones. cAMP is synthesized by a wide variety of adenylyl cyclases that can \ngenerally be grouped in two types: transmembrane adenylyl cyclase and soluble \nadenylyl cyclases. In particular, several aspects of sperm physiology are \nregulated by cAMP produced by a single atypical adenylyl cyclase (Adcy10, aka \nsAC, SACY). The signature that identifies sAC among other ACs, is their direct \nstimulation by bicarbonate. The essential nature of cAMP in sperm function has \nbeen demonstrated using gain of function as well as loss of function approaches. \nThis review unifies state of the art knowledge of the role of cAMP and those \nenzymes involved in cAMP signaling pathways required for the acquisition of \nfertilizing capacity of mammalian sperm. This article is part of a Special Issue \nentitled: The role of soluble adenylyl cyclase in health and disease.", "Forward motility stimulating factor (FMSF), a glycoprotein isolated from buffalo \nserum, binds to the surface of the mature sperm cells to promote their \nprogressive motility. This article reports the mode of signal transduction of \nthis extracellular factor in goat sperm. The mechanism was investigated by \nassaying intracellular second messenger level and forward motility in presence \nof different pharmacological modulators. Mg++-dependent Forskolin responsive \nform of transmembrane adenylyl cyclase (tmAC) of goat spermatozoa was probed for \nits involvement in FMSF action. Dideoxyadenosine, a selective inhibitor of \ntmACs, was used to identify the role of this enzyme in the scheme of \nFMSF-signaling. Involvement of the α-subunit of G-protein in this regard has \nbeen inspected using GTPγS. Participation of protein kinase A (PKA) and tyrosine \nkinase was checked using IP20 and genistein, respectively. FMSF promotes tmAC \nactivity in a dose-dependent manner through receptor/G-protein activation to \nenhance intracellular cAMP and forward motility. Motility boosting effects of \nthis glycoprotein are almost lost in presence of dideoxyadenosine. But, FMSF \ndisplayed substantial motility promoting activity when movement of spermatozoa \nwas inhibited with KH7, the specific inhibitor of soluble adenylyl cyclase \nindicating tmAC to be the primary target of FMSF action. Involvement of cAMP in \nmediating FMSF action was confirmed by the application of dibutyryl cAMP. \nObserved motility regulatory effects with IP20 and genistein indicate \ncontribution of PKA and tyrosine kinase in FMSF activity; enhanced \nphosphorylation of a tyrosine containing ≈50 kDa protein was detected in this \nregard. FMSF initiates a novel signaling cascade to stimulate tmAC activity that \naugments intracellular cAMP, which through downstream crosstalk of \nphosphokinases leads to enhanced forward motility in mature spermatozoa. Thus, \nthis article for the first time describes conventional tmAC-dependent profound \nactivation of progressive motility by a physiologic extracellular factor in a \nmammalian species." ]	nan
587e1e57fc7e8dd84f000003	[ 22673945, 22328099, 22318908 ]	train	Are alterations in ultraconserved elements associated with colorectal adenocarcinoma?	yesno	yes	yes	[ "BACKGROUND: Ultraconserved elements (UCEs) are noncoding genomic sequences that \ncompletely identical among human, mouse, and rat species and harbor critical \nbiologic functions. The authors hypothesized that single nucleotide \npolymorphisms (SNPs) within UCEs are associated with clinical outcomes in \npatients with colorectal cancer (CRC).\nMETHODS: Forty-eight SNPs within UCEs were genotyped in 662 patients with stage \nI through III CRC. The associations between genotypes and recurrence and \nsurvival were analyzed in patients with stage II or III CRC who received \nfluoropyrimidine-based adjuvant chemotherapy using a training and validation \ndesign. The training set included 115 patients with stage II disease and 170 \npatients with stage III disease, and the validation set included 88 patients \nwith stage II disease and 112 patients with stage III disease.\nRESULTS: Eight SNPs were associated with clinical outcomes stratified by disease \nstage. In particular, for patients with stage II CRC who had at least 1 variant \nallele of reference SNP sequence 7849 (rs7849), a consistent association with \nincreased recurrence risk was observed in the training set (hazard ratio [HR], \n2.39; 95% confidence interval [CI], 1.04-5.52), in the replication set (HR, \n3.70; 95% CI, 1.42-9.64), and in a meta-analysis (HR, 2.89; 95% CI, 1.54-5.41). \nSeveral other SNPs were significant in the training set but not in the \nvalidation set. These included rs2421099, rs16983007, and rs10211390 for \nrecurrence and rs6590611 for survival in patients with stage II disease; and \nSNPs rs6124509 and rs11195893 for recurrence in patients with stage III disease. \nIn addition, a significant cumulative effect was observed of multiple risk \ngenotypes and potential gene-gene interactions on recurrence risk.\nCONCLUSIONS: To the authors' knowledge, this is the first study to evaluate the \nassociation between SNPs within UCEs and clinical outcome in patients with CRC. \nThe results suggested that SNPs within UCEs may be valuable prognostic \nbiomarkers for patients with locally advanced CRC who receive \n5-fluorouracil-based chemotherapy.", "OBJECTIVES: The development of colorectal cancer (CRC) is characterized by \nmultiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a \nsubset of 481 sequences longer than 200 bp, which are absolutely conserved \nbetween orthologous regions of human, rat and mouse genomes, and are actively \ntranscribed. It has recently been proven in cancer systems that differentially \nexpressed T-UCRs could alter the functional characteristics of malignant cells. \nGenome-wide profiling revealed that T-UCRs have distinct signatures in human \nleukemia and carcinoma.\nMETHODS: In our study, we examined the expression levels of uc.43, uc.73, \nuc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal \ncarcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR. \nT-UCR expression levels were also correlated with commonly used \nclinicopathological features of CRC.\nRESULTS: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were \nsignificantly decreased in CRC tissue, and uc.73 indicated a positive \ncorrelation with overall survival (p = 0.0315). The lower expression of uc.388 \nwas associated with the distal location of CRC (p = 0.0183), but no correlation \nof any evaluated T-UCR with clinical stage, grade and tumor diameter was \nobserved.\nCONCLUSION: Our preliminary results suggest that uc.73 and uc.388 could be \npotential diagnostic and prognostic biomarkers in CRC patients.", "We investigated whether single nucleotide polymorphisms within ultraconserved \nelements (UCEs) are associated with susceptibility to overall colorectal cancer \n(CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC \npatients and 551 healthy controls. The study comprised of a training set (520 \ncases and 341 controls) and a replication set (267 cases and 210 controls). We \nobserved associations in rs7849 and rs1399685 with CRC risk. For example, a \ndose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval \n(CI), 0.63-1.00; P for trend = 0.05) associated with the variant allele of \nrs7849 in the training set. The significant trend toward a decrease in CRC risk \nwas confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52-0.99; P \nfor trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) \nrisk, significant association was observed for the variant-containing genotypes \nof rs1399685 (OR, 1.77; 95% CI, 1.02-3.06) and the risk was replicated in the \nreplication population (OR, 2.04; 95% CI, 1.02-4.07). The variant genotypes of \nrs9784100 and rs7849 conferred decreased risk but the associations were not \nreplicated. Three right-sided CRC (RCRC) susceptibility loci were identified in \nrs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint \neffects and potential higher order gene-gene interactions among significant \nvariants further categorized patients into different risk groups. Our results \nstrongly suggest that several genetic variants in the UCEs may contribute to CRC \nsusceptibility, individually and jointly, and that different genetic etiology \nmay be involved in RCRC and LCRC." ]	['http://www.disease-ontology.org/api/metadata/DOID:0050861', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D050436', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D015179']
587e276be96a600607000001	[ 18174240, 21331621 ]	train	Are alterations in ultraconserved elements implicated in breast cancer?	yesno	Yes. SNPs in ultraconserved elements (UCEs) might be associated with cancer risk.	yes	[ "Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute \nsequence identity between orthologous regions of human, rat and mouse genomes. \nThe selection factors acting on these UCEs are still unknown. Recent studies \nhave shown that UCEs function as long-range enhancers of flanking genes or are \ninvolved in splicing when overlapping with exons. The depletion of UCEs among \ncopy number variation as well as the significant under-representation of \nsingle-nucleotide polymorphisms (SNPs) within UCEs have also revealed their \nevolutional and functional importance indicating their potential impact on \ndisease, such as cancer. In the present study, we investigated the influence of \nsix SNPs within UCEs on familial breast cancer risk. Two out of six SNPs showed \nan association with familial breast cancer risk. Whereas rs9572903 showed only a \nborderline significant association, the frequency of the rare [G] allele of \nrs2056116 was higher in cases than in controls indicating an increased familial \nbreast cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence \ninterval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI \n1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the \nORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = \n1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI \n1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is \nthe first study indicating that SNPs in UCEs might be associated with cancer \nrisk.", "Ultraconserved elements (UCEs) are the most extreme representatives of conserved \nnon-coding sequences. Recent studies have indicated that UCEs are not mutation \ncold regions and likely to be concerned with cancers, including breast cancer \n(BC). In this study, we first screened common single-nucleotide polymorphisms \n(SNPs) (minor allele frequency, MAF > 0.05) in Chinese population located in 481 \nUCEs sequences and selected seven SNPs (rs17049105, rs13020355, rs2682406, \nrs2056116, rs11190870, rs9572903, and rs8004379) of uc.51, uc.82, uc.133, \nuc.140, uc.302, uc.353, and uc.368, respectively. A two-stage case-control study \nof BC with a total of 1,497 cases and 1,497 controls in Chinese population was \nconducted to test the hypothesis that these SNPs of UCEs are associated with BC \nrisk. Stage I with 735 cases and 735 controls was designed to discover the risk \nvariants, followed by stage II with 762 cases and 762 controls to validate the \nsignificant variants. In stage I, although the genotype distributions of all \nseven SNPs were not significantly different between BC cases and controls, \nlogistic regression analyses revealed that the variant genotypes of rs8004379 \nwere significantly associated with the increased risk of BC (dominant model: \nadjusted OR = 1.27, 95% CI = 1.01-1.58, P = 0.039). We then selected two SNPs, \nrs8004379 A/C and rs2056116 A/G, with lowest P values of the associations into \nthe stage II analysis. However, none of above two SNPs were significantly \nassociated with BC risk in both stage II and pooled set (rs8004379 AC/CC vs. AA: \nadjusted OR = 0.88, 95% CI = 0.68-1.13 for stage II and adjusted OR = 1.09, 95% \nCI = 0.92-1.29 for the pooled set; rs2056116 AG/GG vs. AA: adjusted OR = 1.12, \n95% CI = 0.87-1.45 for stage II and adjusted OR = 1.11, 95% CI = 0.94-1.31 for \nthe pooled set). These findings did not support a significant association \nbetween UCEs SNPs and the risk of BC in Chinese population." ]	['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000069584', 'http://www.disease-ontology.org/api/metadata/DOID:0060548', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D061325', 'http://www.disease-ontology.org/api/metadata/DOID:1612', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D001943', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000072656', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D050436', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D058922', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D001940', 'http://www.disease-ontology.org/api/metadata/DOID:14521', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018567', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D064726']
5c8857e975a4a5d219000009	[ 22965147 ]	train	Are apoE mimetics being considered as a treatment against Alzheimer's disease?	yesno	Yes, apoE mimetics are being considered as a treatment against Alzheimer's disease, and they have been shown to protect AD mouse models against these AD-like features.	yes	[ "BACKGROUND: Amyloid-β (Aβ) peptides derive from the amyloid precursor protein \n(APP) and play a pivotal role in Alzheimer's disease (AD) pathogenesis. Our \nprevious work showed that the APP intracellular domain (AICD), which is produced \nsimultaneously with Aβ, also contributes to the development of AD-like features. \nStudies show that administration of apolipoprotein E (apoE) and apoE-derived \nsmall peptide mimetics protect AD mouse models against these AD-like features. \nHowever, the effects of apoE-mimetic treatment on AICD-mediated AD-like \npathologies remain to be elucidated.\nOBJECTIVE: To study the effects of an apoE mimetic (COG112) on \nneuroinflammation, hyperphosphorylation of tau and defects in adult neurogenesis \nin AICD- overexpressing transgenic mice (FeCγ25 line).\nMETHODS: Beginning at 1 month of age, animals were administered subcutaneous \nCOG112 3 times per week for 3 months, followed by immunohistochemical analysis \nfor neuroinflammation, neurogenesis and phosphorylated tau.\nRESULTS: Treatment with COG112 significantly reduced neuroinflammation in AICD \nmice and protected against impaired adult hippocampal neurogenesis. We also \nfound that COG112 treatment reduced hyperphosphorylation and somatodendritic \naccumulation of tau in the hippocampus and cerebral cortex of AICD mice.\nCONCLUSIONS: Reduction of neuroinflammation by the apoE-mimetic COG112 protects \nagainst impaired neurogenesis and tau pathology in AICD transgenic mice. These \ndata suggest that neuroinflammation plays an important role in AICD-induced \nAD-like pathologies." ]	nan
5ca0fa96ecadf2e73f000048	[ 28406466, 20234994 ]	train	Are artificial blood cells available?	yesno	No, The critical point for the break through for artificial blood products did not come yet but could be ahead-	no	[ "We suggest a novel method that uses artificial blood cells (hemoglobin vesicles, \nHb-Vs) as photosensitizers in dye laser treatment (at 595-nm wavelength) for \nport-wine stains (i.e., capillary malformations presenting as red birthmarks) \nbased on the results of animal experiments. As compared with human red blood \ncells, Hb-Vs have the same absorbance of 595 nm wavelength light and produce the \nsame level of heat following dye laser irradiation. Small sized Hb-Vs (250 nm) \ndistribute in the plasma phase in blood and tend to flow in the marginal zone of \nmicrovessels. Intravenous injections of Hb-Vs caused the dilatation of \nmicrovessels, and dye laser treatment with Hb-Vs destroyed the vessel wall \neffectively. Following the intravenous injection of Hb-Vs, the microvessels \ncontained more Hb that absorbed laser photons and produced heat. This extra Hb \ntended to flow near the endothelial cells, which were the target of the laser \ntreatment. These attributes of Hb-Vs will potentially contribute to enhancing \nthe efficacy of dye laser treatment for port-wine stains. Hemoglobin is a type \nof porphyrin. Thus, our proposed treatment may have aspects of photodynamic \ntherapy using porphyrin that leads to a cytotoxicity effect by active oxygen.", "Formerly developed resuscitation fluids solely imitated the main function of the \nblood -oxygen transport. A research driven by the army requested an oxygen \ncarrier that does not need cross typing and cooled storage. Artificial oxygen \ncarriers (AOC) use either the molecular oxygen bondage to hemoglobin: HBOC- \n\"hemoglobin based oxygen carriers\" or the physical dissolution of oxygen in the \nblood plasma compartment by hyperbaric pressure in perfluorocarbon emulsions \n(PFC). Decades of preclinical and clinical research did pass but the results \nwere disappointing- in Russia, a not well designed PFC is available locally and \nthe only approved HBOC in South Africa is not being used much. Other products, \njust prior to filing for FDA approval, did not achieve convincing study results \nand research and production was stopped. Some trials have been stopped by the \nFDA for safety reasons, half of trials with the primary endpoint reduction of \nallogeneic transfusion requirement were unsuccessful or offset by an increased \nblood requirement later. However, some ventures currently are trying to use the \nknowledge gained so far and are investigating third and fourth generation \nproducts of artificial blood components. These imitate the cellular structure of \nred cells as micells, nanocapsules, (ABC- artificial blood cells) or gas bubbles \n(microbubbles), admixture of volume substitutes such as starches, gelatin or \nalbumin or use hyperbaric oxygenation [38]. Artificial platelets are in clinical \nphase IIa, recombinant albumin in phase III. In this article, a short overview \nabout the current situation on artificial blood products is given. The critical \npoint for the break through for artificial blood products did not come yet but \ncould be ahead-" ]	nan
5e480909d14c9f295d000003	[ 29644336, 29855508 ]	train	Are astronauts in higher risk for developing cancer?	yesno	No significant associations between space radiation dose and mortality were found using logistic regression with an internal reference group, adjusting for medical radiation.	no	[ "Despite years of research, understanding of the space radiation environment and \nthe risk it poses to long-duration astronauts remains limited. There is a \ndisparity between research results and observed empirical effects seen in human \nastronaut crews, likely due to the numerous factors that limit terrestrial \nsimulation of the complex space environment and extrapolation of human clinical \nconsequences from varied animal models. Given the intended future of human \nspaceflight, with efforts now to rapidly expand capabilities for human missions \nto the moon and Mars, there is a pressing need to improve upon the understanding \nof the space radiation risk, predict likely clinical outcomes of interplanetary \nradiation exposure, and develop appropriate and effective mitigation strategies \nfor future missions. To achieve this goal, the space radiation and aerospace \ncommunity must recognize the historical limitations of radiation research and \nhow such limitations could be addressed in future research endeavors. We have \nsought to highlight the numerous factors that limit understanding of the risk of \nspace radiation for human crews and to identify ways in which these limitations \ncould be addressed for improved understanding and appropriate risk posture \nregarding future human spaceflight.", "Understanding space radiation health effects is critical due to potential \nincreased morbidity and mortality following spaceflight. We evaluated whether \nthere is evidence for excess cardiovascular disease or cancer mortality in early \nNASA astronauts and if a correlation exists between space radiation exposure and \nmortality. Astronauts selected from 1959-1969 were included and followed until \ndeath or February 2017, with 39 of 73 individuals still alive at that time. \nCalculated standardized mortality rates for tested outcomes were significantly \nbelow U.S. white male population rates, including all-cardiovascular disease \n(n = 7, SMR = 33; 95% CI, 14-65) and all-cancer (n = 7, SMR = 43; 95% CI, \n18-83), as anticipated in a healthy worker population. Space radiation doses for \ncohort members ranged from 0-78 mGy. No significant associations between space \nradiation dose and mortality were found using logistic regression with an \ninternal reference group, adjusting for medical radiation. Statistical power of \nthe logistic regression was <6%, remaining <12% even when expected risk level or \nobserved deaths were assumed to be 10 times higher than currently reported. \nWhile no excess radiation-associated cardiovascular or cancer mortality risk was \nobserved, findings must be tempered by the statistical limitations of this \ncohort; notwithstanding, this small unique cohort provides a foundation for \nassessment of astronaut health." ]	nan
5e6f774ec6a8763d23000009	[ 18430081, 25700419, 31076745, 20526574, 31991218, 26231446, 21067677 ]	train	Are bacteria in the genus Clostridium facultative anaerobes?	yesno	Clostridia belong to those bacteria which are considered as obligate anaerobe, e.g. oxygen is harmful or lethal to these bacteria.	no	[ "Clostridia belong to those bacteria which are considered as obligate anaerobe, \ne.g. oxygen is harmful or lethal to these bacteria. Nevertheless, it is known \nthat they can survive limited exposure to air, and often eliminate oxygen or \nreactive derivatives via NAD(P)H-dependent reduction. This system does \napparently contribute to survival after oxidative stress, but is insufficient to \nestablish long-term tolerance of aerobic conditions. Here we show that \nmanipulation of the regulatory mechanism of this defence mechanism can trigger \naerotolerance in the obligate anaerobe Clostridium acetobutylicum. Deletion of a \nperoxide repressor (PerR)-homologous protein resulted in prolonged \naerotolerance, limited growth under aerobic conditions and rapid consumption of \noxygen from an aerobic environment. The mutant strain also revealed higher \nresistance to H2O2 and activities of NADH-dependent scavenging of H2O2 and \norganic peroxides in cell-free extracts increased by at least one order of \nmagnitude. Several genes encoding the putative enzymes were upregulated and \nidentified as members of the clostridial PerR regulon, including the heat shock \nprotein Hsp21, a reverse rubrerythrin which was massively produced and became \nthe most abundant protein in the absence of PerR. This multifunctional protein \nis proposed to play the crucial role in the oxidative stress defence.", "Author information:\n(1)Genomic and Applied Microbiology & Göttingen Genomics Laboratory, \nGeorg-August-University Göttingen, Göttingen, Germany.\n(2)The Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre, \nSchool of Life Sciences, Centre for Biomolecular Sciences, University of \nNottingham, Nottingham, United Kingdom.\n(3)Unilever, Research and Development, Bedford, United Kingdom.\n(4)The Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre, \nSchool of Life Sciences, Centre for Biomolecular Sciences, University of \nNottingham, Nottingham, United Kingdom nigel.minton@nottingham.ac.uk.", "Clostridium is a large genus of obligate anaerobes belonging to the Firmicutes \nphylum of bacteria, most of which have a Gram-positive cell wall structure. The \ngenus includes significant human and animal pathogens, causative of potentially \ndeadly diseases such as tetanus and botulism. Despite their relevance and many \nstudies suggesting that they are not a monophyletic group, the taxonomy of the \ngroup has largely been neglected. Currently, species belonging to the genus are \nplaced in the unnatural order defined as Clostridiales, which includes the class \nClostridia. Here, we used genomic data from 779 strains to study the taxonomy \nand evolution of the group. This analysis allowed us to 1) confirm that the \ngroup is composed of more than one genus, 2) detect major differences between \npathogens classified as a single species within the group of authentic \nClostridium spp. (sensu stricto), 3) identify inconsistencies between taxonomy \nand toxin evolution that reflect on the pervasive misclassification of strains, \nand 4) identify differential traits within central metabolism of members of what \nhas been defined earlier and confirmed by us as cluster I. Our analysis shows \nthat the current taxonomic classification of Clostridium species hinders the \nprediction of functions and traits, suggests a new classification for this \nfascinating class of bacteria, and highlights the importance of phylogenomics \nfor taxonomic studies.", "Cancer has become the second ranking cause of death in the industrialized world. \nConventional anti-cancer therapies such as surgery, radiotherapy, and \nchemotherapy are effective in the treatment of solid tumors only to some extent. \nFurthermore, they are often associated with severe side effects. Use of bacteria \nas alternative cancer therapeutics has sporadically been followed over more than \na century. The potential to target and colonize solid tumors could be shown for \nmany different bacteria in the meantime. Such bacteria are either obligate \nanaerobic bacteria like Clostridium or Bifidobacterium or facultative anaerobic \nlike Escherichia coli or Salmonella. Here we describe bacterial strains that \nwere successfully applied mostly in animals bearing model tumors, although first \nclinical trials have been reported as well. Our review mainly concentrates on \nSalmonella enterica serovar Typhimurium (S. Typhimurium) since these bacteria \nwere studied most intensively thus far. Importantly, S. Typhimurium were shown \nnot only to colonize large established tumors but also exhibit the property to \ninvade and affect metastases. We report on a potential mechanism by which such \nbacteria can invade solid tumors. Furthermore, we describe several successful \nattempts in which the bacteria have been used as carriers for recombinant \ntherapeutic molecules that render bacteria more powerful in eradication of the \nestablished tumor. Such attempts should be considered starting points on the way \nto an effective and safe tumor therapy with the help of bacteria.", "Antimicrobial resistance continues to rise on a global scale, affecting the \nenvironment, humans, animals and food systems. Use of natural antimicrobials has \nbeen favoured over synthetic molecules in food preservation owing to concerns \nover the adverse health effects of synthetic chemicals. The continuing need for \nnovel natural antimicrobial compounds has spurred research to investigate \nnatural sources, such as bacteria, for antimicrobials. The \nantimicrobial-producing potential of bacteria has been investigated in numerous \nstudies. However, the discovery of antimicrobials has been biased towards \naerobes and facultative anaerobes, and strict anaerobes such as Clostridium spp. \nhave been largely neglected. In recent years, genomic studies have indicated the \ngenetic potential of strict anaerobes to produce putative bioactive molecules \nand this has encouraged the exploration of Clostridium spp. for their \nantimicrobial production. So far, only a limited number of antimicrobial \ncompounds have been isolated, identified and characterised from the genus \nClostridium. This review discusses our current knowledge and understanding of \nclostridial antimicrobial compounds as well as recent genome mining studies of \nClostridium spp. focused at identification of putative gene clusters encoding \nbacterial secondary metabolite groups and peptides reported to possess \nantimicrobial properties. Furthermore, opportunities and challenges in the \nidentification of antimicrobials from Clostridium spp. using genomic-guided \napproaches are discussed. The limited studies conducted so far have identified \nthe genus Clostridium as a viable source of antimicrobial compounds for future \ninvestigations.", "Clostridium difficile is a spore-forming obligate anaerobe that is a leading \ncause of healthcare-associated infections. C. difficile infections begin when \nits metabolically dormant spores germinate in the gut of susceptible \nindividuals. Binding of bile salt germinants to the Csp family pseudoprotease \nCspC triggers a proteolytic signaling cascade consisting of the Csp family \nprotease CspB and the cortex hydrolase SleC. Conserved across many of the \nClostridia, Csp proteases are subtilisin-like serine proteases that activate \npro-SleC by cleaving off its inhibitory pro-peptide. Active SleC degrades the \nprotective cortex layer, allowing spores to resume metabolism and growth. This \nsignaling pathway, however, is differentially regulated in C. difficile, since \nCspC functions both as a germinant receptor and regulator of CspB activity. CspB \nis also produced as a fusion to a catalytically inactive CspA domain that \nsubsequently undergoes interdomain processing during spore formation. In this \nstudy, we investigated the role of the CspA pseudoprotease domain in regulating \nC. difficile spore germination. Mutational analyses revealed that the CspA \ndomain controls CspC germinant receptor levels in mature spores and is required \nfor optimal spore germination, particularly when CspA is fused to the CspB \nprotease. During spore formation, the YabG protease separates these domains, \nalthough YabG itself is dispensable for germination. Bioinformatic analyses of \nCsp family members suggest that the CspC-regulated signaling pathway \ncharacterized in C. difficile is conserved in related Peptostreptococcaceae \nfamily members but not in the Clostridiaceae or Lachnospiraceae. Our results \nindicate that pseudoproteases play critical roles in regulating C. difficile \nspore germination and highlight that diverse mechanisms control spore \ngermination in the Clostridia.", "Clostridium pasteurianum BB, a saccharolytic and spore-forming obligate \nanaerobe, was isolated and identified from shelf-stable apple juice that was \nresponsible for multiple large spoilage outbreaks. The growth and sporulation \nconditions of C. pasteurianum were atypical compared with those previously \npublished. C. pasteurianum spores were heat resistant in apple juice at pH 3.80, \nwith D-values at 80, 85, and 90°C being 34.4, 15.9, and 4.4 min, respectively, \nand a z-value of 11°C. The survival curves for thermal inactivation obeyed \nlinear first-order kinetics. Apple juice with varying pH values was used to \ndetermine the effect of pH on germination capability of C. pasteurianum spores. \nThe spores were found to be able to germinate at pH as low as 4.3 in pH-adjusted \napple juice at low contamination levels. It was confirmed by PCR that C. \npasteurianum isolated from spoiled apple juice did not contain the genes for \nbotulinum toxins B and E, which were more commonly found in neurotoxigenic \nbutyric clostridia. Control of finished-juice pH to below 4.0 in combination \nwith mild heating was proposed to prevent potential spoilage of shelf-stable \napple juice made with spore-contaminated apple juice concentrate." ]	nan
5e3c6e15b5b409ea53000023	[ 6445538, 20079875, 1540967, 29956296, 29043625, 23948232, 29787435, 9665145, 31652722, 10639091, 16650867, 7683090, 26089209 ]	train	Are breaks in double stranded DNA associated with ionizing radiation?	yesno	Yes, double-strand breaks in double stranded DNA may be associated with ionizing radiation risk.	yes	[ "Gamma-ray irradiation introduces single and/or double strand breaks into the DNA \nmolecule of the cells. In the case of mammalian cells, these breaks are being \nrepaired in general during the first hr following exposure to ionizing \nradiation. The article reports on the results obtained from testing the ability \nof cultured lymphocytes from patients with Down's syndrome to repair \nradiation-induced DNA single-strand breaks. The ability to repair was deduced \nfrom the study of the DNA sedimentation profiles in alkaline sucrose gradients. \nIt was found that lymphocytes from Down's syndrome patients are less efficient \nin repairing single-strand DNA breaks than are lymphocytes from normal \nindividuals. This significantly increased fraction of unrepaired DNA strand \nbreaks might be associated with the unusually high level of radiation-induced \nchromosome aberrations as compared with normals.", "The induction of DNA interstrand cross-links by ionizing radiation has been \nlargely ignored in favour of studies on double-strand break formation and \nrepair. At least part of the problem is technical; it is difficult to detect and \nquantify interstrand cross-links when the same agent forms both cross-links and \nsingle strand breaks because the detection of interstrand cross-links generally \ninvolves a denaturation step. Our group has studied the induction of interstrand \ncross-links following irradiation of DNA containing bromouracil at specific \nsites. We found that the formation of interstrand cross-links requires the \npresence of a few (3-5) mismatched bases, comprising the bromouracil. In the \nabsence of mismatched bases, no radiation-induced cross-linking was observed; \nhowever, even in the absence of bromouracil, cross-linking still occurred, \nalbeit at a lower efficiency. Our molecular modelling studies demonstrate that \nthe mobility of the bases in the mismatched region is essential for the \ncross-linking process. Thus, our hypothesis is that ionizing radiation induces \nDNA interstrand cross-links in non-hybridized regions of DNA. Some obvious \nexamples of such DNA regions are replication forks, transcription bubbles and \nthe D-loop of telomeres. However, an abundance of studies have made it clear \nthat there must be many single-stranded regions in the genome, such as hairpins \nand cruciforms. For example, alpha satellite DNA, in centromere regions of human \nchromosomes, forms hairpins. Thus, a variety of non-B DNA structures (hairpins, \nslipped DNA and tetrahelical structures) exist in the genome and should be \nsusceptible to the formation of radiation-induced interstrand cross-links. \nAlthough interstrand cross-links have thus far been virtually ignored in \nradiation biology, it will be worthwhile to develop methods to detect their \npresence following exposure of cells to biologically relevant levels of ionizing \nradiation, since, on a per lesions basis, they are probably more toxic than \ndouble-strand breaks.", "Pulsed field gel electrophoresis was used to examine the influence of chromatin \nstructure on the induction of DNA double strand breaks by gamma-irradiation in \nCHO-WBL cells, nuclei, and a series of protein-depleted chromatin substrates. We \ndeveloped a method to isolate intact nuclei in agarose plugs that avoids DNA \nshearing and nucleolytic degradation during sample preparation, and facilitates \nnuclear protein extraction. Agarose plug-isolated nuclei are extracted with \nincreasing concentrations of NaCl to selectively strip off: (a) nonhistone \nchromosomal proteins (NHP); (b) NHP and histone H1; (c) NHP, H1, and histone \nH2A-H2B dimers; or (d) NHP, H1, and H2A-H2B dimers and histone H3-H4 tetramers. \nFollowing treatment with up to 40 Gy of gamma-radiation, DNA from each sample is \npurified and the relative induction of DNA double strand breaks is assayed by \nasymmetric field inversion gel electrophoresis. At a dose of 20 Gy, removal of \nnonhistone proteins from nuclei results in a 3-fold increase in DNA double \nstrand breaks, compared to intact CHO cells. Additional stripping of histone H1 \nresults in an incremental increase in double strand break induction, whereas \nfurther removal of H2A-H2B dimers yields a greater than 10-fold increase in DNA \ndouble strand breaks compared to intact CHO cells. The dose-response profile for \nthis latter sample is similar to that observed for purified DNA. These data \nindicate that distinct classes of chromosomal proteins afford the DNA with \ndifferent levels of protection against gamma-ray-induced DNA double strand \nbreaks. Thus, chromatin domains that differ in tertiary structure and protein \ncomposition may also differ in their susceptibility to DNA double strand breaks \ninduced by ionizing radiation and, perhaps, other clastogens.", "Whereas most endogenous and exogenous DNA damaging agents typically generate \nlesions that are relatively isolated and can be repaired easily, ionizing \nradiation (IR) also induces clustered lesions causing DNA double strand breaks \n(DSBs). Moreover, forms of IR characterized by high linear energy transfer (LET) \ninduce not only isolated DSBs but also DSB clusters - multiple DSBs in close \nproximity -that pose increased risks for the cell. DSB clusters can destabilize \nchromatin locally and compromise processing of individual DSBs within the \ncluster. Since the discovery of chromothripsis, a phenomenon whereby multiple \nDSBs locally generated by a catastrophic event causes genomic rearrangements \nthat feed carcinogenesis, DSB clusters receive increased attention also in the \nfield of cancer. While formation of DSB clusters after exposure to high LET is a \ndirect and inherent consequence of the spatial distribution of the constituting \nenergy deposition events, also called track structure, the sources of local \ngenomic shattering underpinning chromothripsis are under investigation. Notably, \nmany consequences of DSB clusters in the affected genome reflect processing by \npathways that have evolved to repair DSBs, but which operate with widely \ndifferent degrees of fidelity. The molecular underpinnings and the basis of the \nunderlying repair pathway choices that ultimately lead to the observed \nconsequences from DSB clusters remain unknown. We developed a tractable model of \nDSB clustering that allows direct analysis in cells of the consequences of \ncertain configurations of DSB clusters. We outline the rationale for the \ndevelopment of this model and describe its key characteristics. We summarize \nresults suggesting that DSB clusters compromise the first-line DSB-processing \npathways of c-NHEJ and HRR, increasing as a consequence the contribution of \nalt-EJ, which has high propensity of generating chromosomal rearrangements. The \nresults suggest a mechanism for the increased toxicity of high LET radiation and \nthe extensive genomic rearrangements associated with chromothripsis.", "DNA double-strand breaks (DSBs) are major DNA lesions that are constantly formed \nduring physiological processes such as DNA replication, transcription, and \nrecombination, or as a result of exogenous agents such as ionizing radiation, \nradiomimetic drugs, and genome editing nucleases. Unrepaired DSBs threaten \ngenomic stability by leading to the formation of potentially oncogenic \nrearrangements such as translocations. In past few years, several methods based \non next-generation sequencing (NGS) have been developed to study the genome-wide \ndistribution of DSBs or their conversion to translocation events. We developed \nBreaks Labeling, Enrichment on Streptavidin, and Sequencing (BLESS), which was \nthe first method for direct labeling of DSBs in situ followed by their \ngenome-wide mapping at nucleotide resolution (Crosetto et al., Nat Methods \n10:361-365, 2013). Recently, we have further expanded the quantitative nature, \napplicability, and scalability of BLESS by developing Breaks Labeling In Situ \nand Sequencing (BLISS) (Yan et al., Nat Commun 8:15058, 2017). Here, we first \npresent an overview of existing methods for genome-wide localization of DSBs, \nand then focus on the BLESS and BLISS methods, discussing different assay design \noptions depending on the sample type and application.", "While much is known about radiation-induced DNA double-strand breaks (DSBs) and \ntheir repair, the question of how deletions of different sizes arise as a result \nof the processing of DSBs by the cell's repair systems has not been fully \nanswered. In order to bridge this gap between DSBs and deletions, we critically \nreviewed published data on mechanisms pertaining to: (a) repair of DNA DSBs \n(from basic studies in this area); (b) formation of naturally occurring \nstructural variation (SV) - especially of deletions - in the human genome (from \ngenomic studies) and (c) radiation-induced mutations and structural chromosomal \naberrations in mammalian somatic cells (from radiation mutagenesis and radiation \ncytogenetic studies). The specific aim was to assess the relative importance of \nthe postulated mechanisms in generating deletions in the human genome and \nexamine whether empirical data on radiation-induced deletions in mouse germ \ncells are consistent with predictions of these mechanisms. The mechanisms \ninclude (a) NHEJ, a DSB repair process that does not require any homology and \nwhich functions in all stages of the cell cycle (and is of particular relevance \nin G0/G1); (b) MMEJ, also a DSB repair process but which requires microhomology \nand which presumably functions in all cell cycle stages; (c) NAHR, a \nrecombination-based DSB repair mechanism which operates in prophase I of meiosis \nin germ cells; (d) MMBIR, a microhomology-mediated, replication-based mechanism \nwhich operates in the S phase of the cell cycle, and (e) strand slippage during \nreplication (involved in the origin of small insertions and deletions (INDELs). \nOur analysis permits the inference that, between them, these five mechanisms can \nexplain nearly all naturally occurring deletions of different sizes identified \nin the human genome, NAHR and MMBIR being potentially more versatile in this \nregard. With respect to radiation-induced deletions, the basic studies suggest \nthat those arising as a result of the operation of NHEJ/MMEJ processes, as \ncurrently formulated, are expected to be relatively small. However, data on \ninduced mutations in mouse spermatogonial stem cells (irradiation in G0/G1 phase \nof the cell cycle and DSB repair presumed to be via NHEJ predominantly) show \nthat most are associated with deletions of different sizes, some in the megabase \nrange. There is thus a 'discrepancy' between what the basic studies suggest and \nthe empirical observations in mutagenesis studies. This discrepancy, however, is \nonly an apparent but not a real one. It can be resolved by considering the issue \nof deletions in the broader context of and in conjunction with the organization \nof chromatin in chromosomes and nuclear architecture, the conceptual framework \nfor which already exists in studies carried out during the past fifteen years or \nso. In this paper, we specifically hypothesize that repair of DSBs induced in \nchromatin loops may offer a basis to explain the induction of deletions of \ndifferent sizes and suggest an approach to test the hypothesis. We emphasize \nthat the bridging of the gap between induced DSB and resulting deletions of \ndifferent sizes is critical for current efforts in computational modeling of \ngenetic risks.", "Exposure of cells to ionizing radiation induces DNA double-strand breaks. To \nrepair double-strand breaks correctly, cells must distinguish between the ends \nof chromosomes (telomeres) and DNA double-strand breaks within chromosomes. \nDouble-strand breaks in telomeric DNA may lead to telomere shortening and \nmutagenesis. Eukaryotic cells repair double-strand breaks primarily by two \nmechanisms: error-free homologous recombination and error-prone nonhomologous \nend joining, of which homologous recombination is used in early meiotic prophase \nI to create recombined haploid gametes by two meiotic cell divisions lacking an \nintervening S-phase. Genotoxic exposures put meiosis at risk to transmit \nmutations, and ionizing radiation is known to induce large double-strand \nbreak-marking phospho (gamma)-H2AX foci along the cores and ends of mouse \nmeiotic chromosomes. However, it remained unclear through which repair pathway \nthe ionizing radiation-induced telomeric double-strand breaks are repaired in \nlate prophase I spermatocytes. Using male wild-type and nonhomologous end \njoining-deficient (severe combined immunodeficient) mice, this study \ninvestigated the kinetics of in vivo double-strand break formation and repair at \ntelomeres of late prophase I chromosomes up to 12 h after 0.5 Gy of whole-body \ngamma irradiation. Late pachytene and diplotene spermatocytes revealed \noverlapping gamma-H2AX and telomere repeat signal foci, indicating telomeric DNA \ndamage. The comparison of double-strand break repair rates at telomeres and \ninternal prophase chromosome sites revealed a more rapid double-strand break \nrepair at wild-type telomeres during the first hour after irradiation. Increased \ndouble-strand break foci numbers at nonhomologous end joining-deficient \ntelomeres and chromosomes and a slowed repair rate in this DNA-dependent protein \nkinase catalytic subunit mutant suggest that the fast repair of double-strand \nbreaks in telomeric DNA repeats during late prophase I is largely mediated by \ncanonical nonhomologous end joining.", "BACKGROUND: The protein product of the BRCA2 gene mediates repair of \ndouble-strand breaks in DNA. Because a number of cancer therapies exert \ncytotoxic effects via the initiation of double-strand breaks, cancers comprised \nof cells carrying BRCA2 gene mutations may be more amenable to treatment with \nagents that cause such breaks.\nMETHODS: We identified a human pancreatic adenocarcinoma cell line lacking one \ncopy of the BRCA2 gene and containing a mutation (6174delT) in the remaining \ncopy. In vitro and in vivo experiments were conducted with this cell line and \nwith other carcinoma cell lines matched for similar genetic mutations, similar \ndifferentiation status, and/or similar carcinoma type to examine double-strand \nbreak repair, sensitivity to drugs that induce double-strand breaks, and \nradiation sensitivity.\nRESULTS: BRCA2-defective cells were unable to repair the double-strand DNA \nbreaks induced by ionizing radiation. These cells were also markedly sensitive \nto mitoxantrone, amsacrine, and etoposide (drugs that induce double-strand \nbreaks) (two-sided P = .002) and to ionizing radiation (two-sided P = .001). \nIntroduction of antisense BRCA2 deoxyribonucleotides into cells possessing \nnormal BRCA2 function led to increased sensitivity to mitoxantrone (two-sided P \n= .008). Tumors formed by injection of BRCA2-defective cells into nude mice were \nhighly sensitive (>90% tumor size reduction, two-sided P = .002) to both \nionizing radiation and mitoxantrone when compared with tumors exhibiting normal \nBRCA2 function. Histologic analysis of irradiated BRCA2-defective tumors showed \na large degree of necrosis compared with that observed for control tumors \npossessing normal BRCA2 function.\nCONCLUSION: BRCA2-defective cancer cells are highly sensitive to agents that \ncause double-strand breaks in DNA.", "Author information:\n(1)Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center \n(CI-IPOP), Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal. \naugusto.andre.nogueira@ipoporto.min-saude.pt.\n(2)Faculty of Medicine of University of Porto (FMUP), 4200-319 Porto, Portugal. \naugusto.andre.nogueira@ipoporto.min-saude.pt.\n(3)Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center \n(CI-IPOP), Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal. \nmara.aires.fernandes@ipoporto.min-saude.pt.\n(4)Faculty of Medicine of University of Porto (FMUP), 4200-319 Porto, Portugal. \nmara.aires.fernandes@ipoporto.min-saude.pt.\n(5)Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center \n(CI-IPOP), Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal. \nraquelcatarino@gmail.com.\n(6)Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center \n(CI-IPOP), Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal. \nruimedei@ipoporto.min-saude.pt.\n(7)Faculty of Medicine of University of Porto (FMUP), 4200-319 Porto, Portugal. \nruimedei@ipoporto.min-saude.pt.\n(8)Biomedical Research Center (CEBIMED), Faculty of Health Sciences of Fernando \nPessoa University, 4249-004 Porto, Portugal. ruimedei@ipoporto.min-saude.pt.\n(9)Research Department, Portuguese League against Cancer (NRNorte), 4200-172 \nPorto, Portugal. ruimedei@ipoporto.min-saude.pt.", "Ionizing radiation and radiomimetic drugs such as bleomycin, calichieamycin, \nneocarzinostatin chromophore, and other synthetic agents can produce both single \nand double strand breaks in DNA. The ability to study the structure-activity \nrelationships of single and double-strand break repair, lethality, and \nmutagenesis in vivo is complicated by the numerous types and sites of DNA \ncleavage products that can be induced by such agents. The ability to \"cage\" such \nbreaks in DNA might help to further such studies and additionally afford a \nmechanism for activating and deactivating nucleic acid based drugs and probes. \nThe major type of single strand break induced by ionizing radiation is a 3'- and \n5'-phosphate terminated single nucleotide gap. Previously, a caged strand break \nof this type had been developed that was designed to produce the 5'-phosphate \ndirectly upon irradiation with 366 nm light, and the 3'-phosphate by a \nsubsequent beta-elimination reaction [Ordoukhanian, P., and Taylor, J.-S. (1995) \nJ. Am. Chem. Soc. 117, 9570]. Unfortunately, the release of the 3'-phosphate \ngroup was quite slow at pH 7. To circumvent this problem, a second caged strand \nbreak has been developed that produces the 3'-phosphate directly upon \nirradiation, and the 5'-phosphate by a subsequent beta-elimination reaction. \nWhen this caged strand break was used in tandem with the previous caged strand \nbreak, 5'- and 3'-phosphate terminated gaps could be directly produced by \nirradiation with 366 nm light. These caged single strand breaks were also \nincorporated in tandem into hairpin substrates to demonstrate that they could be \nused to cage double strand breaks. These caged single strand breaks should be \ngenerally useful for generating site-specific DNA single and double strand \nbreaks and gaps, using wavelengths and doses of light that are nondetrimental to \nbiological systems. Because the position of the single strand break can be \nvaried, it should now be possible to examine the effect of the sequence context \nand cleavage pattern of single and double strand breaks on the lethality and \nmutagenicity of this important class of DNA damage.", "BACKGROUND: Induction of DNA double strand breaks and alterations in the repair \nof these breaks is implicated in breast carcinogenesis. Prior studies have \ndemonstrated that peripheral blood mononuclear cells (PBMC) from breast cancer \npatients exhibit increased numbers of DNA strand breaks after exposure to \nionizing radiation, but these studies did not specifically measure DNA double \nstrand breaks and it is not known whether chemical carcinogens produce similar \neffects.\nMATERIALS AND METHODS: PBMC from 32 women undergoing breast surgery were \ngenotyped at nine loci of seven DNA repair genes. DNA double strand break repair \nwas measured using the neutral comet assay after exposure to ionizing radiation \n(0.5 Gy) or bioactivated benzo[a]pyrene (B[a]P, 5 microM.\nRESULTS: PBMC from breast cancer patients showed higher levels of residual DNA \ndouble strand breaks 30 min after exposure to radiation than PBMC from patients \nwith benign breast disease (1.40 times baseline [95% confidence intervals [CI] \n1.29-1.51] versus 1.24 times baseline [95% CI 1.15-1.33], respectively, P = \n0.04). The response to B[a]P trended in the same direction, but did not reach \nstatistical significance. The MGMT K178R variant genotype was associated with \nimproved DNA double strand break repair in PBMC exposed to B[a]P.\nCONCLUSIONS: Reduced repair of radiation-induced DNA double strand breaks in \nPBMC is a robust biomarker of breast cancer risk. Reduced DNA repair capacity \nmay have a genetic component even in sporadic breast cancer.", "DNA double-strand breaks are considered to be the most deleterious lesion \ninduced by ionizing radiation. However, the mechanism of rejoining of these \nlesions has not been extensively studied at the molecular level. We have used a \nshuttle vector, pHAZE, to analyze the mechanism of rejoining of DNA \ndouble-strand breaks in human cells. The advantage of this vector system is \nthat, unlike many previously described shuttle vectors, it has a large target \ngene for the detection of deletions and it is maintained as a freely replicating \nepisome with chromatin conformation in the nucleus of human cells. In this study \nwe compare data obtained on the spectrum of mutations induced in pHAZE by \nionizing radiation (alpha-particles) and restriction enzymes (PvuII, ClaI, and \nPvuI). Unlike ionizing radiation, restriction enzymes induce double-strand \nbreaks in DNA with known end structures at defined locations and therefore \nprovide a model system for analyzing cellular responses to DNA double-strand \nbreaks. Exposure of human cells containing the vector to alpha-particle \nirradiation produced both point mutations and large deletions in pHAZE. When the \njunction regions of the deletions were sequenced it was found that 65% were \nrejoined with up to 6 bp of homology at the junction region. Analysis of \nrestriction-enzyme-induced mutations suggests that double-strand break ends are \nmodified to facilitate rejoining and that the type of modification is \ncharacteristic for different end structures. Double-strand breaks with cohesive \nends appear to have fewer modifications introduced at the break points before \nrejoining than breaks with blunt ends. When considered in relation to the data \nobtained with ionizing radiation this suggests that the presence of cohesive \nsequences either at, or in proximity to, the ends enhances rejoining of DNA \ndouble-strand breaks.", "Double-stranded breaks (DSBs) are cytotoxic DNA lesions caused by oxygen \nradicals, ionizing radiation, and radiomimetic chemicals. Increasing \nunderstanding of DNA damage signaling has provided an ever-expanding list of \nmodulators reported to orchestrate DNA damage repair and ataxia telangiectasia \nmutated (ATM) is the master regulator and main transducer of the DSB response. \nIncreasingly, it is being realized that DNA damage response is a synchronized \nand branched network that functionalizes different molecular cascades to \nactivate special checkpoints, thus temporarily arresting progression of the cell \ncycle while damage is being assessed and processed. It is noteworthy that both \nnutrigenetics and nutrigenomics have revolutionized the field of molecular \nbiology and rapidly accumulating experimental evidence has started to shed light \non biological activities of a wide range of phytochemicals reported to modulate \ncell cycle, DNA repair, cell growth, differentiation and apoptosis as evidenced \nby cell-based studies. In this review, we have attempted to provide an overview \nof DNA damage signaling, how ATM signaling regulates tumor necrosis \nfactors-related apoptosis inducing ligand (TRAIL)-induced intracellular network. \nWe also illuminate on how resveratrol, epigallocatechin gallate, curcumin, \njaceosidin, cucurbitacin, apigenin, genistein, and others trigger activation of \nATM in different cancer cells as well as agents for ATM inactivation. \nUnderstanding the interplay of TRAIL-induced intracellular signaling and ATM \nmodulation of downstream effectors is very important. This holds particularly \nfor a reconceptualization of the apparently paradoxical roles and \ntherapeutically targetable for enhancing the response to DNA damage-inducing \ntherapy." ]	nan
5c9906dcecadf2e73f00002f	[ 30372816, 29683473, 30053394 ]	train	Are cardenolides inhibitors of Na+/K+ ATPase?	yesno	Yes, Cardenolides have shown significant antitumor activity due to their ability to inhibit the Na+K+ATPase enzyme, and the expression of this enzyme is increased in tumor cells.	yes	[ "Cancer is an important public health problem, being one of the leading causes of \ndeath worldwide. Most antineoplastic agents cause severe toxic effects and some \ntypes of cancer do not respond or are resistant to the existing pharmacotherapy, \nnecessitating the research and development of new therapeutic strategies. \nCardenolides have shown significant antitumor activity due to their ability to \ninhibit the Na+K+ATPase enzyme, and the expression of this enzyme is increased \nin tumor cells. Glucoevatromonoside containing peracetylated glucose hydroxyl \ngroups (GEVPG) is a cardenolide derivative that has low solubility in aqueous \nmedia, which constitutes a barrier to its potential biological applications. In \nthis context, the use of liposomes represents a promising strategy to deliver \nGEVPG, thus allowing its intravenous administration. In this study, \nlong-circulating and fusogenic liposomes containing GEVPG (SpHL-GEVPG) were \ndeveloped, and their chemical and physicochemical properties were evaluated. \nSpHL-GEVPG presented adequate properties, including a mean diameter of \n182.2 ± 2.7 nm, a polydispersity index equal to 0.36 ± 0.03, a zeta potential of \n-2.37 ± 0.31 mV, and a GEVPG entrapment of 0.38 ± 0.04 mg/mL. Moreover, this \nformulation showed a good stability after having been stored for 30 days at \n4 °C. The cytotoxic studies against breast (MDA-MB-231, MCF-7, and SKBR-3) and \nlung (A549) cancer cell lines demonstrated that SpHL-GEVPG treatment \nsignificantly reduced the cell viability. In addition, the SpHL-GEVPG \nformulation presented a good selectivity toward these cancer cells. The \nevaluation of the therapeutic efficacy of the treatment with SpHL-GEVPG showed a \npotent anticancer effect in an A549 human lung cancer xenograft model. \nSpHL-GEVPG administered at doses of 1.0 and 2.0 mg/kg (i.v.) induced antitumor \neffect comparable to paclitaxel given at dose of 10 mg/kg (i.v.) to mice. \nTherefore, the results of the present work indicate the potential applicability \nof SpHL-GEVPG as a new anticancer formulation.", "PREMISE OF THE STUDY: Pachypodium (Apocynaceae) is a genus of iconic \nstem-succulent and poisonous plants endemic to Madagascar and southern Africa. \nWe tested hypotheses about the mode of action and macroevolution of toxicity in \nthis group. We further hypothesized that while monarch butterflies are highly \nresistant to cardenolide toxins (a type of cardiac glycoside) from American \nAsclepias, they may be negatively affected by Pachypodium defenses, which \nevolved independently.\nMETHODS: We grew 16 of 21 known Pachypodium spp. and quantified putative \ncardenolides by HPLC and also by inhibition of animal Na+ /K+ -ATPase (the \nphysiological target of cardiac glycosides) using an in vitro assay. Pachypodium \nextracts were tested against monarch caterpillars in a feeding bioassay. We also \ntested four Asclepias spp. and five Pachypodium spp. extracts, contrasting \ninhibition of the cardenolide-sensitive porcine Na+ /K+ -ATPase to the monarch's \nresistant form.\nKEY RESULTS: We found evidence for low cardenolides by HPLC, but substantial \ntoxicity when extracts were assayed on Na+ /K+ -ATPases. Toxicity showed \nphylogenetic signal, and taller species showed greater toxicity (this was \nmarginal after phylogenetic correction). Application of Pachypodium extracts to \nmilkweed leaves reduced monarch growth, and this was predicted by inhibition of \nthe sensitive Na+ /K+ -ATPase in phylogenetic analyses. Asclepias extracts were \n100-fold less potent against the monarch compared to the porcine Na+ /K+ \n-ATPase, but this difference was absent for Pachypodium extracts.\nCONCLUSIONS: Pachypodium contains potent toxicity capable of inhibiting \nsensitive and cardenolide-adapted Na+ /K+ -ATPases. Given the monarch's \nsensitivity to Pachypodium, we suggest that these plants contain novel cardiac \nglycosides or other compounds that facilitate toxicity by binding to Na+ /K+ \n-ATPases.", "Cardenolides are plant-derived toxic substances. Their cytotoxicity and the \nunderlying mechanistic signaling axes have been extensively documented, but only \na few anti-viral activities of cardenolides and the associated signaling \npathways have been reported. Previously, we reported that a variety of \ncardenolides impart anti-transmissible gastroenteritis coronavirus (TGEV) \nactivity in swine testicular (ST) cells, through targeting of the cell membrane \nsodium/potassium pump, Na+/K+-ATPase. Herein, we further explore the potential \nsignaling cascades associated with this anti-TGEV activity in ST cells. Ouabain, \na representative cardenolide, was found to potently diminish TGEV titers and \ninhibit the TGEV-induced production of IL-6 in a dose dependent manner, with 50% \ninhibitory concentrations of 37 nM and 23 nM respectively. By pharmacological \ninhibition and gene silencing, we demonstrated that PI3K_PDK1_RSK2 signaling was \ninduced in TGEV-infected ST cells, and ouabain imparted a degree of anti-TGEV \nactivity via further augmentation of this existing PI3K_PDK1 axis signaling, in \na manner dependent upon its association with the Na+/K+-ATPase. Finally, \ninhibition of PI3K by LY294002 or PDK1 by BX795 antagonized the anti-viral \nactivity of ouabain and restored the TGEV virus titer and yields. This finding \nis the first report of a PI3K_PDK1 signaling axis further induced by ouabain and \nimplicated in the suppression of TGEV activity and replication; greatly \nilluminates the underlying mechanism of cardenolide toxicity; and is expected to \nresult in one or more anti-viral applications for the cardenolides in the \nfuture." ]	nan
5171833c8ed59a060a00000f	[ 12121623, 23021223, 9584105, 11459824, 12151602, 11487702, 18488247, 12740729, 17660570, 20505370 ]	train	Are chromomethylases present in animal genomes?	yesno	No. Multiple lines of experimental evidence suggest that chromomethylases (CMTs) have been hitherto identified in plant genomes(Arabidopsis, maize, tomato). CMTs maintain CpNpG (N = A, T, C, or G) methylation and they are unique to the plant kingdom. The lack of CMT homologs in animal genomes could be explained based on the fact that, in contrast to plants, animals maintain primarily CG methylation. Therefore, the presence of CMTs is not required in the animal genomes.	no	[ "Proper DNA methylation patterning requires the complementary processes of de \nnovo methylation (the initial methylation of unmethylated DNA sequences) and \nmaintenance methylation (the faithful replication of preexisting methylation). \nArabidopsis has two types of methyltransferases with demonstrated maintenance \nactivity: MET1, which maintains CpG methylation and is homologous to mammalian \nDNMT1, and CHROMOMETHYLASE 3 (CMT3), which maintains CpNpG (N = A, T, C, or G) \nmethylation and is unique to the plant kingdom. Here we describe \nloss-of-function mutations in the Arabidopsis DOMAINS REARRANGED METHYLASE (DRM) \ngenes and provide evidence that they encode de novo methyltransferases. drm1 \ndrm2 double mutants retained preexisting CpG methylation at the endogenous FWA \nlocus but blocked de novo CpG methylation that is normally associated with FWA \ntransgene silencing. Furthermore, drm1 drm2 double mutants blocked de novo CpNpG \nand asymmetric methylation and gene silencing of the endogenous SUPERMAN (SUP) \ngene, which is normally triggered by an inverted SUP repeat. However, drm1 drm2 \ndouble mutants did not show reactivation of previously established SUPERMAN \nepigenetic silenced alleles. Thus, drm mutants prevent the establishment but not \nthe maintenance of gene silencing at FWA and SUP, suggesting that the DRMs \nencode the major de novo methylation enzymes affecting these genes.", "DNA methylation and histone modification exert epigenetic control over gene \nexpression. CHG methylation by CHROMOMETHYLASE3 (CMT3) depends on histone H3K9 \ndimethylation (H3K9me2), but the mechanism underlying this relationship is \npoorly understood. Here, we report multiple lines of evidence that CMT3 \ninteracts with H3K9me2-containing nucleosomes. CMT3 genome locations nearly \nperfectly correlated with H3K9me2, and CMT3 stably associated with \nH3K9me2-containing nucleosomes. Crystal structures of maize CMT3 homolog ZMET2, \nin complex with H3K9me2 peptides, showed that ZMET2 binds H3K9me2 via both bromo \nadjacent homology (BAH) and chromo domains. The structures reveal an aromatic \ncage within both BAH and chromo domains as interaction interfaces that capture \nH3K9me2. Mutations that abolish either interaction disrupt CMT3 binding to \nnucleosomes and show a complete loss of CMT3 activity in vivo. Our study \nestablishes dual recognition of H3K9me2 marks by BAH and chromo domains and \nreveals a distinct mechanism of interplay between DNA methylation and histone \nmodification.", "Chromodomains are thought to mediate protein-protein interactions between \nchromatin components. We have detected a chromodomain embedded within the \ncatalytic region of a predicted Arabidopsis DNA methyltransferase that is \ndiverged from other eukaryotic enzymes. The 791 residue \"chromomethylase\" (CMT1) \nis encoded by a floral transcript that is spliced from 20 exons and is present \nat only approximately 1/10(-7) of total mRNA. Genomic sequencing reveals an \nancient haplotype split at CMT1 between Col-0 + Metz and the other ecotypes \nexamined. In the Col-0 + Metz haplotype, alternative mRNA processing at intron \n13 truncates the coding region. In Ler, RLD, and No-0, similar truncation is \ncaused by insertion of an intact retrotransposon, Evelknievel, which is present \nas a single copy in Ler and RLD and is currently methylated and inactive. \nEvelknievel is found at this site on a single branch that connects the Ler, RLD, \nand No-0 ecotypes but is absent from the genomes of all other ecotypes examined. \nA stop codon within exon 6 of the Metz ecotype confirms that CMT1 is \nnonessential. Nevertheless, comparison to CMT1 of Cardaminopsis arenosa, an \noutcrossing relative, indicates conservation for DNA methyltransferase function. \nWe discuss how allelic diversity of CMT1 may reflect loosened selective \nconstraints in a self-fertilizing species such as Arabidopsis thaliana.", "Plants maintain cytosine methylation at CG and non-CG residues to control gene \nexpression and genome stability. In a screen for Arabidopsis mutants that alter \nmethylation and silencing of a densely methylated endogenous reporter gene, we \nrecovered 11 loss-of-function alleles in the CMT3 chromomethylase gene. The cmt3 \nmutants displayed enhanced expression and reduced methylation of the reporter, \nparticularly at non-CG cytosines. CNG methylation was also reduced at repetitive \ncentromeric sequences. Thus, CMT3 is a key determinant for non-CG methylation. \nThe lack of CMT homologs in animal genomes could account for the observation \nthat in contrast to plants, animals maintain primarily CG methylation.", "Many plant, animal, and fungal genomes contain cytosine DNA methylation in \nasymmetric sequence contexts (CpHpH, H = A, T, C). Although the enzymes \nresponsible for this methylation are unknown, it has been assumed that \nasymmetric methylation is maintained by the persistent activity of de novo \nmethyltransferases (enzymes capable of methylating previously unmodified DNA). \nWe recently reported that the DOMAINS REARRANGED METHYLASE (DRM) genes are \nrequired for de novo DNA methylation in Arabidopsis thaliana because drm1 drm2 \ndouble mutants lack the de novo methylation normally associated with transgene \nsilencing. In this study, we have used bisulfite sequencing and Southern blot \nanalysis to examine the role of the DRM loci in the maintenance of asymmetric \nmethylation. At some loci, drm1 drm2 double mutants eliminated all asymmetric \nmethylation. However, at the SUPERMAN locus, asymmetric methylation was only \ncompletely abolished in drm1 drm2 chromomethylase 3 (cmt3) triple mutant plants. \ndrm1 drm2 double mutants also showed a strong reduction of CpNpG (n = A, T, C, \nor G) methylation at some loci, but not at others. The drm1 drm2 cmt3 triple \nmutant plants did not affect CpG methylation at any locus tested, suggesting \nthat the primary CpG methylases are encoded by the MET1 class of genes. Although \nneither the drm1 drm2 double mutants nor the cmt3 single mutants show \nmorphological defects, drm1 drm2 cmt3 triple mutant plants show pleiotropic \neffects on plant development. Our results suggest that the DRM and CMT3 genes \nact in a partially redundant and locus-specific manner to control asymmetric and \nCpNpG methylation.", "A cytosine DNA methyltransferase containing a chromodomain, Zea \nmethyltransferase2 (Zmet2), was cloned from maize. The sequence of ZMET2 is \nsimilar to that of the Arabidopsis chromomethylases CMT1 and CMT3, with \nC-terminal motifs characteristic of eukaryotic and prokaryotic DNA \nmethyltransferases. We used a reverse genetics approach to determine the \nfunction of the Zmet2 gene. Plants homozygous for a Mutator transposable element \ninsertion into motif IX had a 13% reduction in methylated cytosines. DNA gel \nblot analysis of these plants with methylation-sensitive restriction enzymes and \nbisulfite sequencing of a 180-bp knob sequence showed reduced methylation only \nat CpNpG sites. No reductions in methylation were observed at CpG or asymmetric \nsites in heterozygous or homozygous mutant plants. Our research shows that \nchromomethylase Zmet2 is required for in vivo methylation of CpNpG sequences.", "Tomato fruit cells are characterized by a strong increase in nuclear ploidy \nduring fruit development. Average ploidy levels increased to similar levels \n(above 50C) in two distinct fruit tissues, pericarp and locular tissue. However, \nploidy profiles differed significantly between these two tissues suggesting a \ntissue-specific control of endoreduplication in tomato fruit. To determine \npossible relationships between endoreduplication and epigenetic mechanisms, the \nmethylation status of genomic DNA from pericarp and locular tissue of tomato \nfruit was analysed. Pericarp genomic DNA was characterized by an increase of CG \nand/or CNG methylation at the 5S and 18S rDNA loci and at gyspsy-like \nretrotransposon sequences during fruit growth. A sharp decrease of the global \nDNA methylation level together with a reduction of methylation at the rDNA loci \nwas also observed in pericarp during fruit ripening. Inversely, no major \nvariation of DNA methylation either global or locus-specific, was observed in \nlocular tissue. Thus, tissue-specific variations of DNA methylation are unlikely \nto be triggered by the induction of endoreduplication in fruit tissues, but may \nreflect tissue-specific ploidy profiles. Expression analysis of eight putative \ntomato DNA methyltransferases encoding genes showed that one chromomethylase \n(CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed \nin the pericarp during fruit growth and could be involved in the locus-specific \nincrease of methylation observed at this developmental phase in the pericarp.", "By data mining in the sequence of the Corynebacterium glutamicum ATCC 13032 \ngenome, six putative mycolyltransferase genes were identified that code for \nproteins with similarity to the N-terminal domain of the mycolic acid \ntransferase PS1 of the related C. glutamicum strain ATCC 17965. The genes \nidentified were designated cop1, cmt1, cmt2, cmt3, cmt4, and cmt5 ( cmt from \ncorynebacterium mycolyl transferases). cop1 encodes a protein of 657 amino \nacids, which is larger than the proteins encoded by the cmt genes with 365, 341, \n483, 483, and 411 amino acids. Using bioinformatics tools, it was shown that all \nsix gene products are equipped with signal peptides and esterase domains. \nProteome analyses of the cell envelope of C. glutamicum ATCC 13032 resulted in \nidentification of the proteins Cop1, Cmt1, Cmt2, and Cmt4. All six \nmycolyltransferase genes were used for mutational analysis. cmt4 could not be \nmutated and is considered to be essential. cop1 was found to play an additional \nrole in cell shape formation. A triple mutant carrying mutations in cop1, cmt1, \nand cmt2 aggregated when cultivated in MM1 liquid medium. This mutant was also \nno longer able to synthesize trehalose di coryno mycolate (TDCM). Since single \nand double mutants of the genes cop1, cmt1, and cmt2 could form TDCM, it is \nconcluded that the three genes, cop1, cmt1, and cmt2, are involved in TDCM \nbiosynthesis. The presence of the putative esterase domain makes it highly \npossible that cop1, cmt1, and cmt2 encode enzymes synthesizing TDCM from \ntrehalose monocorynomycolate.", "The contribution of epigenetic alterations to natural variation for gene \ntranscription levels remains unclear. In this study, we investigated the \nfunctional targets of the maize chromomethylase ZMET2 in multiple inbred lines \nto determine whether epigenetic changes conditioned by this chromomethylase are \nconserved or variable within the species. Gene expression microarrays were \nhybridized with RNA samples from the inbred lines B73 and Mo17 and from \nnear-isogenic derivatives containing the loss-of-function allele zmet2-m1. A set \nof 126 genes that displayed statistically significant differential expression in \nzmet2 mutants relative to wild-type plants in at least one of the two genetic \nbackgrounds was identified. Analysis of the transcript levels in both wild-type \nand mutant individuals revealed that only 10% of these genes were affected in \nzmet2 mutants in both B73 and Mo17 genetic backgrounds. Over 80% of the genes \nwith expression patterns affected by zmet2 mutations display variation for gene \nexpression between wild-type B73 and Mo17 plants. Further analysis was performed \nfor 7 genes that were transcriptionally silent in wild-type B73, but expressed \nin B73 zmet2-m1, wild-type Mo17, and Mo17 zmet2-m1 lines. Mapping experiments \nconfirmed that the expression differences in wild-type B73 relative to Mo17 \ninbreds for these genes were caused by cis-acting regulatory variation. \nMethylation-sensitive PCR and bisulfite sequencing demonstrated that for 5 of \nthese genes the CpNpG methylation in the wild-type B73 genetic background was \nsubstantially decreased in the B73 zmet2-m1 mutant and in wild-type Mo17. A \nsurvey of eight maize inbreds reveals that each of these 5 genes exhibit \ntranscriptionally silent and methylated states in some inbred lines and \nunmethylated, expressed states in other inbreds, providing evidence for natural \nvariation in epigenetic states for some maize genes.", "During embryogenesis there is a major switch from dependence upon \nmaternally-deposited products to reliance on products of the zygotic genome. In \nanimals, this so-called maternal-to-zygotic transition occurs following a period \nof transcriptional quiescence. Recently, we have shown that the early embryo in \nArabidopsis is also quiescent, a state inherited from the female gamete and \nlinked to specific patterns of H3K9 dimethylation and TERMINAL FLOWER2 (TFL2) \nlocalization. We also demonstrated that CHROMOMETHYLASE 3 (CMT3) is required for \nH3K9 dimethylation in the egg cell and for normal embryogenesis during the first \nfew divisions of the zygote. Subsequent analysis of CMT3 mutants points to a key \nrole in egg cell reprogramming by controlling silencing in both transposon and \neuchromatic regions. A speculative model of the CMT3-induced egg cell silencing \nis presented here, based on these results and current data from the literature \nsuggesting the potential involvement of small RNAs targeted to the egg cell, a \nprocess conceptually similar to the division of labor described in the male \ngametophyte for which we show that H3K9 modifications and TFL2 localization are \nreminiscent of the female gametophyte." ]	['http://www.uniprot.org/uniprot/CMT3_ARATH', 'http://www.uniprot.org/uniprot/CMT2_ARATH', 'http://www.uniprot.org/uniprot/CMT1_ARATH']
56b73c7a345adcac48000002	[ 26052092, 24339831 ]	train	Are circRNAs associated with diseases and traits?	yesno	Yes. Circular RNAs (circRNAs) play a crucial role in fine tuning the level of miRNA mediated regulation of gene expression by sequestering the miRNAs. Their interaction with disease associated miRNAs indicates that circular RNAs are important for disease regulation.	yes	[ "Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form \na covalently closed continuous loop and are highly represented in the eukaryotic \ntranscriptome. Recent studies have discovered thousands of endogenous circRNAs \nin mammalian cells. CircRNAs are largely generated from exonic or intronic \nsequences, and reverse complementary sequences or RNA-binding proteins (RBPs) \nare necessary for circRNA biogenesis. The majority of circRNAs are conserved \nacross species, are stable and resistant to RNase R, and often exhibit \ntissue/developmental-stage-specific expression. Recent research has revealed \nthat circRNAs can function as microRNA (miRNA) sponges, regulators of splicing \nand transcription, and modifiers of parental gene expression. Emerging evidence \nindicates that circRNAs might play important roles in atherosclerotic vascular \ndisease risk, neurological disorders, prion diseases and cancer; exhibit \naberrant expression in colorectal cancer (CRC) and pancreatic ductal \nadenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some \ndiseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are \nbecoming a new research hotspot in the field of RNA and could be widely involved \nin the processes of life. Herein, we review the formation and properties of \ncircRNAs, their functions, and their potential significance in disease.", "Circular RNAs are new players in regulation of post transcriptional gene \nexpression. Animal genomes express many circular RNAs from diverse genomic \nlocations. A recent study has validated a fairly large number of circular RNAs \nin human, mouse, and nematode. Circular RNAs play a crucial role in fine tuning \nthe level of miRNA mediated regulation of gene expression by sequestering the \nmiRNAs. Their interaction with disease associated miRNAs indicates that circular \nRNAs are important for disease regulation. In this paper we studied the \npotential association of circular RNAs (circRNA) with human diseases in two \ndifferent ways. Firstly, the interactions of circRNAs with disease associated \nmiRNAs were identified, following which the likelihood of a circRNA being \nassociated with a disease was calculated. For the miRNAs associated with \nindividual diseases, we constructed a network of predicted interactions between \nthe miRNAs and protein coding, long non-coding and circular RNA genes. We \ncarried out gene ontology (GO) enrichment analysis on the set of protein coding \ngenes in the miRNA- circRNA interactome of individual diseases to check the \nenrichment of genes associated with particular biological processes. Secondly, \ndisease associated SNPs were mapped on circRNA loci, and Argonaute (Ago) \ninteraction sites on circular RNAs were identified. We compiled a database of \ndisease-circRNA association in Circ2Traits (http://gyanxet-beta.com/circdb/), \nthe first comprehensive knowledgebase of potential association of circular RNAs \nwith diseases in human." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=diseases_category', 'http://www.disease-ontology.org/api/metadata/DOID:4', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004194']
62211d6f3a8413c65300006f	[ 29170496, 34453665, 33141028, 31217510, 30259366, 31160488, 26660425, 34269929, 29167634, 33650643, 27929395, 24865493, 34238421, 31556152, 31269210, 32480219, 34232572 ]	train	Are circRNAs susceptible to degradation by RNase R?	yesno	Currently, an increasing body of evidence has demonstrated that 1) majority of circRNAs are evolutionarily conserved across species, stable, and resistant to RNase R degradation.	no	[ "Circular RNAs (circRNAs) are a class of animal non-coding RNAs and play an \nimpor-tant role in animal growth and development. However, the expression and \nfunction of circRNAs in the pituitary gland of sheep are unclear. Transcriptome \nprofiling of circRNAs in the pituitary gland of sheep may enable us to \nunderstand their biological functions. In the present study, we identified \n10,226 circRNAs from RNA-seq data in the pituitary gland of prenatal and \npostnatal sheep. Reverse transcription PCR and DNA sequencing analysis confirmed \nthe presence of several circRNAs. Real-time RT-PCR analysis showed that sheep \ncircRNAs are resistant to RNase R digestion and are expressed in prenatal and \npostnatal pituitary glands. GO and KEGG enrichment analysis showed that host \ngenes of differentially expressed circRNAs are involved in the regulation of \nhormone secretion as well as in several pathways related to these processes. We \ndetermined that numerous circRNAs interact with pituitary-specific miRNAs that \nare involved in the biologic functions of the pituitary gland. Moreover, several \ncircRNAs contain at least one IRES element and open reading frame, indicating \ntheir potential to encode proteins. Our study provides comprehensive expression \nprofiles of circRNAs in the pituitary gland, thereby offering a valuable \nresource for circRNA biology in sheep.", "Author information:\n(1)School of Life Science, Hangzhou Institute for Advanced Study, University of \nChinese Academy of Sciences, Hangzhou, 310024, China.\n(2)State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of \nMolecular Andrology, CAS Center for Excellence in Molecular Cell Science, \nShanghai Institute of Biochemistry and Cell Biology, University of Chinese \nAcademy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.\n(3)CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition \nand Health, Shanghai Institutes for Biological Sciences, University of Chinese \nAcademy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.\n(4)School of Life Science and Technology, ShanghaiTech University, Shanghai, \n201210, China.\n(5)Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, \nHarvard Medical School, Boston, MA, 02115, USA.\n(6)School of Life Science, Hangzhou Institute for Advanced Study, University of \nChinese Academy of Sciences, Hangzhou, 310024, China. linglingchen@sibcb.ac.cn.\n(7)State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of \nMolecular Andrology, CAS Center for Excellence in Molecular Cell Science, \nShanghai Institute of Biochemistry and Cell Biology, University of Chinese \nAcademy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. \nlinglingchen@sibcb.ac.cn.\n(8)School of Life Science and Technology, ShanghaiTech University, Shanghai, \n201210, China. linglingchen@sibcb.ac.cn.", "Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs \ncharacterized by a covalently closed-loop structure generated through a special \ntype of alternative splicing termed back-splicing. Currently, an increasing body \nof evidence has demonstrated that 1) majority of circRNAs are evolutionarily \nconserved across species, stable, and resistant to RNase R degradation, and \noften exhibit cell-specific, and tissue-specific/developmental-stage-specific \nexpression and can be largely independent of the expression levels of the linear \nhost gene-encoded linear RNAs; 2) the biogenesis of circRNAs via back-splicing \nis different from the canonical splicing of linear RNAs; 3) circRNA biogenesis \nis regulated by specific cis-acting elements and trans-acting factors; 4) \ncircRNAs regulate biological and pathological processes by sponging miRNAs, \nbinding to RNA-binding protein (RBP), regulators of splicing and transcription, \nmodifiers of parental gene expression, and regulators of protein translation or \nbeing translated into peptides in various diseases; 5) circRNAs have been \nidentified for their enrichment and stability in exosomes and detected in body \nfluids such as human blood, saliva, and cerebrospinal fluids, suggesting that \nthese exo-circRNAs have potential applications as disease biomarkers and novel \ntherapeutic targets; 6) several circRNAs are regulated by oxidative stress and \nmediate reactive oxygen species (ROS) production as well as promote ROS-induced \ncellular death, cell apoptosis, and inflammation; 7) circRNAs have also emerged \nas important regulators in atherosclerotic cardiovascular disease, metabolic \ndisease, and cancers; 8) the potential mechanisms of several circRNAs have been \ndescribed in diseases, hinting at their potential applications as novel \ntherapeutic targets. In this highlight, we summarized the current understandings \nof the biogenesis and functions of circRNAs and their roles in ROS regulation \nand vascular inflammation-associated with cardiovascular and metabolic disease. \n(Word count: 272).", "MicroRNAs (miRs) are post-transcriptional regulators involved in the initiation \nand progression of many tumors. Recently, naturally occurring circular RNAs \n(circRNAs) have been described in eukaryotic cells:;they comprise a new class of \ngene regulators. Naturally occurring circular miR sponges, which induce miR \nloss-of-function, can prevent endogenous onco-miRs from binding to their cognate \nmRNA targets. These findings suggest that synthetic (artificial) circular RNAs \ncould be constructed as therapeutic molecular sponges to suppress harmful \nonco-miRs. Using enzymatic ligation, we designed and constructed a circular RNA \ncontaining both miR-21 and miR-93 binding sites. The synthetic circular sponge \nwas resistant to digestion with RNase R. Luciferase assays and functional \nexperiments showed that the circular multi-miR sponge was more stable than its \nlinear counterpart. Moreover, endogenous miR-21 and miR-93 were inhibited by the \ncircular sponge. In addition, the synthetic sponge significantly suppressed \ncellular proliferation and migration while promoting apoptosis in esophageal \ncarcinoma cells. Finally, in a murine xenograft model, the circular sponge \nsignificantly inhibited tumor growth in vivo. Taken together, these findings \nestablish that the design and construction of efficient artificial miR sponges \nrepresent a novel strategy to achieve miR loss-of-function in molecular cancer \ntherapeutics.", "As a type of novel noncoding RNAs, circular RNAs (circRNAs) have attracted great \ninterest due to its different characteristics from linear RNAs. They are \nabundantly and stably present in the transcriptome of eukaryotic cells, with \ndevelopment stage specificity and high conservatism. Because circRNAs are not \neasily degraded by exonuclease RNase R, they can exist more stably in body \nfluids than linear RNAs. Based on these unique conditions, circRNAs have great \npotential value as clinical diagnostic and prognostic markers. As the research \ndeepens, more and more evidences suggest that circRNAs may be closely associated \nwith many diseases, especially cancer. Numerous studies have demonstrated the \nabnormal expression of circRNAs in cancer, and they can regulate the occurrence \nand progression of cancer by targeting key genes. Abundant circRNAs in tissues \nand cells can be released into saliva and blood. It is undeniable that circRNAs \nare a class of promising future biomarkers for cancer diagnosis and prognosis. \nHere we summarize the researches on circRNAs and cancer over the past few years. \nWe expect this summary to be a stepping stone to further exploration of possible \ncircRNAs as cancer biomarkers.", "Author information:\n(1)The First Clinical Medical College, Nanjing University of Chinese Medicine, \nXianlin Road 138, Nanjing 210023, P.R. China.\n(2)Department of Head and Neck Surgery, Jiangsu Cancer Hospital and Jiangsu \nInstitute of Cancer Research and The Affiliated Cancer Hospital of Nanjing \nMedical University, Baiziting 42, Nanjing 210029, P.R. China.\n(3)The First Clinical School, Nanjing Medical University, Nanjing 210029, P.R. \nChina.\n(4)Department of Integrated Traditional and Western Medicine, Jinling Hospital, \nSchool of Medicine, Nanjing University, Nanjing 210002, P.R. China.\n(5)The Fourth Clinical School, Nanjing Medical University, Nanjing 210029, P.R. \nChina.\n(6)Center of Clinical Laboratory Science, Jiangsu Cancer Hospital and Jiangsu \nInstitute of Cancer Research and The Affiliated Cancer Hospital of Nanjing \nMedical University, Baiziting 42, Nanjing 210029, P.R. China.\n(7)Department of General Surgery, School of Medicine, Southeast University, 87 \nDing Jia Qiao, Nanjing 210009, P.R. China.\n(8)Center of Clinical Laboratory Science, Jiangsu Cancer Hospital and Jiangsu \nInstitute of Cancer Research and The Affiliated Cancer Hospital of Nanjing \nMedical University, Baiziting 42, Nanjing 210029, P.R. China slzhong@foxmail.com \njhtang@njmu.edu.cn.\n(9)The First Clinical Medical College, Nanjing University of Chinese Medicine, \nXianlin Road 138, Nanjing 210023, P.R. China slzhong@foxmail.com \njhtang@njmu.edu.cn.\n(10)Department of General Surgery, The First Affiliated Hospital with Nanjing \nMedical University, Nanjing 210029, P.R. China.", "In platelets, splicing and translation occur in the absence of a nucleus. \nHowever, the integrity and stability of mRNAs derived from megakaryocyte \nprogenitor cells remain poorly quantified on a transcriptome-wide level. As \ncircular RNAs (circRNAs) are resistant to degradation by exonucleases, their \nabundance relative to linear RNAs can be used as a surrogate marker for mRNA \nstability in the absence of transcription. Here we show that circRNAs are \nenriched in human platelets 17- to 188-fold relative to nucleated tissues and \n14- to 26-fold relative to samples digested with RNAse R to selectively remove \nlinear RNA. We compare RNAseq read depths inside and outside circRNAs to provide \nin silico evidence of transcript circularity, show that exons within circRNAs \nare enriched on average 12.7 times in platelets relative to nucleated tissues \nand identify 3162 genes significantly enriched for circRNAs, including some \nwhere all RNAseq reads appear to be derived from circular molecules. We also \nconfirm that this is a feature of other anucleate cells through transcriptome \nsequencing of mature erythrocytes, demonstrate that circRNAs are not enriched in \ncultured megakaryocytes, and demonstrate that linear RNAs decay more rapidly \nthan circRNAs in platelet preparations. Collectively, these results suggest that \ncirculating platelets have lost >90% of their progenitor mRNAs and that \ntranslation in platelets occurs against the backdrop of a highly degraded \ntranscriptome. Finally, we find that transcripts previously classified as \nproducts of reverse transcriptase template switching are both enriched in \nplatelets and resistant to decay, countering the recent suggestion that up to \n50% of rearranged RNAs are artifacts.", "Circular RNA (circRNA) has a closed-loop structure, and its 3' and 5' ends are \ndirectly covalently connected by reverse splicing, which is more stable than \nlinear RNA. CircRNAs usually possess microRNA (miRNA) binding sites, which can \nbind miRNAs and inhibit miRNA function. Many studies have shown that circRNAs \nare involved in the processes of cell senescence, proliferation and apoptosis \nand a series of signalling pathways, playing an important role in the prevention \nand treatment of diseases. CircRNAs are potential biological diagnostic markers \nand therapeutic targets for cardiovascular diseases (CVDs). To identify \nbiomarkers and potential effective therapeutic targets without toxicity for \nheart disease, we summarize the biogenesis, biology, characterization and \nfunctions of circRNAs in CVDs, hoping that this information will shed new light \non the prevention and treatment of CVDs.", "Circular RNAs (circRNAs) own unique capabilities to communicate with nucleic \nacids and ribonucleoproteins and are emerging as indispensable compositions of \nthe regulatory messages encoded in the genome. Due to lack of 3' termini, \ncircRNAs are more resistant to degradation by exonuclease RNase R and possess \ngreater stability than linear RNAs. Moreover, circRNAs can act as microRNA \n(miRNA) sponge and affect messenger RNA (mRNA) splicing and transcription. By \nvirtue of their great stability and elaborate regulatory mechanisms of gene \nexpression, circRNAs play important roles in certain physiological activities. \nThe development, homeostasis and stress response of the central nervous system \n(CNS) depend upon precise temporal and spatial regulation of gene networks. \nMoreover, emerging evidence has revealed that circRNAs are spatiotemporally \nregulated and dynamically expressed during brain development; therefore, they \ncan exert significant influences on CNS development and diseases. In this \nreview, we highlight the biogenesis of circRNAs and their central roles in \nregulation of CNS development and diseases.", "Circular RNA (circRNA) is a long non‑coding RNA molecule with a closed loop \nstructure lacking a 5'cap and 3'tail. circRNA is stable, difficult to cleave and \nresistant to RNA exonuclease or RNase R degradation. circRNA molecules have \nseveral clinical applications, especially in tumors. For instance, circRNA may \nbe used for non‑invasive diagnosis, therapy and prognosis. Exosomes play a \ncrucial role in the development of tumors. Exosomal circRNA in particular has \nled to increased research interest into tumorigenesis and tumor progression. \nAdditionally, exosomal circRNA plays a role in cell‑cell communication. Exosomal \ncircRNA facilitates tumor metastasis by altering the tumor microenvironment and \nthe pre‑metastatic niche. Additionally, studies have revealed the mechanism by \nwhich exosomal circRNA affects malignant progression through signal \ntransduction. Moreover, exosomal circRNA promotes tumor metastasis by regulating \ngene expression, RNA transcription and protein translation. In this review, the \nbiological features and clinical application of exosomal circRNA are described, \nhighlighting the underlying mechanisms through which they regulate tumor \nmetastasis. The application of circRNA as clinical diagnostic biomarkers and in \nthe development of novel therapeutic strategies is also discussed.", "Our understanding of the highly specialized functions for small non-coding \nsingle-stranded RNA (ssRNA) in the transcriptome of the human central nervous \nsystem (CNS) continues to evolve. Circular RNAs (circRNAs), a recently \ndiscovered class of ssRNA enriched in the brain and retina, are extremely stable \nand intrinsically resilient to degradation by exonuclease. Conventional methods \nof ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation \nrequiring free ribonucleotide ends may have considerably underestimated the \nquantity and significance of CNS circRNA in the CNS. Highly-specific small \nssRNAs, such as the ~23 nucleotide (nt) Homo sapien microRNA-7 (hsa-miRNA-7; chr \n9q21.32), are not only abundant in the human limbic system but are, in addition, \nassociated with a ~1400 nt circRNA for miRNA-7 (ciRS-7) in the same anatomical \nregion. Structurally, ciRS-7 contains about ~70 tandem anti-miRNA-7 sequences \nand acts as an endogenous, anti-complementary miRNA-7 \"sponge\" that attracts, \nbinds, and, hence, quenches, natural miRNA-7 functions. Using a combination of \nDNA and miRNA array technologies, enhanced LED-Northern and Western blot \nhybridization, and the magnesium-dependent exoribonuclease and circRNA-sensitive \nprobe RNaseR, here we provide evidence of a significantly misregulated \nciRS-7-miRNA-7-UBE2A circuit in sporadic Alzheimer's disease (AD) neocortex \n(Brodmann A22) and hippocampal CA1. Deficits in ciRS-7-mediated \"sponging \nevents\", resulting in excess ambient miRNA-7 appear to drive the selective \ndown-regulation in the expression of miRNA-7-sensitive mRNA targets, such as \nthat encoding the ubiquitin conjugating enzyme E2A (UBE2A; chr Xq24). UBE2A, \nwhich normally serves as a central effector in the ubiquitin-26S proteasome \nsystem, coordinates the clearance of amyloid peptides via proteolysis, is known \nto be depleted in sporadic AD brain and, hence, contributes to amyloid \naccumulation and the formation of senile plaque deposits. Dysfunction of \ncircRNA-miRNA-mRNA regulatory systems appears to represent another important \nlayer of epigenetic control over pathogenic gene expression programs in the \nhuman CNS that are targeted by the sporadic AD process.", "During pre-mRNA splicing, exons in the primary transcript are precisely \nconnected to generate an mRNA. Intron lariat RNAs are formed as by-products of \nthis process. In addition, some exonic circular RNAs (circRNAs) may also result \nfrom exon skipping as by-products. Lariat RNAs and circRNAs are both RNase R \nresistant RNAs. RNase R is a strong 3' to 5' exoribonuclease, which efficiently \ndegrades linear RNAs, such as mRNAs and rRNAs; therefore, the circular parts of \nlariat RNAs and the circRNAs can be segregated from eukaryotic total RNAs by \ntheir RNase R resistance. Thus, RNase R resistant RNAs could provide unexplored \nsplicing information not available from mRNAs. Analyses of these RNAs identified \nrepeating splicing phenomena, such as re-splicing of mature mRNAs and nested \nsplicing. Moreover, circRNA might function as microRNA sponges. There is an \nenormous variety of endogenous circRNAs, which are generally synthesized in \ncells and tissues.", "Circular RNA(circRNA)is a novel type of endogenous non-coding RNA.Most circRNAs \nact as microRNA(miRNA)sponges to regulate the expression of functional genes.In \naddition,some circRNAs can be translated and interact with RNA-binding proteins \nto perform biological functions.The expression of circRNAs is prevalent in \ntissues and body fluids,and their abnormal expression is related to tumor \nprogression.circRNAs are stable even under the treatment of RNase R because of \ntheir circular conformation.As circRNAs have construct stability,wide \nvariety,specific regulation of tumor progression and high expression in body \nfluids,it is potential for circRNAs to serve as candidate diagnostic,prognostic \nand therapeutic targets.However,the knowledge about circRNAs remains poor.In \naddition to the not completely resolved functions and generation mechanisms of \ncircRNAs,the annotations of circRNAs are also waiting for expanding.Here,we \nreview the generation mechanisms,biological functions,and application of \ncircRNAs in tumor research,aiming to provide integrated information for the \nfuture research.", "BACKGROUND: In addition to non-coding RNAs (lncRNAs) and microRNAs (miRNAs), \ncircular RNAs (circRNAs) are endogenous RNAs with various functions, which have \nrecently become a research hotspot. CircRNAs are a kind of closed circular RNA \nmolecule widely existing in transcriptomes. Due to lack of free ends, they are \nnot easily cleaved by RNase R, thus avoiding degradation. They are more stable \nthan linear RNAs.\nMETHODS: Data were collected through PubMed. The following search terms were \nused: \"circular RNA,\" \"circRNA,\" \"cancer,\" \"mechanism,\" \"biogenesis,\" \n\"biomarker,\" \"diagnosis.\" Only articles published in English were included.\nRESULTS: Most circRNAs express tissue/developmental stage specificity. Moreover, \ncircRNAs are involved in the regulation of a variety of biological activities. \nIn this review, we discuss the formation, classification, and biological \nfunctions of circRNAs, especially their molecular diagnostic values in common \ncancers, including gastric cancer (hsa_circ_002059, circ_LARP4, \nhsa_circ_0000190, hsa_circ_0000096, circ-SFMBT2, and circ_PVT1), hepatocellular \ncarcinoma (circ_104075, circRNA_100338, circ_MTO1, and circZKSCAN1), colorectal \ncancer (hsa_circ_0136666 and hsa_circ_0000523), lung cancer (hsa_circ_0006427, \ncirc_100876, and circ_ABCB10), breast cancer (hsa_circ_0089105, circAGFG1, and \ncircEPSTI1), bladder cancer (circFNDC3B and circTFRC), and esophageal squamous \ncell carcinoma (circ_100876 and circ-DLG1).\nCONCLUSION: CircRNAs not only play important roles in tumorigenesis, but also \nmay become new diagnostic biomarkers.", "Thousands of eukaryotic protein-coding genes generate circular RNAs that have \ncovalently linked ends and are resistant to degradation by exonucleases. To \nprove their circularity as well as biochemically enrich these transcripts, it \nhas become standard in the field to use the 3'-5' exonuclease RNase R. Here, we \ndemonstrate that standard protocols involving RNase R can fail to digest >20% of \nall highly expressed linear RNAs, but these shortcomings can largely be \novercome. RNAs with highly structured 3' ends, including snRNAs and histone \nmRNAs, are naturally resistant to RNase R, but can be efficiently degraded once \na poly(A) tail has been added to their ends. In addition, RNase R stalls in the \nbody of many polyadenylated mRNAs, especially at G-rich sequences that have been \npreviously annotated as G-quadruplex (G4) structures. Upon replacing K+ (which \nstabilizes G4s) with Li+ in the reaction buffer, we find that RNase R is now \nable to proceed through these sequences and fully degrade the mRNAs in their \nentirety. In total, our results provide important improvements to the current \nmethods used to isolate circular RNAs as well as a way to reveal RNA structures \nthat may naturally inhibit degradation by cellular exonucleases.", "Author information:\n(1)Hengyang Medical School, Institute of Cardiovascular Disease, Key Laboratory \nfor Arteriosclerology of Hunan Province, Hunan International Scientific and \nTechnological Cooperation Base of Arteriosclerotic Disease, University of South \nChina, Hengyang, 421001, China; Institute of Biochemistry & Molecular Biology, \nUniversity of South China, Hengyang, 421001, China; Key Laboratory of Ecological \nEnvironment and Critical Human Diseases Prevention of Hunan Province Department \nof Education, Hengyang, 421001, China; Hunan Province Cooperative Innovation \nCenter for Molecular Target New Drug Study, Hengyang, 421001, China.\n(2)Hengyang Medical School, Institute of Cardiovascular Disease, Key Laboratory \nfor Arteriosclerology of Hunan Province, Hunan International Scientific and \nTechnological Cooperation Base of Arteriosclerotic Disease, University of South \nChina, Hengyang, 421001, China; Institute of Biochemistry & Molecular Biology, \nUniversity of South China, Hengyang, 421001, China.\n(3)Hengyang Medical School, Institute of Cardiovascular Disease, Key Laboratory \nfor Arteriosclerology of Hunan Province, Hunan International Scientific and \nTechnological Cooperation Base of Arteriosclerotic Disease, University of South \nChina, Hengyang, 421001, China. Electronic address: zsjiang2005@163.com.", "Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that have been \nshown to play a role in normal development, homeostasis, and disease, including \ncancer. CircRNAs are formed through a process called back-splicing, which \nresults in a covalently closed loop with a nonlinear back-spliced junction \n(BSJ). In general, circRNA BSJs are predicted in RNA sequencing data using one \nof numerous circRNA detection algorithms. Selected circRNAs are then typically \nvalidated using an orthogonal method such as reverse transcription quantitative \nPCR (RT-qPCR) with circRNA-specific primers. However, linear transcripts \noriginating from endogenous trans-splicing can lead to false-positive signals \nboth in RNA sequencing and in RT-qPCR experiments. Therefore, it is essential to \nperform the RT-qPCR validation step only after linear RNAs have been degraded \nusing an exonuclease such as ribonuclease R (RNase R). Several RNase R protocols \nare available for circRNA detection using RNA sequencing or RT-qPCR. These \nprotocols-which vary in enzyme concentration, RNA input amount, incubation \ntimes, and cleanup steps-typically lack a detailed validated standard protocol \nand fail to provide a range of conditions that deliver accurate results. As \nsuch, some protocols use RNase R concentrations that are too high, resulting in \npartial degradation of the target circRNAs. Here, we describe an optimized \nworkflow for circRNA validation, combining RNase R treatment and RT-qPCR. First, \nwe outline the steps for circRNA primer design and qPCR assay validation. Then, \nwe describe RNase R treatment of total RNA and, importantly, a subsequent \nessential buffer cleanup step. Lastly, we outline the steps to perform the \nRT-qPCR and discuss the downstream data analyses. © 2021 Wiley Periodicals LLC. \nBasic Protocol 1: CircRNA primer design and qPCR assay validation Basic Protocol \n2: RNase R treatment, cleanup, and RT-qPCR." ]	nan
6228b3553a8413c65300008b	[ 30428483, 29803556, 33015046, 30444648, 30654635, 33074445, 31295021, 33133146, 32914551, 32844346, 30597308, 33761053, 31171902 ]	train	Are circular RNAs implicated in diseases of the eye?	yesno	Circular RNA (circRNA) are associated with several eye diseases.	yes	[ "Long non-coding RNAs are 200 nucleotide long RNA molecules which lack or have \nlimited protein-coding potential. They can regulate protein formation through \nseveral different mechanisms. Similarly, circular RNAs are reported to play a \ncritical role in post-transcriptional gene regulation. Changes in the expression \npattern of these molecules are established to underline various diseases, \nincluding cancer, cardiovascular, neurological and immunological disorders. \nRecent studies suggest that they are differentially expressed both in healthy \nocular tissues as well as in eye pathologies, such as neovascularization, \nproliferative vitreoretinopathy, glaucoma, cataract, ocular malignancy or even \nstrabismus. Aetiology of ocular diseases is multifactorial and combines genetic \nand environmental factors, including epigenetic and non-coding RNAs. In \naddition, disorders like diabetic retinopathy or age-related macular \ndegeneration lack biomarkers for early detection as well as effective treatment \nmethods that will allow controlling the disease progression at its early stages. \nThe newly discovered non-coding RNAs seem to be the ideal candidate for novel \nmolecular markers and therapeutic strategies. In this review, we summarize \ncurrent knowledge about gene expression regulators - long non-coding and \ncircular RNA molecules in eye diseases.", "Cystathionine-β-synthase (CBS) gene encodes L-serine hydrolyase which catalyzes \nβ-reaction to condense serine with homocysteine (Hcy) by pyridoxal-5'-phosphate \nhelps to form cystathionine which in turn is converted to cysteine. CBS resides \nat the intersection of transmethylation, transsulfuration, and remethylation \npathways, thus lack of CBS fundamentally blocks Hcy degradation; an essential \nstep in glutathione synthesis. Redox homeostasis, free-radical detoxification \nand one-carbon metabolism (Methionine-Hcy-Folate cycle) require CBS and its \ndeficiency leads to hyperhomocysteinemia (HHcy) causing retinovascular \nthromboembolism and eye-lens dislocation along with vascular cognitive \nimpairment and dementia. HHcy results in retinovascular, coronary, cerebral and \nperipheral vessels' dysfunction and how it causes metabolic dysregulation \npredisposing patients to serious eye conditions remains unknown. HHcy \norchestrates inflammation and redox imbalance via epigenetic remodeling leading \nto neurovascular pathologies. Although circular RNAs (circRNAs) are dominant \nplayers regulating their parental genes' expression dynamics, their importance \nin ocular biology has not been appreciated. Progress in gene-centered analytics \nvia improved microarray and bioinformatics are enabling dissection of genomic \npathways however there is an acute under-representation of circular RNAs in \nocular disorders. This study undertook circRNAs' analysis in the eyes of CBS \ndeficient mice identifying a pool of 12532 circRNAs, 74 exhibited differential \nexpression profile, ∼27% were down-regulated while most were up-regulated \n(∼73%). Findings also revealed several microRNAs that are specific to each \ncircRNA suggesting their roles in HHcy induced ocular disorders. Further \nanalysis of circRNAs helped identify novel parental genes that seem to influence \ncertain eye disease phenotypes.", "A newly rediscovered subclass of noncoding RNAs, circular RNAs (circRNAs), is \nproduced by a back-splicing mechanism with a covalently closed loop structure. \nThey not only serve as the sponge for microRNAs (miRNAs) and proteins but also \nregulate gene expression and epigenetic modification, translate into peptides, \nand generate pseudogenes. Dysregulation of circRNA expression has opened a new \nchapter in the etiology of various human disorders, including cancer and \ncardiovascular, neurodegenerative, and ocular diseases. Recent studies \nrecognized the vital roles that circRNAs played in the pathogenesis of various \neye diseases, highlighting circRNAs as promising biomarkers for diagnosis and \nassessment of progression and prognosis. Interventions targeting circRNAs \nprovide insights for developing novel treatments for these ocular diseases. This \nreview summarizes our current perception of the properties, biogenesis, and \nfunctions of circRNAs and the development of circRNA researches related to \nophthalmologic diseases, including diabetic retinopathy, age-related macular \ndegeneration, retinopathy of prematurity, glaucoma, corneal neovascularization, \ncataract, pterygium, proliferative vitreoretinopathy, retinoblastoma, and ocular \nmelanoma.", "Circular RNAs (circRNAs) are being hailed as a newly rediscovered class of \ncovalently closed transcripts that are produced via alternative, noncanonical \npre-mRNA back-splicing events. These single-stranded RNA molecules have been \nidentified in organisms ranging from the worm (Cortés-López et al. 2018. BMC \nGenomics, 19: 8; Ivanov et al. 2015. Cell Rep. 10: 170-177) to higher eukaryotes \n(Yang et al. 2017. Cell Res. 27: 626-641) to plants (Li et al. 2017. Biochem. \nBiophys. Res. Commun. 488: 382-386). At present, research on circRNAs is an \nactive area because of their diverse roles in development, health, and diseases. \nPartly because their circularity makes them resistant to degradation, they hold \ngreat promise as unique biomarkers for ocular and central nervous system (CNS) \ndisorders. We believe that further work on their applications could help in \ndeveloping them as \"first-in-class\" diagnostics, therapeutics, and prognostic \ntargets for numerous eye conditions. Interestingly, many circRNAs play key roles \nin transcriptional regulation by acting as miRNAs sponges, meaning that they \nserve as master regulators of RNA and protein expression. Since the retina is an \nextension of the brain and is part of the CNS, we highlight the current state of \ncircRNA biogenesis, properties, and function and we review the crucial roles \nthat they play in the eye and the brain. We also discuss their regulatory roles \nas miRNA sponges, regulation of their parental genes or linear mRNAs, \ntranslation into micropeptides or proteins, and responses to cellular stress. We \nposit that future advances will provide newer insights into the fields of RNA \nmetabolism in general and diseases of the aging eye and brain in particular. \nFurthermore, in keeping pace with the rapidly evolving discipline of \nRNA\"omics\"-centered metabolism and to achieve uniformity among researchers, we \nrecently introduced the term \"cromics\" (circular ribonucleic acids based omics) \n(Singh et al. 2018. Exp. Eye Res. 174: 80-92).", "Circular RNAs are important regulators of multiple biological processes such as \norganogenesis and oncogenesis. Although the bulk of concerning studies focused \non revealing their diversified roles in various types of cancers, reports began \nto accumulate in cardiovascular field these days. We summarize circular RNAs \nimplicated in cardiovascular diseases, aiming to highlight the advances in the \nknowledge of such diseases and their potential of being promising target for \ndiagnosis and therapy.", "Epigenetic memory plays crucial roles in gene regulation. It not only modulates \nthe expression of specific genes but also has ripple effects on transcription as \nwell as translation of other genes. Very often an alteration in expression \noccurs either via methylation or demethylation. In this context, \"1-carbon \nmetabolism\" assumes a special significance since its dysregulation by higher \nlevels of homocysteine; Hcy (known as hyperhomocysteinemia; HHcy), a byproduct \nof \"1-Carbon Metabolism\" during methionine biosynthesis leads to serious \nimplications in cardiovascular, renal, cerebrovascular systems, and a host of \nother conditions. Currently, the circular RNAs (circRNAs) generated via \nnon-canonical back-splicing events from the pre-mRNA molecules are at the center \nstage for their essential roles in diseases via their epigenetic manifestations. \nWe recently identified a circular RNA transcript (circGRM4) that is \nsignificantly upregulated in the eye of cystathionine β-synthase-deficient mice. \nWe also discovered a concurrent over-expression of the mGLUR4 receptor in the \neyes of these mice. In brief, circGRM4 is selectively transcribed from its \nparental mGLUR4 receptor gene (GRM4) functions as a \"molecular-sponge\" for the \nmiRNAs and results into excessive turnover of the mGLUR4 receptor in the eye in \nresponse to extremely high circulating glutamate concentration. We opine that \nthis epigenetic manifestation potentially predisposes HHcy people to \nretinovascular malfunctioning.", "Circular RNAs (circRNAs), as with other noncoding RNAs, have emerged as novel \nmolecules of interest in gene regulation and in the development of many \ndiseases. However, the expression and function of circRNAs in \ninflammation-induced lymphangiogenesis (LG) are still unknown. Microarray \nprofiling in inflamed human lymphatic endothelial cells identified 82 \ndifferentially expressed circRNAs, including 6 downregulated and 76 upregulated \ncircRNAs. One of the top 10 upregulated circRNAs, cZNF609, was selected for \nsubsequent quantitative real-time PCR validation, and was found to be \nsignificantly upregulated in inflamed corneas from both mouse and human eyes. \nThe expression of miR-184 was significantly lower in inflamed corneas than in \ncontrol ones, which suggested that cZNF609 might serve as a sponge for miR-184. \nThe expression of heparanase, a potential target gene of miR-184, was \nsignificantly increased in inflamed corneas. Therefore, circRNAs may serve as \npotential regulators of corneal LG. These findings lay a foundation for \nfunctional research on circRNAs in corneal LG pathogenesis.", "Circular RNAs are characterized as a class of covalently closed circular RNA \ntranscripts and are associated with a variety of cellular processes and \nneurological diseases by sponging microRNAs. Expression profiling of circular \nRNAs in glaucoma, which is a form of optic neuropathy, has not been performed to \ndate. The most common characteristic of all forms of glaucoma is the loss of \nretinal ganglion cells. While the pathogenesis of glaucoma is not fully \nunderstood, intraocular pressure is unquestionably the only proven modifiable \nfactor which makes chronic ocular hypertension (COH) animals the classical \nglaucoma models. Based on these findings, we completed the first in-depth study \nof rat retinal circular RNA expression profiling to identify probable biomarkers \nfor the diagnosis of glaucoma. Two ocular hypertension models were induced by \nepiscleral vein ligation (EVL) and microbead injection in rats. Overall, 15,819 \ncircular RNA were detected. Furthermore, 3,502 differentially expressed circular \nRNAs verified in both COH rats were identified, of which 691 were upregulated \nand 2,811 were downregulated. Seven significantly downregulated (both \nlog2FoldChange < -2.5 and adjusted P < 0.001) and seven significantly \nupregulated (both log2FoldChange > 2.5 and adjusted P < 0.001) circular RNAs \nwere shown. Six target microRNAs aligned with the top 14 circular RNAs were \nidentified. According to the construction of the circular RNA-microRNA network \nand circBase information, only RNO_CIRCpedia_1775 had the homologous \nhsa_circ_0023826 in the human genome. The hsa_circ_0023826 and mRNA of the host \ngene TENM4 (teneurin transmembrane protein 4) were validated in aqueous humor \nsamples of five glaucoma patients and five cataract control patients. The \nexpression of hsa_circ_0023826 showed a significant decrease in glaucoma \npatients, while TENM4 mRNA showed no significant difference compared to cataract \npatients (P = 0.024 and P = 0.294, respectively). The results of this study \ncomprehensively characterized the expression profiles of circular RNA in \nglaucoma-affected eyes, as verified by two different ocular hypertension rat \nmodels. Together with the target microRNAs underlying the top differentially \nexpressed circular RNAs, a new target of hsa_circ_0023826 and its host gene \nTENM4 were identified and further verified in the aqueous humor of glaucoma \npatients, indicating a promising biomarker for the disease.", "PURPOSE: This study aimed to determine whether circular RNAs (circRNAs) in whole \nblood could be served as novel non-invasive biomarkers for proliferative \ndiabetic retinopathy (PDR).\nMETHODS: This retrospective cross-sectional study comprised 34 healthy \nparticipants, 34 PDR patients and 34 non-proliferative DR (NPDR) patients. \nHigh-throughput whole transcriptome sequencing was performed to explore the \nexpression profile of circRNAs in the whole blood, and the candidate circRNAs \nwere validated by quantitative real-time polymerase chain reaction (qRT-PCR). \nReceiver operating characteristic (ROC) analysis evaluated the ability of these \ncandidate circRNAs in discriminating PDR patients from NPDR patients and healthy \nsubjects. Finally, the networks of circRNA-miRNA-mRNA based on the candidate \ncircRNAs were constructed.\nRESULTS: Using sequencing and qRT-PCR, hsa_circ_0001953 was found to be elevated \nin PDR patients in contrast with the other two groups. Statistical analysis \nshowed that the expression levels of hsa_circ_0001953 in PDR patients were \npositively related to the duration of diabetes and HbAc1. Receiver operating \ncharacteristic (ROC) curve analysis revealed that hsa_circ_0001953 was \nassociated with a high diagnostic accuracy in discriminating PDR patients from \nNPDR patients and healthy controls, resulting in an area under the curve (AUC) \nof 0.87 and 0.92, respectively. The circRNA-miRNA-target gene networks for \nhsa_circ_0001953 showed that hsa_circ_0001953 could interact with dozens of \nmiRNAs and some targeted mRNAs have been potentially involved in the \npathogenesis of diabetes.\nCONCLUSION: The present findings indicate that hsa_circ_0001953 in the whole \nblood may serve as a novel diagnostic biomarker and potential therapeutic target \nfor PDR.", "Retinoblastoma (RB) is an intraocular malignancy that mainly occurs in infants \nand young children under 5 years of age. Circular RNA hsa_circ_0000034 \n(circ_0000034) was reported to be upregulated in RB tissues. Nevertheless, the \nfunction and mechanism of circ_0000034 in RB are unclear. Expression of \ncirc_0000034, microRNA-361-3p (miR-361-3p), and a disintegrin and \nmetalloproteinase 19 (ADAM19) was examined via quantitative real-time polymerase \nchain reaction (qRT-PCR). Cell viability, migration, invasion, and apoptosis \nwere determined though Cell Counting Kit-8 (CCK-8), transwell, or flow cytometry \nassays. Caspase-3 activity was detected using a caspase-3 activity assay kit. \nSome protein levels were examined using Western blot analysis. Dual-luciferase \nreporter assay, RNA immunoprecipitation (RIP) assay, or RNA pull-down assay were \nperformed to verify the relationship between circ_0000034 or ADAM19 and \nmiR-361-3p. The function of circ_0000034 in vivo was confirmed via animal \nexperiment. We verified that circ_0000034 expression was elevated in RB tissues \nand cells. Circ_0000034 silencing reduced RB growth in vivo, repressed \nviability, migration, invasion, and EMT, and induced apoptosis of RB cells in \nvitro. Circ_0000034 acted as a sponge for miR-361-3p, which targeted ADAM19 in \nRB cells. Furthermore, the inhibition of miR-361-3p restored circ_0000034 \nknockdown-mediated impacts on viability, migration, invasion, apoptosis, and EMT \nof RB cells. Moreover, ADAM19 overexpression abolished the influence of \nmiR-361-3p mimic on viability, migration, invasion, apoptosis, and EMT of RB \ncells. Circ_0000034 expedited RB progression through upregulating ADAM19 via \nsponging miR-361-3p, which indicated that circ_0000034 might a target for RB \ntherapy.", "Author information:\n(1)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The \nFourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.\n(2)Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical \nUniversity, Nanjing, China.\n(3)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.\n(4)Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan \nUniversity, Shanghai, China.\n(5)The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China; The \nFourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China. \nElectronic address: jqin710@vip.sina.com.\n(6)Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical \nUniversity, Nanjing, China; Eye Institute, Eye & ENT Hospital, Shanghai Medical \nCollege, Fudan University, Shanghai, China. Electronic address: \ndr_zhaochen@163.com.\n(7)Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan \nUniversity, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University), \nKey Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key \nLaboratory of Visual Impairment and Restoration (Fudan University), Shanghai, \nChina. Electronic address: biao.yan@fdeent.org.", "In diabetic patients, diabetic retinopathy (DR) is the leading cause of \nblindness and seriously affects the quality of life. However, current treatment \nmethods of DR are not satisfactory. Advances have been made in understanding \nabnormal protein interactions and signaling pathways in DR pathology, but little \nis known about epigenetic regulation. Non-coding RNAs, such as circular RNAs \n(circRNAs), have been shown to be associated with DR. In this review, we \nsummarized the function of circRNAs and indicated their roles in the \npathogenesis of DR, which may provide new therapeutic targets for clinical \ntreatment.", "Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs \nproduced by back-splicing. They are found to be expressed in eukaryotic cells \nand play certain roles in various cellular functions, including fibrosis, cell \nproliferation, differentiation, apoptosis and angiogenesis. Dysregulated \ncircRNAs are found in several human disorders including, malignancy, vascular, \ninflammatory as well as nervous diseases. Although, increasing evidence suggests \nthat circRNAs may also contribute in different ocular diseases, the outline of \ncircRNAs in ocular diseases remains obscure. In this review we consider the \ncurrent state of knowledge regarding the potential role and underlying mechanism \nof circRNAs in ocular diseases including pterygium, age-related cataract, \nglaucoma, diabetic retinopathy, retinoblastoma, retinal vascular dysfunction and \nhyperhomocysteinemia induced ocular diseases, emphasizing that circRNAs could be \npromising biomarkers for the diagnosis and prognosis evaluation. Future \ncircRNAs-targeted intervention may become a novel therapeutic tool for the \ntreatment of ocular diseases." ]	nan
553d02c1f321868558000012	[ 19562753, 16630819, 21175683, 17387144, 16859531, 19073165, 18282512, 16533910, 19698106, 18279518 ]	train	Are conserved noncoding elements associated with developmental genes?	yesno	Yes. Numerous studies suggest that conserved noncoding elements span developmental regulatory genes and define regulatory domains.	yes	[ "Fibroblast growth factors (Fgfs) encode small signaling proteins that help \nregulate embryo patterning. Fgfs fall into seven families, including FgfD. \nNonvertebrate chordates have a single FgfD gene; mammals have three (Fgf8, \nFgf17, and Fgf18); and teleosts have six (fgf8a, fgf8b, fgf17, fgf18a, fgf18b, \nand fgf24). What are the evolutionary processes that led to the structural \nduplication and functional diversification of FgfD genes during vertebrate \nphylogeny? To study this question, we investigated conserved syntenies, patterns \nof gene expression, and the distribution of conserved noncoding elements (CNEs) \nin FgfD genes of stickleback and zebrafish, and compared them with data from \ncephalochordates, urochordates, and mammals. Genomic analysis suggests that \nFgf8, Fgf17, Fgf18, and Fgf24 arose in two rounds of whole genome duplication at \nthe base of the vertebrate radiation; that fgf8 and fgf18 duplications occurred \nat the base of the teleost radiation; and that Fgf24 is an ohnolog that was lost \nin the mammalian lineage. Expression analysis suggests that ancestral \nsubfunctions partitioned between gene duplicates and points to the evolution of \nnovel expression domains. Analysis of CNEs, at least some of which are candidate \nregulatory elements, suggests that ancestral CNEs partitioned between gene \nduplicates. These results help explain the evolutionary pathways by which the \ndevelopmentally important family of FgfD molecules arose and the deduced \nprinciples that guided FgfD evolution are likely applicable to the evolution of \ndevelopmental regulation in many vertebrate multigene families.", "The most highly conserved noncoding elements (HCNEs) in mammalian genomes \ncluster within regions enriched for genes encoding developmentally important \ntranscription factors (TFs). This suggests that HCNE-rich regions may contain \nkey regulatory controls involved in development. We explored this by examining \nhistone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich \nloci. We identified a specific modification pattern, termed \"bivalent domains,\" \nconsisting of large regions of H3 lysine 27 methylation harboring smaller \nregions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF \ngenes expressed at low levels. We propose that bivalent domains silence \ndevelopmental genes in ES cells while keeping them poised for activation. We \nalso found striking correspondences between genome sequence and histone \nmethylation in ES cells, which become notably weaker in differentiated cells. \nThese results highlight the importance of DNA sequence in defining the initial \nepigenetic landscape and suggest a novel chromatin-based mechanism for \nmaintaining pluripotency.", "One of the key discoveries of vertebrate genome sequencing projects has been the \nidentification of highly conserved noncoding elements (CNEs). Some \ncharacteristics of CNEs include their high frequency in mammalian genomes, their \npotential regulatory role in gene expression, and their enrichment in gene \ndeserts nearby master developmental genes. The abnormal development of neural \ncrest cells (NCCs) leads to a broad spectrum of congenital malformation(s), \ntermed neurocristopathies, and/or tumor predisposition. Here we review recent \nfindings that disruptions of CNEs, within or at long distance from the coding \nsequences of key genes involved in NCC development, result in neurocristopathies \nvia the alteration of tissue- or stage-specific long-distance regulation of gene \nexpression. While most studies on human genetic disorders have focused on \nprotein-coding sequences, these examples suggest that investigation of genomic \nalterations of CNEs will provide a broader understanding of the molecular \netiology of both rare and common human congenital malformations.", "We report evidence for a mechanism for the maintenance of long-range conserved \nsynteny across vertebrate genomes. We found the largest mammal-teleost conserved \nchromosomal segments to be spanned by highly conserved noncoding elements \n(HCNEs), their developmental regulatory target genes, and phylogenetically and \nfunctionally unrelated \"bystander\" genes. Bystander genes are not specifically \nunder the control of the regulatory elements that drive the target genes and are \nexpressed in patterns that are different from those of the target genes. \nReporter insertions distal to zebrafish developmental regulatory genes pax6.1/2, \nrx3, id1, and fgf8 and miRNA genes mirn9-1 and mirn9-5 recapitulate the \nexpression patterns of these genes even if located inside or beyond bystander \ngenes, suggesting that the regulatory domain of a developmental regulatory gene \ncan extend into and beyond adjacent transcriptional units. We termed these \nchromosomal segments genomic regulatory blocks (GRBs). After whole genome \nduplication in teleosts, GRBs, including HCNEs and target genes, were often \nmaintained in both copies, while bystander genes were typically lost from one \nGRB, strongly suggesting that evolutionary pressure acts to keep the single-copy \nGRBs of higher vertebrates intact. We show that loss of bystander genes and \nother mutational events suffered by duplicated GRBs in teleost genomes permits \ntarget gene identification and HCNE/target gene assignment. These findings \nexplain the absence of evolutionary breakpoints from large vertebrate \nchromosomal segments and will aid in the recognition of position effect \nmutations within human GRBs.", "BACKGROUND: All vertebrates share a remarkable degree of similarity in their \ndevelopment as well as in the basic functions of their cells. Despite this, \nattempts at unearthing genome-wide regulatory elements conserved throughout the \nvertebrate lineage using BLAST-like approaches have thus far detected noncoding \nconservation in only a few hundred genes, mostly associated with regulation of \ntranscription and development.\nRESULTS: We used a unique combination of tools to obtain regional global-local \nalignments of orthologous loci. This approach takes into account shuffling of \nregulatory regions that are likely to occur over evolutionary distances greater \nthan those separating mammalian genomes. This approach revealed one order of \nmagnitude more vertebrate conserved elements than was previously reported in \nover 2,000 genes, including a high number of genes found in the membrane and \nextracellular regions. Our analysis revealed that 72% of the elements identified \nhave undergone shuffling. We tested the ability of the elements identified to \nenhance transcription in zebrafish embryos and compared their activity with a \nset of control fragments. We found that more than 80% of the elements tested \nwere able to enhance transcription significantly, prevalently in a \ntissue-restricted manner corresponding to the expression domain of the \nneighboring gene.\nCONCLUSION: Our work elucidates the importance of shuffling in the detection of \ncis-regulatory elements. It also elucidates how similarities across the \nvertebrate lineage, which go well beyond development, can be explained not only \nwithin the realm of coding genes but also in that of the sequences that \nultimately govern their expression.", "Pan-vertebrate developmental cis-regulatory elements are discernible as highly \nconserved noncoding elements (HCNEs) and are often dispersed over large areas \naround the pleiotropic genes whose expression they control. On the loci of two \ndevelopmental transcription factor genes, SOX3 and PAX6, we demonstrate that \nHCNEs conserved between human and zebrafish can be systematically and reliably \ntested for their regulatory function in multiple stable transgenes in zebrafish, \nand their genomic reach estimated with confidence using synteny conservation and \nHCNE density along these loci. HCNEs of both human and zebrafish function as \nspecific developmental enhancers in zebrafish. We show that human HCNEs result \nin expression patterns in zebrafish equivalent to those in mouse, establishing \nzebrafish as a suitable model for large-scale testing of human developmental \nenhancers. Orthologous human and zebrafish enhancers underwent functional \nevolution within their sequence and often directed related but non-identical \nexpression patterns. Despite an evolutionary distance of 450 million years, one \npax6 HCNE drove expression in identical areas when comparing zebrafish vs. human \nHCNEs. HCNEs from the same area often drive overlapping patterns, suggesting \nthat multiple regulatory inputs are required to achieve robust and precise \ncomplex expression patterns exhibited by developmental genes.", "Sequence conservation has traditionally been used as a means to target \nfunctional regions of complex genomes. In addition to its use in identifying \ncoding regions of genes, the recent availability of whole genome data for a \nnumber of vertebrates has permitted high-resolution analyses of the noncoding \n\"dark matter\" of the genome. This has resulted in the identification of a large \nnumber of highly conserved sequence elements that appear to be preserved in all \nbony vertebrates. Further positional analysis of these conserved noncoding \nelements (CNEs) in the genome demonstrates that they cluster around genes \ninvolved in developmental regulation. This chapter describes the identification \nand characterization of these elements, with particular reference to their \ncomposition and organization.", "Fish-mammal genomic comparisons have proved powerful in identifying conserved \nnoncoding elements likely to be cis-regulatory in nature, and the majority of \nthose tested in vivo have been shown to act as tissue-specific enhancers \nassociated with genes involved in transcriptional regulation of development. \nAlthough most of these elements share little sequence identity to each other, a \nsmall number are remarkably similar and appear to be the product of duplication \nevents. Here, we searched for duplicated conserved noncoding elements in the \nhuman genome, using comparisons with Fugu to select putative cis-regulatory \nsequences. We identified 124 families of duplicated elements, each containing \nbetween two and five members, that are highly conserved within and between \nvertebrate genomes. In 74% of cases, we were able to assign a specific set of \nparalogous genes with annotation relating to transcriptional regulation and/or \ndevelopment to each family, thus removing much of the ambiguity in identifying \nassociated genes. We find that duplicate elements have the potential to \nup-regulate reporter gene expression in a tissue-specific manner and that \nexpression domains often overlap, but are not necessarily identical, between \nfamily members. Over two thirds of the families are conserved in duplicate in \nfish and appear to predate the large-scale duplication events thought to have \noccurred at the origin of vertebrates. We propose a model whereby gene \nduplication and the evolution of cis-regulatory elements can be considered in \nthe context of increased morphological diversity and the emergence of the modern \nvertebrate body plan.", "Genomic regulatory blocks are chromosomal regions spanned by long clusters of \nhighly conserved noncoding elements devoted to long-range regulation of \ndevelopmental genes, often immobilizing other, unrelated genes into long-lasting \nsyntenic arrangements. Synorth http://synorth.genereg.net/ is a web resource for \nexploring and categorizing the syntenic relationships in genomic regulatory \nblocks across multiple genomes, tracing their evolutionary fate after teleost \nwhole genome duplication at the level of genomic regulatory block loci, \nindividual genes, and their phylogenetic context.", "Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) \nthat span developmental regulatory genes and define regulatory domains. We \ndescribe Ancora http://ancora.genereg.net, a web resource that provides data and \ntools for exploring genomic organization of HCNEs for multiple genomes. Ancora \nincludes a genome browser that shows HCNE locations and features novel HCNE \ndensity plots as a powerful tool to discover developmental regulatory genes and \ndistinguish their regulatory elements and domains." ]	['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0051094', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0048589', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D050437', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0050793', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0032502']
56b8a222156496395c000001	[ 19492354 ]	train	Are conserved noncoding elements associated with the evolution of animal body plans?	yesno	Yes. Cis-regulatory inputs identified by CNEs arose during the "re-wiring" of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups.	yes	[ "The genomes of vertebrates, flies, and nematodes contain highly conserved \nnoncoding elements (CNEs). CNEs cluster around genes that regulate development, \nand where tested, they can act as transcriptional enhancers. Within an animal \ngroup CNEs are the most conserved sequences but between groups they are normally \ndiverged beyond recognition. Alternative CNEs are, however, associated with an \noverlapping set of genes that control development in all animals. Here, we \ndiscuss the evidence that CNEs are part of the core gene regulatory networks \n(GRNs) that specify alternative animal body plans. The major animal groups arose \n>550 million years ago. We propose that the cis-regulatory inputs identified by \nCNEs arose during the \"re-wiring\" of regulatory interactions that occurred \nduring early animal evolution. Consequently, different animal groups, with \ndifferent core GRNs, contain alternative sets of CNEs. Due to the subsequent \nstability of animal body plans, these core regulatory sequences have been \nevolving in parallel under strong purifying selection in different animal \ngroups." ]	nan
58e11b9b6fddd3e83e00000b	[ 11202049, 15868463, 12859407 ]	train	Are cutaneous porphyrias inherited with a recessive pattern?	yesno	No, cutaneous porphyrias are inherited in a dominant (not recessive) pattern.	no	[ "The acute porphyrias constitute a group of metabolic disorders engaging enzymes \nin the haem synthetic chain and generally following dominant inheritance \npatterns. Some gene carriers are vulnerable to a range of exogenous and \nendogenous factors, which may trigger neuropsychiatric symptoms. Early diagnosis \nis of prime importance since it makes way for counselling with the aim to block \nthe development of acute, as well as late, disease. The medical and \npsycho-social consequences of a porphyria diagnosis are considerable and the \nfreedom for maldiagnosis correspondingly small. The strain imposed upon the \ndiagnostic process makes management in specialized laboratories necessary. \nInadvertent handling of the diagnostic procedures in laboratories lacking in \nknowledge, experience and technical competence is repeatedly the reason for \nharmful underdiagnosis and overdiagnosis. Gene diagnosis of the carrier \ncondition, principally within reach in all types of acute porphyria, is of \nincomparable versatility and accuracy. However, despite recent great \nachievements in the molecular biology of porphyric disease, genomic procedures \ncannot replace biochemical methods in monitoring the activity and progress of \nthe disease, or the effects of therapy. The classical methods are also useful \nwhen it comes to screening for the associated disease states. In these tasks, \nprofessional handling of the methods and skillful interpretation of the results \nare of paramount importance. Knowledge of the limitations and pitfalls of the \nprocedures is a guard against maldiagnosis, which may be fatal. In the article \nthe main diagnostic challenges are discussed; the strategy for early detection \nof the gene carrier state, the recognition and surveillance of the acute \nporphyric crisis, the evaluation of subacute/subchronic symptoms, the \ndifferential diagnoses of the cutaneous porphyrias and the monitoring of late \ncomplications.", "Partial deficiency of enzymes in the haem synthetic pathway gives rise to a \ngroup of seven inherited metabolic disorders, the porphyrias. Each deficiency is \nassociated with a characteristic increase in haem precursors that correlates \nwith the symptoms associated with individual porphyrias and allows accurate \ndiagnosis. Two types of clinical presentation occur separately or in \ncombination; acute life-threatening neurovisceral attacks and/or cutaneous \nsymptoms. Five of the porphyrias are low-penetrance autosomal dominant \nconditions in which clinical expression results from additional factors that act \nby increasing demand for haem or by causing an additional decrease in enzyme \nactivity or by a combination of these effects. These include both genetic and \nenvironmental factors. In familial porphyria cutanea tarda (PCTF), environmental \nfactors that include alcohol, exogenous oestrogens and hepatotropic viruses \nresult in inhibition of hepatic enzyme activity via a mechanism that involves \nexcess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance \nof a functional polymorphism in trans to a null ferrochelatase allele accounts \nfor most clinically overt cases. In the autosomal dominant acute hepatic \nporphyrias (acute intermittent porphyria, variegate porphyria, hereditary \ncoproporphyria), acute neurovisceral attacks occur in a minority of those who \ninherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) \nand endogenous factors (e.g. hormones) have been identified as provoking acute \nattacks, these do not provide a full explanation for the low penetrance of these \ndisorders. It seems probable that genetic background influences susceptibility \nto acute attacks, but the genes that are involved have not yet been identified.", "Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by \ninheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC \n1.3.3.4). It is characterized by cutaneous photosensitivity and/or various \nneurological manifestations. Protoporphyrinogen oxidase catalyses the \npenultimate step of haem biosynthesis, and mutations in the PPOX gene have been \ncoupled to VP. In the present study, sequencing analysis revealed 10 different \nmutations in the PPOX gene in 14 out of 17 apparently unrelated Swedish VP \nfamilies. Six of the identified mutations, 3G > A (exon 2), 454C > T (exon 5), \n472G > C (exon 6), 614C > T (exon 6), 988G > C (exon 10) and IVS12 + 2T > G \n(intron 12), are single nucleotide substitutions, while 604delC (exon 6), \n916-17delCT (exon 9) and 1330-31delCT (exon 13) are small deletions, and IVS12 + \n2-3insT (intron 12) is a small insertion. Only one of these 10 mutations has \nbeen reported previously. Three of the mutations were each identified in two or \nmore families, while the remaining mutations were specific for an individual \nfamily. In addition to the 10 mutations, one previously unreported single \nnucleotide polymorphism was identified. Mutation analysis of family members \nrevealed two adults and four children who were silent carriers of the VP trait. \nGenetic analysis can now be added to the conventional biochemical analyses and \nused in investigation of putative carriers of a VP trait in these families." ]	nan
56f6a63d09dd18d46b00000c	[ 24831536, 12358793, 18823995, 25967372 ]	train	Are cyclophilins proteins that bind to prolines?	yesno	Cyclophilins are ubiquitously expressed proteins that bind to prolines.	yes	[ "The cyclophilins are widely expressed enzymes that catalyze the interconversion \nof the cis and trans peptide bonds of prolines. The immunosuppressive natural \nproducts cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the \ncyclophilins. Chemical modification of both the cyclosporine and sanglifehrin \nscaffolds has produced many analogues that inhibit cyclophilins in vitro but \nhave reduced immunosuppressive properties. Three nonimmunosuppressive \ncyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated \nclinical efficacy for the treatment of hepatitis C infection. Additional \ncandidates are in various stages of preclinical development for the treatment of \nhepatitis C or myocardial reperfusion injury. Recent publications suggest that \ncyclophilin inhibitors may have utility for the treatment of diverse viral \ninfections, inflammatory indications, and cancer. In this review, we document \nthe structure-activity relationships of the nonimmunosuppressive cyclosporins \nand sanglifehrins in clinical and preclinical development. Aspects of the \npharmacokinetic behavior and chemical biology of these drug candidates are also \ndescribed.", "The immunosuppressor cyclosporin A inhibits the \npeptidyl-prolyl-cis/trans-isomerase activity of cyclophilins and the resulting \ncomplex inhibits the phosphatase activity of calcineurin. Both enzymes were \ndetected in peripheral nerve endings isolated from the electric organ of Torpedo \nand shown to be affected by 10 micro m cyclosporin A. Among the cholinergic \nproperties studied, choline uptake was specifically inhibited by cyclosporin A \nto a maximum of 40%. Cyclosporin A decreased the rate of choline transport but \nnot the binding of the non-transportable choline analogue hemicholinium-3, \nindicating that the number of membrane transporters was not affected. Through \nthe use of two other immunosuppressors, FK506, which also inhibits calcineurin, \nand rapamycin, which does not, two different mechanisms of choline uptake \ninhibition were uncovered. FK506 inhibited the rate of choline transport, \nwhereas rapamycin diminished the affinity for choline. The Torpedo homologue of \nthe high affinity choline transporter CHT1 was cloned and its activity was \nreconstituted in Xenopus oocytes. Choline uptake by oocytes expressing tCHT1 was \ninhibited by all three immunosuppressors and also by microinjection of the \nspecific calcineurin autoinhibitory domain A457-481, indicating that the \nphosphatase calcineurin regulates CHT1 activity and could be the common target \nof cyclosporin and FK506. Rapamycin, which changed the affinity of the \ntransporter, may have acted through an immunophilin on the isomerization of \ncritical prolines that are found in the tCHT1 sequence.", "The sensor histidine kinase A (KinA) from Bacillus subtilis triggers a \nphosphorelay that activates sporulation. The antikinase KipI prevents \nsporulation by binding KinA and inhibiting the autophosphorylation reaction. \nUsing neutron contrast variation, mutagenesis, and fluorescence data, we show \nthat two KipI monomers bind via their C-domains at a conserved proline in the \nKinA dimerization and histidine-phosphotransfer (DHp) domain. Our crystal \nstructure of the KipI C-domain reveals the binding motif has a distinctive \nhydrophobic groove formed by a five-stranded antiparallel beta-sheet; a \ncharacteristic of the cyclophilin family of proteins that bind prolines and \noften act as cis-trans peptidyl-prolyl isomerases. We propose that the DHp \ndomain of KinA transmits conformational signals to regulate kinase activity via \nthis proline-mediated interaction. Given that both KinA and KipI homologues are \nwidespread in the bacterial kingdom, this mechanism has broad significance in \nbacterial signal transduction.", "Cyclophilins are ubiquitously expressed proteins that bind to prolines and can \ncatalyse cis/trans isomerization of proline residues. There are 17 annotated \nmembers of the cyclophilin family in humans, ubiquitously expressed and \nlocalized variously to the cytoplasm, nucleus or mitochondria. Surprisingly, all \neight of the nuclear localized cyclophilins are found associated with \nspliceosomal complexes. However, their particular functions within this context \nare unknown. We have therefore adapted three established assays for in vitro \npre-mRNA splicing to probe the functional roles of nuclear cyclophilins in the \ncontext of the human spliceosome. We find that four of the eight \nspliceosom-associated cyclophilins exert strong effects on splicing in vitro. \nThese effects are dose-dependent and, remarkably, uniquely characteristic of \neach cyclophilin. Using both qualitative and quantitative means, we show that at \nleast half of the nuclear cyclophilins can act as regulatory factors of \nspliceosome function in vitro. The present work provides the first quantifiable \nevidence that nuclear cyclophilins are splicing factors and provides a novel \napproach for future work into small molecule-based modulation of pre-mRNA \nsplicing." ]	nan
56f6ab7009dd18d46b00000d	[ 16928193, 19923714, 15869639, 21087465, 14568539, 25259854, 15735342, 15935056, 19403925, 17103061, 23849880, 23123451, 24887548 ]	train	Are cyclophilins ubiquitously expressed?	yesno	Yes, cyps (cyclophilins) are ubiquitous proteins of the immunophilin superfamily.	yes	[ "Cyps (cyclophilins) are ubiquitous proteins of the immunophilin superfamily with \nproposed functions in protein folding, protein degradation, stress response and \nsignal transduction. Conserved cysteine residues further suggest a role in redox \nregulation. In order to get insight into the conformational change mechanism and \nfunctional properties of the chloroplast-located CYP20-3, site-directed \nmutagenized cysteine-->serine variants were generated and analysed for enzymatic \nand conformational properties under reducing and oxidizing conditions. Compared \nwith the wild-type form, elimination of three out of the four cysteine residues \ndecreased the catalytic efficiency of PPI (peptidyl-prolyl cis-trans isomerase) \nactivity of the reduced CYP20-3, indicating a regulatory role of \ndithiol-disulfide transitions in protein function. Oxidation was accompanied by \nconformational changes with a predominant role in the structural rearrangement \nof the disulfide bridge formed between Cys(54) and Cys(171). The rather negative \nE(m) (midpoint redox potential) of -319 mV places CYP20-3 into the redox \nhierarchy of the chloroplast, suggesting the activation of CYP20-3 in the light \nunder conditions of limited acceptor availability for photosynthesis as realized \nunder environmental stress. Chloroplast Prx (peroxiredoxins) were identified as \ninteracting partners of CYP20-3 in a DNA-protection assay. A catalytic role in \nthe reduction of 2-Cys PrxA and 2-Cys PrxB was assigned to Cys(129) and \nCys(171). In addition, it was shown that the isomerization and \ndisulfide-reduction activities are two independent functions of CYP20-3 that \nboth are regulated by the redox state of its active centre.", "Drug development against Leishmania donovani, the pathogen that causes visceral \nleishmaniasis in humans, is currently an active area of research given the \nwidespread prevalence of the disease and the emergence of resistant strains. The \nimmunosuppressive drug cyclosporin is known to have antiparasitic activity \nagainst a variety of pathogens. The receptor for cyclosporin is the protein \ncyclophilin, which is a ubiquitous peptidylprolyl isomerase. The crystal \nstructure of cyclophilin from L. donovani complexed with cyclosporin has been \nsolved at 2.6 A resolution. The thermodynamic parameters of the interaction have \nbeen determined using spectroscopic and calorimetric techniques. A detailed \neffort has been made to predict the thermodynamic parameters of binding from \ncomputations based on the three-dimensional crystal structure. These results \nwere in good agreement with the corresponding experimental values. Furthermore, \nthe structural and biophysical results have been discussed in the context of \nleishmanial drug resistance and could also set the stage for the design of \npotent non-immunosuppressive antileishmanials.", "Originally identified as the cellular targets of immunosuppressant drugs, the \nimmunophilins encompass two ubiquitous protein families: the FK-506 binding \nproteins or FKBPs, and the cyclosporin-binding proteins or cyclophilins. Present \nin organisms ranging from bacteria to animals and plants, these proteins are \ncharacterized by their enzymatic activity; the peptidyl-prolyl cis-trans \nisomerization of polypeptides. Whilst this function is important for protein \nfolding, it has formed the functional basis for more complex interactions \nbetween immunophilins and their target proteins. Beginning with a brief \nhistorical overview of the immunophilin family, and a representative \nillustration of the current state of knowledge that has accumulated for these \nproteins in diverse organisms, a detailed description is presented of the recent \nadvances in the elucidation of the role of this ubiquitous protein family in \nplant biology. Though still in its infancy, investigation into the function of \nplant immunophilins has so far yielded interesting results--as a significant \ncomponent of the chloroplast proteome, the abundance of immunophilins located in \nthe thylakoid lumen suggests that these proteins may play important roles in \nthis relatively uncharacterized subcellular compartment. Moreover, the \nimportance of the complex multidomain immunophilins in functions pertaining to \ndevelopment is underscored by the strong phenotypes displayed by their \ncorresponding mutants.", "BACKGROUND: FK506 binding proteins (FKBPs) and cyclophilins (CYPs) are abundant \nand ubiquitous proteins belonging to the peptidyl-prolyl cis/trans isomerase \n(PPIase) superfamily, which regulate much of metabolism through a chaperone or \nan isomerization of proline residues during protein folding. They are \ncollectively referred to as immunophilin (IMM), being present in almost all \ncellular organs. In particular, a number of IMMs relate to environmental \nstresses.\nRESULTS: FKBP and CYP proteins in rice (Oryza sativa cv. Japonica) were \nidentified and classified, and given the appropriate name for each IMM, \nconsidering the ortholog-relation with Arabidopsis and Chlamydomonas or \nmolecular weight of the proteins. 29 FKBP and 27 CYP genes can putatively be \nidentified in rice; among them, a number of genes can be putatively classified \nas orthologs of Arabidopsis IMMs. However, some genes were novel, did not match \nwith those of Arabidopsis and Chlamydomonas, and several genes were paralogs by \ngenetic duplication. Among 56 IMMs in rice, a significant number are regulated \nby salt and/or desiccation stress. In addition, their expression levels \nresponding to the water-stress have been analyzed in different tissues, and some \nsubcellular IMMs located by means of tagging with GFP protein.\nCONCLUSION: Like other green photosynthetic organisms such as Arabidopsis (23 \nFKBPs and 29 CYPs) and Chlamydomonas (23 FKBs and 26 CYNs), rice has the highest \nnumber of IMM genes among organisms reported so far, suggesting that the numbers \nrelate closely to photosynthesis. Classification of the putative FKBPs and CYPs \nin rice provides the information about their evolutional/functional significance \nwhen comparisons are drawn with the relatively well studied genera, Arabidopsis \nand Chlamydomonas. In addition, many of the genes upregulated by water stress \noffer the possibility of manipulating the stress responses in rice.", "Cyclophilins belong to the family of peptidyl-prolyl cis/trans isomerases \n(PPIases), which are ubiquitous and highly conserved enzymes capable of \ncis/trans isomerizing Xaa-Pro peptide bonds. Members of the CyP40-type \ncyclophilins have originally been described as components of hormone receptor \ncomplexes. Here, we describe NcCyP41, a CyP40 ortholog from Neurospora crassa, \nits expression in Escherichia coli and subsequent purification. Characterization \nof NcCyP41 reveals that it is a heat shock protein, which is active as a \ncyclosporin A-sensitive PPIase. Affinity chromatography using immobilized \nrecombinant NcCyP41 yielded two major NcCyP41-binding proteins: Hsp80 (a Hsp90 \northolog from N.crassa) and CyPBP37. CyPBP37 has not been described. In \naddition, this is the first record describing an interaction between a member of \nCyp40-type cyclophilins and of CyPBP37-type proteins, respectively. CyPBP37 \nexpression is repressed by thiamine and in the stationary phase in N.crassa. \nCyPBP37 is present in different isoforms. The expression of a CyPBP37 ortholog \nin yeast, Thi4p, is diminished in a mutant lacking one of the two CyP40 \northologs (Cpr7p). In addition, the DeltaCpr7p deletion mutant shows a \nthiamine-dependent growth defect. We conclude that, in yeast, Cpr7p and Thi4p \ninteract functionally.", "Abstract Phoma stem canker (blackleg) is a disease of world-wide importance on \noilseed rape (Brassica napus) and can cause serious losses for crops globally. \nThe disease is caused by dothideomycetous fungus, Leptosphaeria maculans, which \nis highly virulent/aggressive. Cyclophilins (CYPs) and FK506-binding proteins \n(FKBPs) are ubiquitous proteins belonging to the peptidyl-prolyl cis/trans \nisomerase (PPIase) family. They are collectively referred to as immunophilins \n(IMMs). In the present study, IMM genes, CYP and FKBP in haploid strain v23.1.3 \nof L. maculans genome, were identified and classified. Twelve CYPs and five \nFKBPs were determined in total. Domain architecture analysis revealed the \npresence of a conserved cyclophilin-like domain (CLD) in the case of CYPs and \nFKBP_C in the case of FKBPs. Interestingly, IMMs in L. maculans also subgrouped \ninto single domain (SD) and multidomain (MD) proteins. They were primarily found \nto be localized in cytoplasm, nuclei, and mitochondria. Homologous and \northologous gene pairs were also determined by comparison with the model \norganism Saccharomyces cerevisiae. Remarkably, IMMs of L. maculans contain \nshorter introns in comparison to exons. Moreover, CYPs, in contrast with FKBPs, \ncontain few exons. However, two CYPs were determined as being intronless. The \nexpression profile of IMMs in both mycelium and infected primary leaves of B. \nnapus demonstrated their potential role during infection. Secondary structure \nanalysis revealed the presence of atypical eight β strands and two α helices \nfold architecture. Gene ontology analysis of IMMs predicted their significant \nrole in protein folding and PPIase activity. Taken together, our findings for \nthe first time present new prospects of this highly conserved gene family in \nphytopathogenic fungus.", "Cyclophilins (CyPs) are a large class of highly conserved ubiquitous \npeptidyl-prolyl cis-trans isomerases. CyPs have also been identified as being a \nspecific receptor for the immunosuppressive drug cyclosporin A and are involved \nin a variety of biological functions. CyPJ is a novel member of the CyP family \nand human CyPJ (hCyPJ) is the protein encoded by a cyclophilin-like gene from \nhuman foetal brain, which shows 50% sequence identity to human cyclophilin A \n(hCyPA). Recombinant hCyPJ was expressed in Escherichia coli and purified. The \nthree-dimensional structure of hCyPJ has been determined by molecular \nreplacement using the hCyPA structure as the search model and has been refined \nat 2.6 angstroms resolution. The hCyPJ molecule contains four helices and one \nbeta-barrel composed of eight antiparallel beta-strands. The overall secondary \nand tertiary structures of hCyPJ are similar to those of hCyPA, but hCyPJ \ncontains an additional disulfide bridge and four segments with conformations \nthat are strikingly different from those of hCyPA. His43 and Gln52 of hCyPJ are \nexpected to be the active sites based on sequence alignment with hCyPA. The \nhCyPJ structure shows a conserved water molecule close to His43 and Gln52 which \nappears to support the solvent-assisted mechanism.", "Immunophilins are ubiquitous enzymes responsible for proline isomerisation \nduring protein synthesis and for the chaperoning of several membrane proteins. \nThese activities can be blocked by the immunosuppressants cyclosporin A, FK506 \nand rapamycin. It has been shown that all three immunosuppressants have \nneurotrophic activity and can modulate neurotransmitter release, but the \nmolecular basis of these effects is currently unknown. Here, we show that \nsynapsin I, a synaptic vesicle-associated protein, can be purified from Torpedo \ncholinergic synaptosomes through its affinity to cyclophilin B, an immunophilin \nthat is particularly abundant in brain. The interaction is direct and conserved \nin mammals, and shows a dissociation constant of about 0.5 microM in vitro. The \nbinding between the two proteins can be disrupted by cyclosporin A and inhibited \nby physiological concentrations of ATP. Furthermore, cyclophilin B co-localizes \nwith synapsin I in rat synaptic vesicle fractions and its levels in synaptic \nvesicle-containing fractions are decreased in synapsin knockout mice. These \nresults suggest that immunophilins are involved in the complex protein networks \noperating at the presynaptic level and implicate the interaction between \ncyclophilin B and synapsins in presynaptic function.", "Cyclophilin is a ubiquitous peptidyl prolyl cis/trans isomerase that plays \ncritical roles in many biological processes. A number of cyclophilin inhibitors \nhave been designed based on the structure of the immunosuppressant cyclosporin \nA. To discover inhibitors that have other structures, the authors established \nthe high-throughput screening (HTS) method using FDSS6000 real-time fluorescence \ndetector. The inhibitors identified with this HTS showed significant correlation \nwith direct interaction as measured by surface plasmon resonance. This \nhigh-throughput assay system is a powerful tool for the discovery of \npeptidylprolyl isomerase inhibitors.", "Cyclophilins are folding helper enzymes belonging to the class of \npeptidyl-prolyl cis-trans isomerases (PPIases; EC 5.2.1.8) that catalyze the \ncis-trans isomerization of peptidyl-prolyl bonds in proteins. They are \nubiquitous proteins present in almost all living organisms analyzed to date, \nwith extremely rare exceptions. Few cyclophilins have been described in \nActinobacteria, except for three reported in the genus Streptomyces and another \none in Mycobacterium tuberculosis. In this study, we performed a complete \nphylogenetic analysis of all Actinobacteria cyclophilins available in sequence \ndatabases and new Streptomyces cyclophilin genes sequenced in our laboratory. \nPhylogenetic analyses of cyclophilins recovered six highly supported groups of \nparalogy. Streptomyces appears as the bacteria having the highest cyclophilin \ndiversity, harboring proteins from four groups. The first group was named \"A\" \nand is made up of highly conserved cytosolic proteins of approximately 18 kDa \npresent in all Actinobacteria. The second group, \"B,\" includes cytosolic \nproteins widely distributed throughout the genus Streptomyces and closely \nrelated to eukaryotic cyclophilins. The third group, \"M\" cyclophilins, consists \nof high molecular mass cyclophilins ( approximately 30 kDa) that contain \nputative membrane binding domains and would constitute the only membrane \ncyclophilins described to date in bacteria. The fourth group, named \"C\" \ncyclophilins, is made up of proteins of approximately 18 kDa that are \northologous to Gram-negative proteobacteria cyclophilins. Ancestral character \nreconstruction under parsimony was used to identify shared-derived (and likely \nfunctionally important) amino acid residues of each paralogue. Southern and \nWestern blot experiments were performed to determine the taxonomic distribution \nof the different cyclophilins in Actinobacteria.", "Cyclophilins (Cyps) are ubiquitous proteins that effect the cis-trans \nisomerization of Pro amide bonds, and are thus crucial to protein folding. CypA \nis the most prevalent of the ~19 human Cyps, and plays a crucial role in viral \ninfectivity, most notably for HIV-1 and HCV. Cyclophilins have been shown to \nplay key roles in effective replication of a number of viruses from different \nfamilies. A drug template for CypA inhibition is cyclosporine A (CsA), a cyclic \nundecapeptide that simultaneously binds to both CypA and the Ca(2+)-dependent \nphosphatase calcineurin (CN), and can attenuate immune responses. Synthetic \nmodifications of the CsA scaffold allows for selective binding to CypA and CN \nseparately, thus providing access to novel, non-immunosuppressive antiviral \nagents.", "Cyclophilins constitute a subgroup of large family of proteins called \nimmunophilins, which also include FKBPs and Parvulins. They are remarkably \nconserved in all genera, highlighting their pivotal role in important cellular \nprocesses. Most cyclophilins display PPIase enzymatic activity, multiplicity, \ndiverse cellular locations and active role in protein folding which render them \nto be included in the class of diverse set of proteins called molecular \nchaperones. Due to their distinct PPIase function, besides protein disulfide \nisomerases and protein foldases, cyclophilins have been deemed necessary for in \nvivo chaperoning activity. Unlike other cellular chaperones, these proteins are \nspecific in their respective targets. Not all cyclophilin proteins possess \nPPIase activity, indicating a loss of their PPIase activity during the course of \nevolution and gain of function independent of their PPIase activity. The PPIase \nfunction of cyclophilins is also compensated by their functional homologs, like \nFKBPs. Multiple cyclophilin members in plants like Arabidopsis and rice have \nbeen reported to be associated with diverse functions and regulatory pathways \nthrough their foldase, scaffolding, chaperoning or other unknown activities. \nAlthough many functions of plant cyclophilins were reported or suggested, the \nphysiological relevance and molecular basis of stress-responsive expression of \nplant cyclophilins is still largely unknown. However, their wide distribution \nand ubiquitous nature signifies their fundamental importance in plant survival. \nSeveral of these members have also been directly linked to multiple stresses. \nThis review attempts to deal with plant cyclophilins with respect to their role \nin stress response.", "Cyclophilin from Leishmania donovani (LdCyp) is a ubiquitous peptidyl-prolyl \ncis-trans isomerase involved in a host of important cellular activities, such as \nsignaling, heat shock response, chaperone activity, mitochondrial pore \nmaintenance and regulation of HIV-1 infectivity. It also acts as the prime \ncellular target for the auto-immune drug cyclosporine A (CsA). LdCyp is composed \nof a beta barrel encompassing the unique hydrophobic core of the molecule and is \nflanked by two helices (H1, H2) on either end of the barrel. The protein \ncontains a lone partially exposed tryptophan. In the present work the \nequilibrium unfolding of LdCyp has been studied by fluorescence, circular \ndichroism and the non-coincidence of their respective Cm's, indicates a non-two \nstate transition. This fact was further corroborated by binding studies of the \nprotein with bis-ANS and the lack of an isochromatic point in far UV CD. The \nthermal stability of the possible intermediates was characterized by \ndifferential scanning calorimetry. Further, MD simulations performed at 310, 400 \nand 450K exhibited the tendency of both helices to partially unwind and adopt \nnon-native geometries with respect to the core, quite early in the unfolding \nprocess, in contrast to the relatively stable beta barrel." ]	nan
5c643485e842deac67000015	[ 29562236 ]	train	Are de novo mutations in regulatory elements responsible for neurodevelopmental disorders?	yesno	Yes. De novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. It is estimated that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism.	yes	[ "We previously estimated that 42% of patients with severe developmental disorders \ncarry pathogenic de novo mutations in coding sequences. The role of de novo \nmutations in regulatory elements affecting genes associated with developmental \ndisorders, or other genes, has been essentially unexplored. We identified de \nnovo mutations in three classes of putative regulatory elements in almost 8,000 \npatients with developmental disorders. Here we show that de novo mutations in \nhighly evolutionarily conserved fetal brain-active elements are significantly \nand specifically enriched in neurodevelopmental disorders. We identified a \nsignificant twofold enrichment of recurrently mutated elements. We estimate \nthat, genome-wide, 1-3% of patients without a diagnostic coding variant carry \npathogenic de novo mutations in fetal brain-active regulatory elements and that \nonly 0.15% of all possible mutations within highly conserved fetal brain-active \nelements cause neurodevelopmental disorders with a dominant mechanism. Our \nfindings represent a robust estimate of the contribution of de novo mutations in \nregulatory elements to this genetically heterogeneous set of disorders, and \nemphasize the importance of combining functional and evolutionary evidence to \nidentify regulatory causes of genetic disorders." ]	nan
52f77f752059c6d71c00002b	[ 16258176, 12592385, 12865926, 12016139, 12427531, 12488587, 20298636, 17363343, 12191483, 23628323, 22798379, 23675572, 24104500, 17397816, 23541693, 11395777, 17636314, 21427292, 16555998, 23125219, 11178982, 24051048, 22665067, 15660524, 23620081, 21267443, 21404276, 22276468, 23721719, 10753787, 19083132 ]	train	Are defects in recombination repair involved in carcinogenesis?	yesno	Yes. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in recombination repair.	yes	[ "Mitomycin C (MMC) induces various types of DNA damages that cause significant \ncytotoxicity to cells. Accordingly, repair of MMC-induced damages involves \nmultiple repair pathways such as nucleotide excision repair, homologous \nrecombination repair and translesion bypass repair pathways. Nonetheless, repair \nof the MMC-induced DNA damages in mammals have not been fully delineated. In \nthis study, we investigated potential roles for Xeroderma pigmentosum (XP) \nproteins in the repair of MMC-induced DNA damages using an assay that detects \nthe ssDNA patches generated following treatment with MMC or 8'-methoxy-psoralen \n(8-MOP) + UVA (ultraviolet light A). Human wild-type cells formed distinctive \nssDNA foci following treatment with MMC or 8-MOP + UVA, but not with those \ninducing alkylation damage, oxidative damage or strand-break damage, suggesting \nthat the foci represent ssDNA patches formed during the crosslink repair. In \ncontrast to wild-type cells, mutant defective in XPE orXPG did not form the \nssDNA foci following MMC treatment, while XPF mutant cells showed a \nsignificantly delayed response in forming the foci. A positive role for XPG in \nthe repair of MMC-induced DNA damages was further supported by observations that \ncells treated with MMC induced a tight association of XPG with chromatin, and a \ntargeted inhibition of XPG abolished MMC-induced ssDNA foci formation, rendering \ncells hypersensitive to MMC. Together, our results suggest that XPG along with \nXPE and XPF play unique role(s) in the repair of MMC-induced DNA damages.", "The breast- and ovarian-specific tumor suppressor, BRCA1, has been implicated to \nfunction in many nuclear processes, including DNA damage repair, recombination, \ntranscription, ubiquitination, cell cycle checkpoint enforcement, and centrosome \nregulation. Utilizing a previously described interaction between BRCA1 and RNA \nhelicase A (RHA), we have developed a dominant-negative approach to block BRCA1 \nfunction in human breast epithelial cells. Overexpression of a truncated RHA \npeptide that can bind to the BRCA1 carboxy-terminus prevents normal BRCA1 \nfunction, such as BRCA1 association with nuclear foci following DNA damage. \nOverexpression of this dominant-negative protein induces pleomorphic nuclei, \naberrant mitoses with extra centrosomes, and tetraploidy. This model system \nallows us to observe changes to mammary epithelial cells that occur acutely \nfollowing loss of BRCA1 function. Furthermore, inhibition of BRCA1 via \noverexpressing the RHA fragment coincides with a reduction in PARP-1 protein \nexpression, suggesting a possible mechanism for BRCA1 in the maintenance of \ngenomic integrity.", "DNA repair has an essential role in protecting the genome from damage by \nendogenous and environmental agents. Polymorphisms in DNA repair genes and \ndifferences in repair capacity between individuals have been widely documented. \nFor colorectal cancer, the loss of mismatch repair gene activity is a key \ngenetic determinant. Nucleotide excision repair (NER), recombination repair (RR) \nand base excision repair (BER) pathways have critical roles in protection \nagainst other cancers, and we wished to investigate their role in colorectal \ncancer. We have compared the frequency of polymorphisms in the NER genes, XPD, \nXPF, XPG, ERCC1; in the BER gene, XRCC1; and in the RR gene, XRCC3; in \ncolorectal cancer patients and in a control group. No significant associations \nwere found for any of the NER gene polymorphisms or for the XRCC1 polymorphism. \nThe C allele (position 18067) of the XRCC3 gene was weakly but significantly \nassociated with colorectal cancer (odds ratio 1.52, 95% confidence interval \n1.04-2.22, P=0.03). For all patients who were heterozygous for any of the repair \ngenes studied, tumour tissue was investigated for loss of heterozygosity (LOH). \nOnly one example of LOH was found for all the genes examined. From the \nassociation and LOH data, we conclude that these genes do not have an important \nrole in protection against colorectal carcinogenesis.", "The DNA double-strand break (DSB) is the principle cytotoxic lesion for ionizing \nradiation and radio-mimetic chemicals but can also be caused by mechanical \nstress on chromosomes or when a replicative DNA polymerase encounters a DNA \nsingle-strand break or other type of DNA lesion. DSBs also occur as \nintermediates in various biological events, such as V(D)J recombination in \ndeveloping lymphoid cells. Inaccurate repair or lack of repair of a DSB can lead \nto mutations or to larger-scale genomic instability through the generation of \ndicentric or acentric chromosomal fragments. Such genome changes may have \ntumourigenic potential. In other instances, DSBs can be sufficient to induce \napoptosis. Because of the threats posed by DSBs, eukaryotic cells have evolved \ncomplex and highly conserved systems to rapidly and efficiently detect these \nlesions, signal their presence and bring about their repair. Here, I provide an \noverview of these systems, with particular emphasis on the two major pathways of \nDSB repair: non-homologous end-joining and homologous recombination. Inherited \nor acquired defects in these pathways may lead to cancer or to other human \ndiseases, and may affect the sensitivity of patients or tumour cells to \nradiotherapy and certain chemotherapies. An increased knowledge of DSB repair \nand of other DNA DSB responses may therefore provide opportunities for \ndeveloping more effective treatments for cancer.", "We review the genes and proteins related to the homologous recombinational \nrepair (HRR) pathway that are implicated in cancer through either genetic \ndisorders that predispose to cancer through chromosome instability or the \noccurrence of somatic mutations that contribute to carcinogenesis. Ataxia \ntelangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like \ndisorder (ATLD), are chromosome instability disorders that are defective in the \nataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These \ngenes are critical in maintaining cellular resistance to ionizing radiation \n(IR), which kills largely by the production of double-strand breaks (DSBs). \nBloom syndrome involves a defect in the BLM helicase, which seems to play a role \nin restarting DNA replication forks that are blocked at lesions, thereby \npromoting chromosome stability. The Werner syndrome gene (WRN) helicase, another \nmember of the RecQ family like BLM, has very recently been found to help mediate \nhomologous recombination. Fanconi anemia (FA) is a genetically complex \nchromosomal instability disorder involving seven or more genes, one of which is \nBRCA2. FA may be at least partially caused by the aberrant production of \nreactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 \nproteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears \nto regulate its activity. We discuss in detail the phenotypes of the various \nmutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's \nphosphorylation targets can be grouped into oxidative stress-mediated \ntranscriptional changes, cell cycle checkpoints, and recombinational repair. We \npresent the DNA damage response pathways by using the DSB as the prototype \nlesion, whose incorrect repair can initiate and augment karyotypic \nabnormalities.", "Cancer develops when cells no longer follow their normal pattern of controlled \ngrowth. In the absence or disregard of such regulation, resulting from changes \nin their genetic makeup, these errant cells acquire a growth advantage, \nexpanding into precancerous clones. Over the last decade, many studies have \nrevealed the relevance of genomic mutation in this process, be it by \nmisreplication, environmental damage, or a deficiency in repairing endogenous \nand exogenous damage. Here, we discuss homologous recombination as another \nmechanism that can result in a loss of heterozygosity or genetic rearrangements. \nSome of these genetic alterations may play a primary role in carcinogenesis, but \nthey are more likely to be involved in secondary and subsequent steps of \ncarcinogenesis by which recessive oncogenic mutations are revealed. Patients, \nwhose cells display an increased frequency of recombination, also have an \nelevated frequency of cancer, further supporting the link between recombination \nand carcinogenesis.", "DNA-repair pathways recognise and repair DNA damaged by exogenous and endogenous \nagents to maintain genomic integrity. Defects in these pathways lead to \nreplication errors, loss or rearrangement of genomic material and eventually \ncell death or carcinogenesis. The creation of diverse lymphocyte receptors to \nidentify potential pathogens requires breaking and randomly resorting gene \nsegments encoding antigen receptors. Subsequent repair of the gene segments \nutilises ubiquitous DNA-repair proteins. Individuals with defective repair \npathways are found to be immunodeficient and many are radiosensitive. The role \nof repair proteins in the development of adaptive immunity by VDJ recombination, \nantibody isotype class switching and affinity maturation by somatic \nhypermutation has become clearer over the past few years, partly because of \nidentification of the genes involved in human disease. We describe the \nmechanisms involved in the development of adaptive immunity relating to DNA \nrepair, and the clinical consequences and treatment of the primary \nimmunodeficiency resulting from such defects.", "Accurate repair of DNA double-strand breaks is essential to life. Indeed, \ndefective DNA double-strand break repair can lead to toxicity and large scale \nsequence rearrangements that cause cancer and promote premature aging. Here, we \nhighlight the two major repair systems for handling DNA double-strand breaks: \nhomologous recombination and non-homologous end joining. To clarify \nrecombination mechanisms, we present animations that illustrate DNA strand \nmovements. In addition to describing how these pathways operate, we also \ndescribe why appropriate pathway choice is critical to genomic stability, and we \nsummarize key pathway control features related to cell cycle checkpoint and \napoptosis signaling. Importantly, recent progress in delineating the effects of \nspecific defects in repair and checkpoint control has helped to explain several \ndisease phenotypes, including cancer and premature aging. Improved understanding \nof these pathways has also sparked development of novel chemotherapeutic \nstrategies that kill tumors with increased specificity and efficacy. This review \naims to provide a foundational understanding of how the homologous recombination \nand non-homologous end joining pathways operate, and to demonstrate how a better \nunderstanding of these processes has advanced both our understanding of the \nunderlying causes of cancer and our ability to innovate novel cancer treatment \nstrategies.", "XRCC3 is a RAD51 paralog that functions in the repair of DNA double-strand \nbreaks (DSBs) by homologous recombination (HR). XRCC3 mutation causes severe \nchromosome instability. We find that XRCC3 mutant cells display radically \naltered HR product spectra, with increased gene conversion tract lengths, \nincreased frequencies of discontinuous tracts, and frequent local rearrangements \nassociated with HR. These results indicate that XRCC3 function is not limited to \nHR initiation, but extends to later stages in formation and resolution of HR \nintermediates, possibly by stabilizing heteroduplex DNA. The results further \ndemonstrate that HR defects can promote genomic instability not only through \nfailure to initiate HR (leading to nonhomologous repair) but also through \naberrant processing of HR intermediates. Both mechanisms may contribute to \ncarcinogenesis in HR-deficient cells.", "Hexavalent chromium [Cr(VI)] is a well known mutagen and carcinogen. Since \ngenomic instability due to generation of double strand breaks (DSBs) is causally \nlinked to carcinogenesis, we tested a hypothesis that Cr(VI) causes in vivo \ngeneration of DSBs and elicits DNA damage response. We fed repair proficient \nDrosophila melanogaster (Oregon R(+)) larvae Cr(VI) (20.0μg/ml) mixed food for \n24 and 48h and observed a significant (p<0.05) induction of DSBs in their midgut \ncells after 48h using neutral Comet assay. Global gene expression profiling in \nCr(VI)-exposed Oregon R(+) larvae unveiled mis-regulation of DSBs responsive \nrepair genes both after 24 and 48h. In vivo generation of DSBs in exposed \nDrosophila was confirmed by an increased pH2Av immunostaining along with the \nactivation of cell cycle regulation genes. Analysis of mis-regulated genes \ngrouped under DSB response by GOEAST indicated the participation of \nnon-homologous end joining (NHEJ) DSB repair pathway. We selected two strains, \none mutant (ligIV) and another ku80-RNAi (knockdown of ku80), whose functions \nare essentially linked to NHEJ-DSB repair pathway. As a proof of principle, we \ncompared the DSBs generation in larvae of these two strains with that of repair \nproficient Oregon R(+). Along with this, DSBs generation in spn-A and okr \n[essential genes in homologous recombination repair (HR) pathway] mutants was \nalso tested for the possible involvement of HR-DSB repair. A significantly \nincreased DSBs generation in the exposed ku80-RNAi and ligIV (mutant) larvae \nbecause of impaired repair, concomitant with an insignificant DSBs generation in \nokr and spn-A mutant larvae indicates an active participation of NHEJ repair \npathway. The study, first of its kind to our knowledge, while providing \nevidences for in vivo generation of DSBs in Cr(VI) exposed Drosophila larvae, \nassumes significance for its relevance to higher organisms due to causal link \nbetween DSB generation and Cr(VI)-induced carcinogenesis.", "MicroRNA (miRNA) influences carcinogenesis at multiple stages and it can \neffectively control tumor radiosensitivity by affecting DNA damage repair, cell \ncycle checkpoint, apoptosis, radio-related signal transduction pathways and \ntumor microenvironment. MiRNA also efficiently modulates tumor radiosensitivity \nat multiple levels by blocking the two essential non-homologous end-joining \nrepair and homologous recombination repair pathways in the DNA damage response. \nIt interferes with four radio-related pathways in ionizing radiation, including \nthe PI3-K/Akt, NF-κB, MAPK and TGFβ signaling pathways. Moreover, the regulatory \neffect of miRNA in radiosensitivity can be enhanced when interacting with \nvarious key molecules, including H2AX, BRCA1, ATM, DNA-PK, RAD51, Chk1, Cdc25A, \np53, PLK1, HIF-1 and VEGF, which are involved in these processes. Therefore, \nthoroughly understanding the mechanism of miRNA in tumor radiosensitivity could \nassist in finding novel targets to improve the radiotherapeutic effects and \nprovide new clinical perspectives and insights for developing effective cancer \ntreatments.", "Radiation therapy plays an important role in the management of a wide range of \ncancers. Besides innovations in the physical application of radiation dose, \nradiation therapy is likely to benefit from novel approaches exploiting \ndifferences in radiation response between normal and tumor cells. While ionizing \nradiation induces a variety of DNA lesions, including base damages and \nsingle-strand breaks, the DNA double-strand break (DSB) is widely considered as \nthe lesion responsible not only for the aimed cell killing of tumor cells, but \nalso for the general genomic instability that leads to the development of \nsecondary cancers among normal cells. Homologous recombination repair (HRR), \nnon-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, \nare the major pathways utilized by cells for the processing of DSBs. Therefore, \ntheir function represents a major mechanism of radiation resistance in tumor \ncells. HRR is also required to overcome replication stress - a potent \ncontributor to genomic instability that fuels cancer development. HRR and \nalternative NHEJ show strong cell-cycle dependency and are likely to benefit \nfrom radiation therapy mediated redistribution of tumor cells throughout the \ncell-cycle. Moreover, the synthetic lethality phenotype documented between HRR \ndeficiency and PARP inhibition has opened new avenues for targeted therapies. \nThese observations make HRR a particularly intriguing target for treatments \naiming to improve the efficacy of radiation therapy. Here, we briefly describe \nthe major pathways of DSB repair and review their possible contribution to \ncancer cell radioresistance. Finally, we discuss promising alternatives for \ntargeting DSB repair to improve radiation therapy and cancer treatment.", "The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination \nrepair (HRR) pathway plays a vital role in DNA double-strand break repair \n(DSBR). Variants in the XRCC3 gene might result in altered protein structure or \nfunction which may influence DSBR efficiency and lead to cancer. Numerous \nepidemiological studies have been conducted to evaluate the association between \nXRCC3 polymorphisms and bladder cancer risk. However, the results of these \nprevious studies have been inconsistent. To derive a more precise estimation of \nthe association, we performed a meta-analysis of all available studies relating \nXRCC3 polymorphisms and bladder cancer. All studies published up to April 2013 \non the association between XRCC3 polymorphisms and bladder cancer risk were \nidentified by searching electronic databases PubMed, EMBASE, and Chinese \nBiomedical Literature databases. The association between the XRCC3 polymorphisms \nand bladder cancer risk was assessed by odds ratios (ORs) together with their \n95% confidence intervals (CIs). A total of 16 case-control studies met the \ninclusion criteria and were selected. With respect to C18067T polymorphism, \nsignificant increased bladder cancer risk was found when all eligible studies \nwere pooled into the meta-analysis (TT vs. CC: OR = 1.174, 95%CI = 1.033-1.335, \nP = 0.014 and recessive model TT vs. TC + CC: OR = 1.147, 95%CI = 1.020-1.290, \nP = 0.022, respectively). The results were still significant after excluding the \nHardy-Weinberg equilibrium violation studies (TT vs. CC: OR = 1.178, \n95%CI = 1.036-1.339, P = 0.013 and recessive model TT vs. TC + CC: OR = 1.144, \n95%CI = 1.017-1.287, P = 0.025, respectively). In subgroup analysis by \nethnicity, significant elevated risk was found among Asians (dominant model \nTT + TC vs. CC: OR = 1.285, 95%CI = 1.012-1.631). In the subgroup analyses \naccording to smoking status, no significant association was detected in all \ngenetic comparison models. With respect to A17893G and A4541G polymorphisms, no \nsignificant association with bladder cancer risk was observed in the overall and \nsubgroup analyses. This meta-analysis suggests that the XRCC3 C18067T \npolymorphism was associated with increased bladder cancer risk especially among \nAsians. However, the XRCC3 A17893G and A4541G polymorphisms may not play \nimportant roles in bladder carcinogenesis. Further studies with larger sample \nsizes are needed to validate our finds.", "This work focuses on the main DNA repair pathways, highlighting their role in \ngastrointestinal carcinogenesis and the role of mitochondrial DNA (mtDNA), \nmutations being described in several tumor types, including those of the \ngastrointestinal tract. The mismatch repair (MMR) system is inherently altered \nin patients with hereditary non-polyposis colorectal cancer, and plays a role in \ncarcinogenesis in a subset of sporadic colorectal, gastric and esophageal \ncancers. Alterations in homologous recombination (HR) and non-homologous \nend-joining (NHEJ) also contribute to the development of pancreatic cancer. Gene \npolymorphisms of some X-ray cross-complementing (XRCCs), cofactor proteins \ninvolved in the base excision repair pathway, have been investigated in relation \nto gastric, colorectal and pancreatic cancer. Yet only one polymorphism, XRCC1 \nArg194Trp, appears to be involved in smoking-related cancers and in early onset \npancreatic cancer. Although evidence in the literature indicates that mtDNA \nsomatic mutations play a role in gastric and colorectal carcinogenesis, no sound \nconclusions have yet been drawn regarding this issue in pancreatic cancer, \nalthough an mtDNA variant at 16519 is believed to worsen the outcome of \npancreatic cancer patients, possibly because it is involved in altering cellular \nmetabolism.", "Copy number variations (CNVs) encompass a variety of genetic alterations \nincluding deletions and amplifications and cluster in regions of the human \ngenome with intrinsic instability. Small-sized CNVs can act as initial genetic \nchanges giving rise to larger CNVs such as acquired somatic copy number \naberrations (CNAs) promoting cancer formation. Previous studies provided \nevidence for CNVs as an underlying cause of elevated breast cancer risk when \ntargeting breast cancer susceptibility genes and of accelerated breast cancer \nprogression when targeting oncogenes. With the development of novel techniques \nfor genome-wide detection of CNVs at increasingly higher resolution, it became \npossible to qualitatively and quantitatively analyse manifestation of DNA damage \nresulting from defects in any of the large variety of DNA double-strand break \n(DSB) repair mechanisms. Breast carcinogenesis, particularly in familial cases, \nhas been linked with a defect in the homologous recombination (HR) pathway, \nwhich in turn switches damage removal towards alternative, more error-prone DSB \nrepair pathways such as microhomology-mediated non-homologous end joining \n(mmNHEJ). Indeed, increased error-prone DSB repair activities were detected in \nperipheral blood lymphocytes from individuals with familial breast cancer risk \nindependently of specific gene mutations. Intriguingly, sequence analysis of \nbreakpoint regions revealed that the majority of genome aberrations found in \nbreast cancer specimens are formed by mmNHEJ. Detection of pathway-specific \nerror-prone DSB repair activities by functional testing was proposed to serve as \nbiomarker for hereditary breast cancer risk and responsiveness to therapies \ntargeting HR dysfunction. Identification of specific error-prone DSB repair \nmechanisms underlying CNAs and ultimately mammary tumour formation highlights \npotential targets for future breast cancer prevention regimens.", "Mismatch repair has a central role in maintaining genomic stability by repairing \nDNA replication errors and inhibiting recombination between non-identical \n(homeologous) sequences. Defects in mismatch repair have been linked to certain \nhuman cancers, including hereditary non-polyposis colorectal cancer (HNPCC) and \nsporadic tumours. A crucial requirement for tumour cell proliferation is the \nmaintenance of telomere length, and most tumours achieve this by reactivating \ntelomerase. In both yeast and human cells, however, telomerase-independent \ntelomere maintenance can occur as a result of recombination-dependent exchanges \nbetween often imperfectly matched telomeric sequences. Here we show that loss of \nmismatch-repair function promotes cellular proliferation in the absence of \ntelomerase. Defects in mismatch repair, including mutations that correspond to \nthe same amino-acid changes recovered from HNPCC tumours, enhance \ntelomerase-independent survival in both Saccharomyces cerevisiae and a related \nbudding yeast with a degree of telomere sequence homology that is similar to \nhuman telomeres. These results indicate that enhanced telomeric recombination in \nhuman cells with mismatch-repair defects may contribute to cell immortalization \nand hence tumorigenesis.", "The efficient repair of double-strand breaks (DSBs) is crucial in maintaining \ngenomic integrity. Sister chromatid cohesion is important for not only faithful \nchromosome segregation but also for proper DSB repair. During DSB repair, the \nSmc1-Smc3 cohesin complex is loaded onto chromatin around the DSB to support \nrecombination-mediated DSB repair. In this study, we investigated whether Ctf18, \na factor implicated in the establishment of sister chromatid cohesion, is \ninvolved in DSB repair in budding yeast. Ctf18 was recruited to HO-endonuclease \ninduced DSB sites in an Mre11-dependent manner and to damaged chromatin in G2/M \nphase-arrested cells. The ctf18 mutant cells showed high sensitivity to \nDSB-inducible genotoxic agents and defects in DSB repair, as well as defects in \ndamage-induced recombination between sister chromatids and between homologous \nchromosomes. These results suggest that Ctf18 is involved in damage-induced \nhomologous recombination.", "Whereas oncogenic retroviruses are common in animals, human T-lymphotropic virus \n1 (HTLV-1) is the only transmissible retrovirus associated with cancer in humans \nand is etiologically linked to adult T-cell leukemia. The leukemogenesis process \nis still largely unknown, but relies on extended survival and clonal expansion \nof infected cells, which in turn accumulate genetic defects. A common feature of \nhuman tumor viruses is their ability to stimulate proliferation and survival of \ninfected pretumoral cells and then hide by establishing latency in cells that \nhave acquired a transformed phenotype. Whereas disruption of the DNA repair is \none of the major processes responsible for the accumulation of genomic \nabnormalities and carcinogenesis, the absence of DNA repair also poses the \nthreat of cell-cycle arrest or apoptosis of virus-infected cells. This study \ndescribes how the HTLV-1 p30 viral protein inhibits conservative homologous \nrecombination (HR) DNA repair by targeting the MRE11/RAD50/NBS1 complex and \nfavors the error-prone nonhomologous-end-joining (NHEJ) DNA-repair pathway \ninstead. As a result, HTLV-1 p30 may facilitate the accumulation of mutations in \nthe host genome and the cumulative risk of transformation. Our results provide \nnew insights into how human tumor viruses may manipulate cellular DNA-damage \nresponses to promote cancer.", "DNA repair mechanisms are essential for cellular survival in mammals. A rapid \nrepair of DNA breaks ensures faster growth of normal cells as well as cancer \ncells, making DNA repair machinery, a potential therapeutic target. Although \nefficiency of these repair processes substantially decrease the efficacy of \ncancer chemotherapies that target DNA, compromised DNA repair contributes to \nmutagenesis and genomic instability leading to carcinogenesis. Thus, an ideal \ntarget in DNA repair mechanisms would be one that specifically kills the rapidly \ndividing cancer cells without further mutagenesis and does not affect normal \ncells. Endo-exonucleases play a pivotal role in nucleolytic processing of DNA \nends in different DNA repair mechanisms especially in homologous recombination \nrepair (HRR) which mainly repairs damaged DNA in S and G2 phases of the cell \ncycle in rapidly dividing cells. HRR machinery has also been implicated in cell \nsignaling and regulatory functions in response to DNA damage that is essential \nfor cell viability in mammalian cells where as the predominant nonhomologous \nend-joining pathway is constitutive. Although HRR is thought to be involved at \nother stages of the cell cycle, it is predominant in growing phases (S and G2) \nof the cell cycle. The faster growing cells are believed to carryout more HRR in \nreplicative stages of the cell cycle where homologous DNA is available for HRR. \nTargeting endo-exonucleases specifically involved in HRR will make the normal \ncells less prone to mutagenesis, rendering the fast growing tumor cells more \nsusceptible to DNA-damaging agents, used in cancer chemotherapy.", "Although alcohol consumption is related to increased cancer risk, its molecular \nmechanism remains unclear. Here, we demonstrate that an intake of 10% alcohol \nfor 4 weeks in rats is genotoxic due to induction of micronuclei. Acetaldehyde \n(AA), the first product of ethanol metabolism, is believed to be responsible for \nDNA damage induced by alcohol. Here, we observe that AA effectively blocks DNA \nreplication elongation in mammalian cells, resulting in DNA double-strand breaks \nassociated with replication. AA-induced DNA damage sites colocalize with the \nhomologous recombination (HR) repair protein RAD51. HR measured in the \nhypoxhantineguaninefosforibosyltransferase (HPRT) gene is effectively induced by \nAA and recombination defective mammalian cells are hypersensitive to AA, clearly \ndemonstrating that HR is essential in the repair of AA-induced DNA damage. \nAltogether, our data indicate that alcohol genotoxicity related to AA produces \nreplication lesions on DNA triggering HR repair.", "Repair of DNA double-strand breaks (DSB) is essential for cell viability and \ngenome stability. Homologous recombination repair plays an important role in DSB \nrepair and impairment of this repair mechanism may lead to loss of genomic \nintegrity, which is one of the hallmarks of cancer. Recent research has shown \nthat the tumor suppressor genes p53 and BRCA1 and -2 are involved in the proper \ncontrol of homologous recombination, suggesting a role of this type of repair in \nhuman cancer. We developed a novel assay based on recombination between two \nGreen Fluorescent Protein (GFP) sequences in transiently transfected plasmid \nDNA. The plasmid construct contains an intact, emission-shifted, \"blue\" variant \nof GFP (BFP), with a 300 nucleotide stretch of homology to a nonfunctional copy \nof GFP. In the absence of homologous recombination only BFP is present, but \nhomologous recombination can create a functional GFP. The homologous regions in \nthe plasmid were constructed in both the direct and the inverted orientation of \ntranscription to detect possible differences in the recombination mechanisms \ninvolved. A panel of human tumor cell lines was chosen on the basis of genetic \nbackground and chromosome integrity and tested for homologous recombination \nusing this assay. The panel included cell lines with varying levels of \nkaryotypic abnormalities, isogenic cell lines with normal and mutant p53, \nisogenic cell lines with or without DNA mismatch repair, BRCA1 and -2 mutant \ncell lines, and the lymphoma cell line DT40. With this assay, the observed \ndifferences between cell lines with the lowest and highest levels of \nrecombination were about 100-fold. Increased levels of recombination were \nassociated with mutant p53, whereas a low level of recombination was found in \nthe BRCA1 mutant cell line. In the cell line HT1080TG, a mutagenized derivative \nof HT1080 with two mutant alleles of p53, high levels of recombination were \nfound with the direct orientation but not with the inverted orientation plasmid. \nNo difference in recombination was detected between two isogenic cell lines that \nonly differed in DNA mismatch repair capability. We conclude that this assay can \ndetect differences in homologous recombination capacity in cultured cell lines \nand that these differences follow the patterns that would be expected from the \ndifferent genotypes of these cell lines. Future application in normal cells may \nbe useful to identify genetic determinants controlling genomic integrity or to \ndetect differences in DNA repair capacity in individuals.", "In cells of higher eukaryotes, repair of DNA double strand breaks (DSBs) \nutilizes different forms of potentially error-prone non-homologous end joining \n(NHEJ): canonical DNA-PK-dependent (C-NHEJ) and alternative backup pathways \n(A-NHEJ). In contrast to C-NHEJ, A-NHEJ shows pronounced efficiency fluctuations \nthroughout the cell cycle and is severely compromised as cells cease \nproliferating and enter the plateau phase (Windhofer et al., 2007 [23]). The \nmolecular mechanisms underpinning this response remain unknown but changes in \nchromatin structure are prime candidate-A-NHEJ-modulators. Since parameters \nbeyond chromatin acetylation appear to determine A-NHEJ efficiency (Manova et \nal., 2012 [42,76]), we study here the role of chromatin decondensation mediated \neither by treatment with 5'-aza-2'-deoxycytidine (AzadC) or growth in hypotonic \nconditions, on A-NHEJ. We report that both treatments have no detectable effect \non C-NHEJ but provoke, specifically for A-NHEJ, cell-growth-dependent effects. \nThese results uncover for the first time a link between A-NHEJ and chromatin \norganization and provide means for understanding the regulatory mechanisms \nunderpinning the growth-state dependency of A-NHEJ. A-NHEJ is implicated in the \nformation of chromosomal translocations and in chromosome fusions that underlie \ngenomic instability and carcinogenesis. The observations reported here may \ntherefore contribute to the development of drug-based A-NHEJ \nsuppression-strategies aiming at optimizing cancer treatment outcomes and \npossibly also at suppressing carcinogenesis.", "Brca1 deficiency leads to the development of breast cancer. We previously found \nthat Brca1 deficiency activates the Akt oncogenic pathway. Reduced expression of \nBrca1 was highly correlated with increased activated Akt in human breast cancer \nsamples. Furthermore, activation of Akt1 was involved in \nBrca1-deficiency-mediated tumorigenesis in mice. Defective homologous \nrecombination (HR) is thought to be a major contributor to tumorigenesis in \nBrca1 deficiency. Here, we show that Akt1 promotes chromosome instability in \nBrca1-deficent cells. DNA breaks in Brca1-deficent cells are aberrantly joined \ninto complex chromosome rearrangements by a process dependent on Akt1. Depletion \nof Akt1 increases HR in Brca1-mutant cells, which is rescued by expression of \nwild-type, but not mutant Akt1 with deletion of Brca1-binding domain. \nMechanistically, activated Akt1 in Brca1-deficient cells impairs Chk1 nuclear \nlocalization and subsequently disrupts interaction of Chk1 and Rad51 leading to \nHR defects. Our results indicate that Brca1 deficiency might activate Akt1 \ncontributing to tumorigenesis through regulation of the Chk1-Rad51 signaling.", "Cellular DNA is under constant challenge by exogenous and endogenous genotoxic \nstress, which results in both transient and accumulated DNA damage and genomic \ninstability. All cells are equipped with DNA damage response pathways that \ntrigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate \nDNA damage or damaged cells. The consequences of these processes for stem cells \ncan be profound: diminution in stem cell pools, or, because of altered gene \nexpression, an increased chance for stem cell differentiation or malignant \ntransformation. Furthermore, a number of DNA repair abnormalities are linked to \npremature aging syndromes, and these are associated with defects in the stem \ncell population. The specific DNA repair systems for which there are data \nregarding the impact of repair defects on stem cell function include \nO(6)-alkylguanine DNA alkyltransferase, nucleotide excision repair, base \nexcision repair, mismatch repair, non-homologous DNA end-joining Fanconi's \nanemia protein complex, and homologous recombination. It has recently become \nclear that deficiencies of these processes are associated not only with cancer \nand/or aging but also with stem cell defects. This discovery raises the \npossibility of a link between aging and stem cell dysfunction. In this review, \nwe provide evidence for a link between DNA repair systems and the maintenance \nand longevity of stem cells.", "DNA damage response and repair pathways are important barriers to \ncarcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as \nTRIM19), involved in sensing DNA damage and executing homologous recombination \nrepair, is down-regulated in non-tumour liver cells surrounding hepatitis B \nvirus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion \nwas found in HBV-infected liver or HCC cells. Immunohistochemical analysis of \nliver biopsies from patients with breast or liver cancer and HBV reactivation \nafter chemotherapy revealed PML up-regulation and HBV exacerbation in normal \nliver tissue in response to DNA damage (functional PML), PML down-regulation in \nHCC peritumour cells associated with high HBsAg accumulation and low HBV \nreplication activity (suppressive PML), and heterogeneous nuclear PML expression \nin HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage \n(dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome \nbreaks in liver cells and accelerated the accumulation of body and liver fat and \nthe development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an \ninflammation-independent and male-predominant manner, compared to PML knock-out \nor HBsAg-transgenic mice during the same time period. These results indicate \nthat PML deficiency facilitates genomic instability and promotes HBsAg-related \nhepatocarcinogenesis, which also involves androgen and lipid metabolism. These \nfindings uncover a novel PML link between HBV-related tumourigenesis, DNA \nrepair, and metabolism.", "BACKGROUND: Werner syndrome (WS) results from defects in the RecQ helicase (WRN) \nand is characterized by premature aging and accelerated tumorigenesis. \nContradictorily, WRN deficient human fibroblasts derived from WS patients show a \ncharacteristically slower cell proliferation rate, as do primary fibroblasts and \nhuman cancer cell lines with WRN depletion. Previous studies reported that WRN \nsilencing in combination with deficiency in other genes led to significantly \naccelerated cellular proliferation and tumorigenesis. The aim of the present \nstudy was to examine the effects of silencing WRN in p53 deficient HL60 and p53 \nwild-type TK6 hematopoietic cells, in order to further the understanding of \nWRN-associated tumorigenesis.\nMETHODOLOGY/PRINCIPAL FINDINGS: We found that silencing WRN accelerated the \nproliferation of HL60 cells and decreased the cell growth rate of TK6 cells. \nLoss of WRN increased DNA damage in both cell types as measured by COMET assay, \nbut elicited different responses in each cell line. In HL60 cells, but not in \nTK6 cells, the loss of WRN led to significant increases in levels of \nphosphorylated RB and numbers of cells progressing from G1 phase to S phase as \nshown by cell cycle analysis. Moreover, WRN depletion in HL60 cells led to the \nhyper-activation of homologous recombination repair via up-regulation of RAD51 \nand BLM protein levels. This resulted in DNA damage disrepair, apparent by the \nincreased frequencies of both spontaneous and chemically induced structural \nchromosomal aberrations and sister chromatid exchanges.\nCONCLUSIONS/SIGNIFICANCE: Together, our data suggest that the effects of WRN \nsilencing on cell proliferation and genomic instability are modulated probably \nby other genetic factors, including p53, which might play a role in the \ncarcinogenesis induced by WRN deficiency.", "PALB2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair \nvia homologous recombination. Heterozygous germline mutations in PALB2 confer a \nmoderate risk of breast cancer, while biallelic PALB2 mutations are linked to a \nsevere form of Fanconi anaemia characterized by early childhood solid tumours \nand severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated \ncancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss \nof the wild-type allele, suggesting PALB2 might be haploinsufficient for tumour \nsuppression. To study the role of PALB2 in development and tumourigenesis, we \nhave generated Palb2(GT) mouse mutants using a gene trap approach. Whereas \nPalb2(GT/GT) homozygous mutant embryos died at mid-gestation due to massive \napoptosis, Palb2(GT/+) heterozygous mice were viable and did not show any \nobvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2(GT/GT) \nembryos, but did not rescue embryonic lethality. In addition, loss of p53 did \nnot significantly collaborate with Palb2 heterozygosity in tumourigenesis in \nheterozygous or homozygous p53 knockout mice. Tumours arising in Palb2(GT/+) \n;p53(+/-) or Palb2(GT/+) ;p53(-/-) compound mutant mice retained the wild-type \nPalb2 allele and did not display increased genomic instability.", "DNA repair by homologous recombination (HR) may be regarded as the two faces of \na coin: lowering the oncogenetic potential (precise repair with no consequences \non genomic status) or increasing it (deleterious action which may determine \nchromosome rearrangements such as loss of heterozigosity). Inherited mutations \nin genes involved in HR are associated with gene rearrangement and may be a \nprerequisite for tumor development in some cancer-prone hereditary diseases like \nBloom, Werner and Rothmund-Thomson syndromes. Normal eukaryotic cells show some \ndegree of balance between various mechanisms of repair. This review presents the \nmain mechanisms and pathways of homologous recombination repair \n(synthesis-dependent single strand annealing, constitution of Hollidayjunctions \nwith their resolution mechanisms and repair by break induced replication), the \nproteins involved in it and their contribution to oncogenesis.", "A DNA double-strand break (DSB) has long been recognized as a severe cellular \nlesion, potentially representing an initiating event for carcinogenesis or cell \ndeath. The evolution of DSB repair pathways as well as additional processes, \nsuch as cell cycle checkpoint arrest, to minimize the cellular impact of DSB \nformation was, therefore, not surprising. However, the depth and complexity of \nthe DNA damage responses being revealed by current studies were unexpected. \nPerhaps the most surprising finding to emerge is the dramatic changes to \nchromatin architecture that arise in the DSB vicinity. In this review, we \noverview the cellular response to DSBs focusing on DNA repair pathways and the \ninterface between them. We consider additional events which impact upon these \nDSB repair pathways, including regulated arrest of cell cycle progression and \nchromatin architecture alterations. Finally, we discuss the impact of defects in \nthese processes to human disease.", "Human cells can process DNA double-strand breaks (DSBs) by either homology \ndirected or non-homologous repair pathways. Defects in components of DSB repair \npathways are associated with a predisposition to cancer. The products of the \nBRCA1 and BRCA2 genes, which normally confer protection against breast cancer, \nare involved in homology-directed DSB repair. Defects in another \nhomology-directed pathway, single-strand annealing, are associated with genome \ninstability and cancer predisposition in the Nijmegen breakage syndrome and a \nradiation-sensitive ataxia-telangiectasia-like syndrome. Many DSB repair \nproteins also participate in the signaling pathways which underlie the cell's \nresponse to DSBs.", "The maintenance of the stability of genetic material is an essential feature of \nevery living organism. Organisms across all kingdoms have evolved diverse and \nhighly efficient repair mechanisms to protect the genome from deleterious \nconsequences of various genotoxic factors that might tend to destabilize the \nintegrity of the genome in each generation. One such group of proteins that is \nactively involved in genome surveillance is the RecQ helicase family. These \nproteins are highly conserved DNA helicases, which have diverse roles in \nmultiple DNA metabolic processes such as DNA replication, recombination and DNA \nrepair. In humans, five RecQ helicases have been identified and three of them \nnamely, WRN, BLM and RecQL4 have been linked to genetic diseases characterized \nby genome instability, premature aging and cancer predisposition. This helicase \nfamily plays important roles in various DNA repair pathways including protecting \nthe genome from illegitimate recombination during chromosome segregation in \nmitosis and assuring genome stability. This review mainly focuses on various \nroles of human RecQ helicases in the process of recombination-based DNA repair \nto maintain genome stability and physiological consequences of their defects in \nthe development of cancer and premature aging." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004260', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D005785', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0000724', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D059767', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D059765', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006310', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0036298', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D063646', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D011995', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006281', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0000725', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D051721']
587f56c392a5b8ad44000001	[ 25315429 ]	train	Are deletions of chromosomal regulatory boundaries associated with congenital disease?	yesno	Yes. Enhancer adoption caused by deletions of regulatory boundaries may contribute to a substantial minority of copy-number variation phenotypes and should thus be taken into account in their medical interpretation.	yes	[ "BACKGROUND: Recent data from genome-wide chromosome conformation capture \nanalysis indicate that the human genome is divided into conserved megabase-sized \nself-interacting regions called topological domains. These topological domains \nform the regulatory backbone of the genome and are separated by regulatory \nboundary elements or barriers. Copy-number variations can potentially alter the \ntopological domain architecture by deleting or duplicating the barriers and \nthereby allowing enhancers from neighboring domains to ectopically activate \ngenes causing misexpression and disease, a mutational mechanism that has \nrecently been termed enhancer adoption.\nRESULTS: We use the Human Phenotype Ontology database to relate the phenotypes \nof 922 deletion cases recorded in the DECIPHER database to monogenic diseases \nassociated with genes in or adjacent to the deletions. We identify combinations \nof tissue-specific enhancers and genes adjacent to the deletion and associated \nwith phenotypes in the corresponding tissue, whereby the phenotype matched that \nobserved in the deletion. We compare this computationally with a gene-dosage \npathomechanism that attempts to explain the deletion phenotype based on \nhaploinsufficiency of genes located within the deletions. Up to 11.8% of the \ndeletions could be best explained by enhancer adoption or a combination of \nenhancer adoption and gene-dosage effects.\nCONCLUSIONS: Our results suggest that enhancer adoption caused by deletions of \nregulatory boundaries may contribute to a substantial minority of copy-number \nvariation phenotypes and should thus be taken into account in their medical \ninterpretation." ]	['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002872', 'http://www.disease-ontology.org/api/metadata/DOID:1086', 'http://www.disease-ontology.org/api/metadata/DOID:0080014']
54f7291630767eb92e000002	[ 21372004, 23261320, 23640490, 19488075, 22234702, 20881938, 22621747, 22981780, 22035349, 21764886, 22669047, 23448446, 24183004, 22773406, 20603647 ]	train	Are epigenetic modifications implicated in cardiovascular development and disease?	yesno	Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Aberrant epigenetic mechanisms may lead to pathological consequences such as cardiovascular disease (CAD).Recent studies have greatly expanded our understanding of the regulation of cardiovascular development at the chromatin level, including the remodeling of chromatin and the modification of histones. Thus, understanding chromatin-level regulation will allow for a better appreciation of gene regulation as a whole and may set a fundamental basis for cardiovascular disease.	yes	[ "Epigenetic control mechanisms play a key role in the regulation of embryonic \ndevelopment and tissue homeostasis and modulate cardiovascular diseases. \nIncreasing evidence suggests that lineage commitment of stem/progenitor cells is \ntightly regulated by epigenetic mechanisms. These epigenetic control mechanisms \ninclude DNA and histone modifications, which modulate the chromatin structure \nthereby regulating access of transcription factors. Particularly, the \nmodification of histone acetylation and methylation, which is controlled by \nfamilies of histone acetylases/deacetylases and methyltransferases/demethylases, \nrespectively, controls stem cell maintenance, differentiation, and function. \nThis review article summarizes our current understanding of epigenetic \nmechanisms regulating the differentiation of cardiovascular cells, specifically \nendothelial cells and cardiac muscle lineages. In particular, the article will \nfocus on the enzymes which modify histones and are involved in chromatin \nremodelling.", "A commonly-assumed paradigm holds that the primary genetic determinant of \ncardiovascular disease resides within the DNA sequence of our genes. This \nparadigm can be challenged. For example, how do sequence changes in the \nnon-coding region of the genome influence phenotype? Why are all diseases not \nshared between identical twins? Part of the answer lies in the fact that the \nenvironment or exogenous stimuli clearly influence disease susceptibility, but \nit was unclear in the past how these effects were signalled to the static DNA \ncode. Epigenetics is providing a newer perspective on these issues. Epigenetics \nrefers to chromatin-based mechanisms important in the regulation of gene \nexpression that do not involve changes to the DNA sequence per se. The field can \nbe broadly categorized into three areas: DNA base modifications (including \ncytosine methylation and cytosine hydroxymethylation), post-translational \nmodifications of histone proteins, and RNA-based mechanisms that operate in the \nnucleus. Cardiovascular disease pathways are now being approached from the \nepigenetic perspective, including those associated with atherosclerosis, \nangiogenesis, ischemia-reperfusion damage, and the cardiovascular response to \nhypoxia and shear stress, among many others. With increasing interest and \nexpanding partnerships in the field, we can expect new insights to emerge from \nepigenetic perspectives of cardiovascular health. This paper reviews the \nprinciples governing epigenetic regulation, discusses their presently-understood \nimportance in cardiovascular disease, and considers the growing significance we \nare likely to attribute to epigenetic contributions in the future, as they \nprovide new mechanistic insights and a host of novel clinical applications.", "Genetic and epigenetic factors are of great importance in cardiovascular biology \nand disease. Tobacco-smoking, one of the most important cardiovascular risk \nfactors, is itself partially determined by genetic background and is associated \nwith altered epigenetic patterns. This could render the genetics and epigenetics \nof smoking-related cardiovascular disease a textbook example of environmental \nepigenetics and modern approaches to multimodal data analysis. A pronounced \nassociation of smoking-related methylation patterns in the F2RL3 gene with \nprognosis in patients with stable coronary heart disease has recently been \ndescribed. Nonetheless, surprisingly little concrete knowledge on the role of \nspecific genetic variants and epigenetic modifications in the development of \ncardiovascular diseases in people who smoke has been accumulated. Beyond the \ncurrent knowledge, the present review briefly outlines some chief challenges and \npriorities for moving forward in this field.", "Cellular commitment to a specific lineage is controlled by differential \nsilencing of genes, which in turn depends on epigenetic processes such as DNA \nmethylation and histone modification. During early embryogenesis, the mammalian \ngenome is 'wiped clean' of most epigenetic modifications, which are \nprogressively re-established during embryonic development. Thus, the epigenome \nof each mature cellular lineage carries the record of its developmental history. \nThe subsequent trajectory and pattern of development are also responsive to \nenvironmental influences, and such plasticity is likely to have an epigenetic \nbasis. Epigenetic marks may be transmitted across generations, either directly \nby persisting through meiosis or indirectly through replication in the next \ngeneration of the conditions in which the epigenetic change occurred. \nDevelopmental plasticity evolved to match an organism to its environment, and a \nmismatch between the phenotypic outcome of adaptive plasticity and the current \nenvironment increases the risk of metabolic and cardiovascular disease. These \nconsiderations point to epigenetic processes as a key mechanism that underpins \nthe developmental origins of chronic noncommunicable disease. Here, we review \nthe evidence that environmental influences during mammalian development lead to \nstable changes in the epigenome that alter the individual's susceptibility to \nchronic metabolic and cardiovascular disease, and discuss the clinical \nimplications.", "Epigenetics represents a phenomenon of altered heritable phenotypic expression \nof genetic information occurring without changes in DNA sequence. Epigenetic \nmodifications control embryonic development, differentiation and stem cell \n(re)programming. These modifications can be affected by exogenous stimuli (e.g., \ndiabetic milieu, smoking) and oftentimes culminate in disease initiation. DNA \nmethylation has been studied extensively and represents a well-understood \nepigenetic mechanism. During this process cytosine residues preceding a \nguanosine in the DNA sequence are methylated. CpG-islands are short-interspersed \nDNA sequences with clusters of CG sequences. The abnormal methylation of CpG \nislands in the promoter region of genes leads to a silencing of genetic \ninformation and finally to alteration of biological function. Emerging data \nsuggest that these epigenetic modifications also impact on the development of \ncardiovascular disease. Histone modifications lead to the modulation of the \nexpression of genetic information through modification of DNA accessibility. In \naddition, RNA-based mechanisms (e.g., microRNAs and long non-coding RNAs) \ninfluence the development of disease. We here outline the recent work pertaining \nto epigenetic changes in a cardiovascular disease setting.", "Epigenetics refers to a heritable change in the pattern of gene expression that \nis mediated by a mechanism specifically not due to alterations in the primary \nnucleotide sequence. Well-known epigenetic mechanisms encompass DNA methylation, \nchromatin remodeling (histone modifications), and RNA interference. \nFunctionally, epigenetics provides an extra layer of transcriptional control and \nplays a crucial role in normal physiological development, as well as in \npathological conditions. Aberrant DNA methylation is implicated in immune \ndysfunction, inflammation, and insulin resistance. Epigenetic changes may be \nresponsible for 'metabolic memory' and development of micro- and macrovascular \ncomplications of diabetes. MicroRNAs are critical in the maintenance of \nglomerular homeostasis and hence RNA interference may be important in the \nprogression of renal disease. Recent studies have shown that epigenetic \nmodifications orchestrate the epithelial-mesenchymal transition and eventually \nfibrosis of the renal tissue. Oxidative stress, inflammation, \nhyperhomocysteinemia, and uremic toxins could induce epimutations in chronic \nkidney disease. Epigenetic alterations are associated with inflammation and \ncardiovascular disease in patients with chronic kidney disease. Reversible \nnature of the epigenetic changes gives a unique opportunity to halt or even \nreverse the disease process through targeted therapeutic strategies.", "Consolidated knowledge is accumulating as to the role of epigenetic regulatory \nmechanisms in the physiology of vascular development and vascular tone as well \nas in the pathogenesis of cardiovascular disease. The modulation of gene \nexpression through modification of the epigenome by structural changes of the \nchromatin architecture without alterations of the associated genomic DNA \nsequence is part of the cellular response to environmental changes. Such \nenvironmental conditions, which are finally being translated into adaptations of \nthe cardiovascular system, also comprise pathological conditions such as \natherosclerosis or myocardial infarction. This review summarizes recent findings \non the epigenetics of vascular regulation and disease and presents nutritional \nand pharmacological approaches as novel epigenetic strategies in the prevention \nand treatment of cardiovascular disease.", "Epigenetic phenomena are defined as heritable mechanisms that establish and \nmaintain mitotically stable patterns of gene expression without modifying the \nbase sequence of DNA. The major epigenetic features of mammalian cells include \nDNA methylation, post-translational histone modifications and RNA-based \nmechanisms including those controlled by small non-coding RNAs (miRNAs). The \nimpact of epigenetic mechanisms in cardiovascular pathophysiology is now \nemerging as a major player in the interface between genotype to phenotype \nvariability. This topic of research has strict implications on disease \ndevelopment and progression, and opens up possible novel preventive strategies \nin cardiovascular disease. An important aspect of epigenetic mechanisms is that \nthey are potentially reversible and may be influenced by \nnutritional-environmental factors and through gene-environment interactions, all \nof which have an important role in complex, multifactorial diseases such as \nthose affecting the cardiovascular system. Gene expression regulation through \nthe interplay of DNA methylation and histone modifications is well-established, \nalthough the knowledge about the function of epigenetic signatures in \ncardiovascular disease is still largely unexplored. The study of epigenetic \nmarkers is, therefore, a very promising frontier of science which may aid in a \ndeeper understanding of molecular mechanisms underlying the modulation of gene \nexpression in the biomolecule pathways linked to cardiovascular diseases. This \nreview focuses on up-to-date knowledge pertaining to the role of epigenetics, \nfrom DNA methylation to miRNAs, in major cardiovascular diseases such as \nischemic heart disease, hypertension, heart failure and stroke.", "The cardiovascular system is broadly composed of the heart, which pumps blood, \nand the blood vessels, which carry blood to and from tissues of the body. Heart \nmalformations are the most serious common birth defect, affecting at least 2% of \nnewborns and leading to significant morbidity and mortality. Severe heart \nmalformations cause heart failure in fetuses, infants, and children, whereas \nmilder heart defects may not trigger significant heart dysfunction until early \nor midadulthood. Severe vasculogenesis or angiogenesis defects in embryos are \nincompatible with life, and anomalous arterial patterning may cause vascular \naberrancies that often require surgical treatment. It is therefore important to \nunderstand the underlying mechanisms that control cardiovascular development. \nUnderstanding developmental mechanisms will also help us design better \nstrategies to regenerate cardiovascular tissues for therapeutic purposes. An \nimportant mechanism regulating genes involves the modification of chromatin, the \nhigher-order structure in which DNA is packaged. Recent studies have greatly \nexpanded our understanding of the regulation of cardiovascular development at \nthe chromatin level, including the remodeling of chromatin and the modification \nof histones. Chromatin-level regulation integrates multiple inputs and \ncoordinates broad gene expression programs. Thus, understanding chromatin-level \nregulation will allow for a better appreciation of gene regulation as a whole \nand may set a fundamental basis for cardiovascular disease. This review focuses \non how chromatin-remodeling and histone-modifying factors regulate gene \nexpression to control cardiovascular development.", "Several studies indicate that impaired foetal growth, and in utero exposure to \nrisk factors, especially maternal hypercholesterolaemia, may be relevant for the \nearly onset of cardiovascular damage. The exact molecular mechanisms of such \nfoetal programming are still unclear. Epigenetics may represent one of the \npossible scientific explanations of the impact of such intrauterine risk factors \nfor the subsequent development of cardiovascular disease (CVD) during adulthood. \nTranslational studies support this hypothesis; however, a direct causality in \nhumans has not been ascertained. This hypothesis could be investigated in \nprimates and in human post-mortem foetal arteries. Importantly, some studies \nalso suggest the transgenerational transmission of epigenetic risk. The recently \nlaunched International Human Epigenome Consortium and the NIH Roadmap \nEpigenomics Mapping Consortium will provide the rationale for a useful clinical \nscenario for primary prevention and therapy of CVD. Despite the heritable nature \nof epigenetic modification, the clinically relevant information shows that it \ncould be reversible through therapeutic approaches, including histone \ndeacetylase inhibitors, histone acetyltransferase inhibitors, and commonly used \ndrugs such as statins.", "PURPOSE OF REVIEW: Epigenetic modifications are heritable alterations of the \ngenome, which can govern gene expression without altering the DNA sequence. The \npurpose of this review is to render an overview of the possible mechanisms of \nepigenetic regulation of gene expression in response to environmental pollutants \nleading to cardiovascular diseases (CVD).\nRECENT FINDINGS: An era of cataloging epigenetic marks of the various diseased \nstates has recently commenced, including those within the genes responsible for \natherosclerosis, ischemia, hypertension and heart failure. From varied study \napproaches directed either toward the general understanding of the key pathway \nregulatory genes, or sampling population cohorts for global and gene-specific \nchanges, it has been possible to identify several epigenetic signatures of \nenvironmental exposure relevant to CVD. Signatures of epigenetic dysregulation \ncan be detected in peripheral blood samples, even within a few hours of \nenvironmental exposure. However, the field now faces the demand for thorough, \nsystematic, rationalized approaches to establish the relation of exposure-driven \nepigenetic changes to clinical outcomes, by using sophisticated and reliable \nresearch designs and tools.\nSUMMARY: An understanding of chromatin remodelling in response to environmental \nstimuli conducive to CVD is emerging, with the promise of novel diagnostic and \ntherapeutic candidates.", "An epigenetic change is defined as an alteration in gene expression that does \nnot involve a change in the DNA sequence. Epigenetic modifications, including \nDNA methylation, histone modification (acetylation, methylation and \nphosphorylation) and miRNA, are critical for regulating developmental events. \nHowever, aberrant epigenetic mechanisms may lead to pathological consequences \nsuch as cardiovascular disease (CAD), neurodegenerative disease, obesity, \nmetabolic disorder, bone and skeletal diseases and various cancers. Given that \nepigenetic modifications are heritable and reversible, in contrast to genetic \nchanges, they have been identified as promising targets for disease prevention \nstrategies. Over the past few decades, polyphenols, which are widely present in \nfoods such as fruits and vegetables, have been shown to exhibit a broad spectrum \nof biological activities for human health. Polyphenols reverse adverse \nepigenetic regulation by altering DNA methylation and histone modification, and \nthey modulate microRNA expression or directly interact with enzymes that result \nin the reactivation of silenced tumor suppressor genes or the inactivation of \noncogenes. Therefore, dietary polyphenol- targeted epigenetics becomes an \nattractive approach for disease prevention and intervention. In this review, we \nsummarize the current knowledge and underlying mechanisms of the most common \ndietary polyphenols and their influence on major epigenetic mechanisms \nassociated with disease intervention.", "Our understanding of congenital heart defects has been recently advanced by \nwhole exome sequencing projects, which have identified de novo mutations in many \ngenes encoding epigenetic regulators. Notably, multiple subunits of switching \ndefective/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes have \nbeen identified as strong candidates underlying these defects because they \nphysically and functionally interact with cardiogenic transcription factors \ncritical to cardiac development, such as TBX5, GATA-4, and NKX2-5. While these \nstudies indicate a critical role of SWI/SNF complexes in cardiac development and \ncongenital heart disease, many exciting new discoveries have identified their \ncritical role in the adult heart in both physiological and pathological \nconditions involving multiple cell types in the heart, including cardiomyocytes, \nvascular endothelial cells, pericytes, and neural crest cells. This review \nsummarizes the role of SWI/SNF chromatin-remodeling complexes in cardiac \ndevelopment, congenital heart disease, cardiac hypertrophy, and vascular \nendothelial cell survival. Although the clinical relevance of SWI/SNF mutations \nhas traditionally been focused primarily on their role in tumor suppression, \nthese recent studies illustrate their critical role in the heart whereby they \nregulate cell proliferation, differentiation, and apoptosis of cardiac derived \ncell lines.", "Epigenetics, through control of gene expression circuitries, plays important \nroles in various physiological processes such as stem cell differentiation and \nself renewal. This occurs during embryonic development, in different tissues, \nand in response to environmental stimuli. The language of epigenetic program is \nbased on specific covalent modifications of DNA and chromatin. Thus, in addition \nto the individual identity, encoded by sequence of the four bases of the DNA, \nthere is a cell type identity characterized by its positioning in the epigenetic \n\"landscape\". Aberrant changes in epigenetic marks induced by environmental cues \nmay contribute to the development of abnormal phenotypes associated with \ndifferent human diseases such as cancer, neurological disorders and \ninflammation. Most of the epigenetic studies have focused on embryonic \ndevelopment and cancer biology, while little has been done to explore the role \nof epigenetic mechanisms in the pathogenesis of cardiovascular disease. This \nreview highlights our current knowledge of epigenetic gene regulation and the \nevidence that chromatin remodeling and histone modifications play key roles in \nthe pathogenesis of cardiovascular disease through (re)programming of \ncardiovascular (stem) cells commitment, identity and function.", "Despite advances in the prevention and management of cardiovascular disease \n(CVD), this group of multifactorial disorders remains a leading cause of \nmortality worldwide. CVD is associated with multiple genetic and modifiable risk \nfactors; however, known environmental and genetic influences can only explain a \nsmall part of the variability in CVD risk, which is a major obstacle for its \nprevention and treatment. A more thorough understanding of the factors that \ncontribute to CVD is, therefore, needed to develop more efficacious and \ncost-effective therapy. Application of the 'omics' technologies will hopefully \nmake these advances a reality. Epigenomics has emerged as one of the most \npromising areas that will address some of the gaps in our current knowledge of \nthe interaction between nature and nurture in the development of CVD. Epigenetic \nmechanisms include DNA methylation, histone modification, and microRNA \nalterations, which collectively enable the cell to respond quickly to \nenvironmental changes. A number of CVD risk factors, such as nutrition, smoking, \npollution, stress, and the circadian rhythm, have been associated with \nmodification of epigenetic marks. Further examination of these mechanisms may \nlead to earlier prevention and novel therapy for CVD." ]	['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D057890', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002318']
6278ddfe56bf9aee6f000013	[ 31546754, 34155911, 22699538, 31879850, 29167533, 30180785, 22974002, 8347064, 30688316, 30404418, 16102988, 29742798, 31009620, 21800026, 21954141, 28084836, 24762862, 32390640, 32022138, 29174526 ]	train	Are functional tests a good biomarker for Duchenne Muscular Dystrophy?	yesno	North Star Ambulatory Assessment is practical and reliable. allow assessment of high-functioning boys with Duchenne muscular dystrophy.	yes	[ "Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder \ncaused by out of frame mutations in the dystrophin gene. The hallmark symptoms \nof the condition include progressive degeneration of skeletal muscle, \ncardiomyopathy, and respiratory dysfunction. The most recent advances in \ntherapeutic strategies for the treatment of DMD involve exon skipping or \nadministration of minidystrophin, but these strategies are not yet universally \navailable, nor have they proven to be a definitive cure for all DMD patients. \nEarly diagnosis and tracking of symptom progression of DMD usually relies on \ncreatine kinase tests, evaluation of patient performance in various ambulatory \nassessments, and detection of dystrophin from muscle biopsies, which are \ninvasive and painful for the patient. While the current research focuses \nprimarily on restoring functional dystrophin, accurate and minimally invasive \nmethods to detect and track both symptom progression and the success of early \nDMD treatments are not yet available. In recent years, several groups have \nidentified miRNA signature changes in DMD tissue samples, and a number of \npromising studies consistently detected changes in circulating miRNAs in blood \nsamples of DMD patients. These results could potentially lead to non-invasive \ndetection methods, new molecular approaches to treating DMD symptoms, and new \nmethods to monitor of the efficacy of the therapy. In this review, we focus on \nthe role of circulating miRNAs in DMD and highlight their potential both as a \nbiomarker in the early detection of disease and as a therapeutic target in the \nprevention and treatment of DMD symptoms.", "Aim: Using baseline data from a clinical trial of domagrozumab in Duchenne \nmuscular dystrophy, we evaluated the correlation between functional measures and \nquantitative MRI assessments of thigh muscle. Patients & methods: Analysis \nincluded timed functional tests, knee extension/strength and North \nStar Ambulatory Assessment. Patients (n = 120) underwent examinations of one \nthigh, with MRI sequences to enable measurements of muscle volume (MV), MV \nindex, mean T2 relaxation time via T2-mapping and fat fraction. Results: MV was \nmoderately correlated with strength assessments. MV index, fat fraction and \nT2-mapping measures had moderate correlations (r ∼ 0.5) to all functional tests, \nNorth Star Ambulatory Assessment and age. Conclusion: The moderate correlation \nbetween functional tests, age and baseline MRI measures supports MRI as a \nbiomarker in Duchenne muscular dystrophy clinical trials. Trial registration: \nClinicalTrials.gov, NCT02310763; registered 4 November 2014.", "OBJECTIVE: Evaluate muscle force and motor function in patients with Duchenne \nmuscular dystrophy (DMD) in a period of six months.\nMETHOD: Twenty children and adolescents with diagnosis of DMD were evaluated \ntrough: measurement of the strength of the flexors and extensors of the \nshoulder, elbow, wrist, knee and ankle through the Medical Research Council \n(MRC), and application of the Motor Function Measure (MFM). The patients were \nevaluated twice within a six-month interval.\nRESULTS: Loss of muscle strength was identified in the MRC score for upper \nproximal members (t=-2.17, p=0.04). In the MFM, it was noted significant loss in \nthe dimension 1 (t=-3.06, p=0.006). Moderate and strong correlations were found \nbetween the scores for muscular strength and the MFM dimensions.\nCONCLUSION: The MFM scale was a useful instrument in the follow up of patients \nwith DMD. Moreover, it is a more comprehensive scale to assess patients and very \ngood for conducting trials to evaluate treatment.", "As the drug development pipeline for Duchenne muscular dystrophy (DMD) rapidly \nadvances, clinical trial outcomes need to be optimized. Effective assessment of \ndisease burden, natural history progression, and response to therapy in clinical \ntrials for Duchenne muscular dystrophy are critical factors for clinical trial \nsuccess. By choosing optimal biomarkers to better assess therapeutic efficacy, \nstudy costs and sample size requirements can be reduced. Currently, functional \nmeasures continue to serve as the primary outcome for the majority of DMD \nclinical trials. Quantitative measures of muscle health, including magnetic \nresonance imaging and spectroscopy, electrical impedance myography, and \nultrasound, sensitively identify diseased muscle, disease progression, and \nresponse to a therapeutic intervention. Furthermore, such non-invasive \ntechniques have the potential to identify disease pathology prior to onset of \nclinical symptoms. Despite robust supportive evidence, non-invasive quantitative \ntechniques are still not frequently utilized in clinical trials for Duchenne \nmuscular dystrophy. Non-invasive quantitative techniques have demonstrated the \nability to quantify disease progression and potential response to therapeutic \nintervention, and should be used as a supplement to current standard functional \nmeasures. Such methods have the potential to significantly accelerate the \ndevelopment and approval of therapies for DMD.", "Becker muscular dystrophy (BMD) is a neuromuscular disorder allelic to Duchenne \nmuscular dystrophy (DMD), caused by in-frame mutations in the dystrophin gene, \nand characterized by a clinical progression that is both milder and more \nheterogeneous than DMD. Muscle magnetic resonance imaging (MRI) has been \nproposed as biomarker of disease progression in dystrophinopathies. Correlation \nwith clinically meaningful outcome measures such as North Star Ambulatory \nAssessment (NSAA) and 6 minute walk test (6MWT) is paramount for biomarker \nqualification. In this study, 51 molecularly confirmed BMD patients (aged 7-69 \nyears) underwent muscle MRI and were evaluated with functional measures (NSAA \nand 6MWT) at the time of the MRI, and subsequently after one year. We confirmed \na pattern of fatty substitution involving mainly the hip extensors and most \nthigh muscles. Severity of muscle fatty substitution was significantly \ncorrelated with specific DMD mutations: in particular, patients with an isolated \ndeletion of exon 48, or deletions bordering exon 51, showed milder involvement. \nFat infiltration scores correlated with baseline functional measures, and \npredicted changes after 1 year. We conclude that in BMD, skeletal muscle MRI not \nonly strongly correlates with motor function, but also helps in predicting \nfunctional deterioration within a 12-month time frame.", "OBJECTIVE: To investigate the effects of lower limb flexibility on the \nfunctional performance of children with Duchenne muscular dystrophy.\nMETHODS: Thirty children, whose functional levels were at 1 or 2 according to \nthe Brooke Lower Extremity Functional Classification Scale, were included in \nthis study. The flexibilities of the hamstrings, hip flexors, tensor fascia \nlatae, and gastrocnemius muscles were evaluated in the children's dominant lower \nlimbs. The children's functional performance was assessed using 6-minute walk \ntests and timed performance tests. The correlations between the flexibilities of \nthe lower limb muscles and the performance tests were examined.\nRESULTS: The flexibilities of the lower extremity muscles were found to be \ncorrelated to the 6-minute walk tests and the timed performance tests. The \nflexibility of the hamstrings (r = -.825), the gastrocnemius muscles (r = .545), \nthe hip flexors (r = .481), and the tensor fascia latae (r = .445) were found to \nbe correlated with functional performance as measured by the 6-minute walk tests \n(P < .05).\nDISCUSSION: The results of the current study indicate that the flexibility of \nthe lower limbs has an effect on functional performance in the early stages of \nDuchenne muscular dystrophy. More research is needed to determine the functional \neffects of flexibility on performance by adding long-term flexibility exercises \nto the physiotherapy programs of children with Duchenne muscular dystrophy.", "BACKGROUND: The aim of this study was to perform a longitudinal assessment using \nQuantitative Muscle Testing (QMT) in a cohort of ambulant boys affected by \nDuchenne muscular dystrophy (DMD) and to correlate the results of QMT with \nfunctional measures. This study is to date the most thorough long-term \nevaluation of QMT in a cohort of DMD patients correlated with other measures, \nsuch as the North Star Ambulatory Assessment (NSAA) or three 6-min walk test \n(6MWT).\nMETHODS: This is a single centre, prospective, non-randomised, study assessing \nQMT using the Kin Com(®) 125 machine in a study cohort of 28 ambulant DMD boys, \naged 5 to 12 years. This cohort was assessed longitudinally over a 12 months \nperiod of time with 3 monthly assessments for QMT and with assessment of \nfunctional abilities, using the NSAA and the 6MWT at baseline and at 12 months \nonly. QMT was also used in a control group of 13 healthy age-matched boys \nexamined at baseline and at 12 months.\nRESULTS: There was an increase in QMT over 12 months in boys below the age of \n7.5 years while in boys above the age of 7.5 years, QMT showed a significant \ndecrease. All the average one-year changes were significantly different than \nthose experienced by healthy controls. We also found a good correlation between \nquantitative tests and the other measures that was more obvious in the stronger \nchildren.\nCONCLUSION: Our longitudinal data using QMT in a cohort of DMD patients suggest \nthat this could be used as an additional tool to monitor changes, providing \nadditional information on segmental strength.", "Eighteen boys with Duchenne muscular dystrophy (DMD) were assessed for their \nability to perform tasks involving wrist and hand function. Each subject was \nassessed using the Jebsen Test of Hand Function, range of motion measurements, \nand muscle strength tests. Writing and simulated page turning were performed \nsuccessfully by boys in all age groups. Boys over age 15 had difficulty \ncompleting simulated feeding and picking up large and small objects. The muscle \nstrength of the wrist extensors and the radial deviation range of motion at the \nwrist were found to be strongly correlated with six of the seven tasks assessed. \nThese two clinical assessments appear to be good indicators of overall wrist and \nhand function. Life expectancy with DMD is increasing with advances in \nrespiratory care making preservation of wrist and hand function, the major \nactivity remaining with advanced disease, increasingly important.", "While the number of new treatment options tested in patients with Duchenne \nmuscular dystrophy (DMD) is increasing, there is still no defining of the most \nreliable assessments regarding therapeutic efficacy. We present clinical and \nradiological outcome measures used in ambulatory patients participating in our \ntrial \"Treatment with L-citrulline and metformin in Duchenne muscular \ndystrophy\". The motor function measure is a validated test in patients with \nneuromuscular disorders that consists of 32 items and assesses all three \ndimensions of motor performance including standing and transfer (D1 subscore), \naxial and proximal motor function (D2 subscore), and distal motor function (D3 \nsubscore). The test shows high intra- and inter-rater variability but only when \nstrictly following guidelines of the materials, examination steps, and \ncalculation of scores. The 6-minute walk test, timed 10-meter walk/run test, and \nsupine-up time are commonly used timed functional tests that also sufficiently \nmonitor changes in muscle function; however, they strongly depend on patient \ncollaboration. Quantitative MRI is an objective and sensitive biomarker to \ndetect subclinical changes, though the examination costs may be a reason for its \nlimited use. In this study, a high correlation between all clinical assessments \nand quantitative MRI scans was found. The combinational use of these methods \nprovides a better understanding about disease progression; however, longitudinal \nstudies are needed to validate their reliability.", "OBJECTIVE: To develop a simplified functional scale and classification system to \nevaluate the functional abilities of patients with Duchenne muscular dystrophy \n(DMD).\nMETHODS: A Comprehensive Functional Scale for DMD (CFSD) was developed using the \nmodified Delphi method. The accompanying Ambulatory Functional Classification \nSystem for DMD (AFCSD) was developed based on previously published \nclassification systems.\nRESULTS: The CFSD consists of 21 items and 78 sub-items, assessing body \nstructure and function, activities, and participation. Inter-rater intraclass \ncorrelation coefficient values were above 0.7 for 17 items. The overall limits \nof agreement between the two examiners ranged from -6.21 to 3.11. The Spearman \ncorrelation coefficient between the total score on the AFCSD and the Vignos \nFunctional Scale was 0.833, and 0.714 between the total score of the AFCSD and \nthe Brooke scale. Significant negative correlations existed between the total \nscore for each functional level of the AFCSD and each functional grade of the \nVignos and Brooke scales. The total scores of the CFSD varied significantly \nbetween the functional grades of the Vignos scale, and specific grades of the \nBrooke scale. For the AFCSD, total scores of the CFSD varied significantly \nbetween the functional levels.\nCONCLUSION: We have developed a new scale and the associated classification \nsystem, to assess the functional ability of children diagnosed with DMD. \nPreliminary evaluation of the psychometric properties of the functional scale \nand classification systems indicate sufficient reliability and concurrent \nvalidity.", "Neuromuscular disorders are characterised by progressive muscle weakness, which \nin time causes functional impairment. To quantify the extent of disease \nprogression, muscle force and functional ability can be measured. Which of these \nparameters changes most depends on the disease stage. In a previous study, we \nreported normal values for muscle force obtained by hand-held dynamometry in \nhealthy children aged 4-16 years. In the present study, we report normal values \nfor timed functional tests in healthy children aged 4-11 years. These normal \nvalues were compared with values obtained in 16 ambulant patients with Duchenne \nmuscular dystrophy (DMD) aged 5-8 years to study the extent of functional \nimpairment. In ambulant patients with DMD, we found that muscle function \nassessed by timed functional tests (running 9 m and rising up from the floor) \nand muscle force assessed by hand-held dynamometry were severely impaired. \nHowever, a small reduction of muscle force was accompanied by a large reduction \nin functional ability. Therefore, in our group of ambulant patients with DMD, \ntimed functional testing was the most sensitive parameter to determine the \nextent of disease progression. Timed functional testing may therefore be \nconsidered as an additional outcome measure in drug trials to evaluate the \neffects of therapy in ambulant patients with DMD and possibly in other \nneuromuscular disorders.", "INTRODUCTION: Tests of ambulatory function are common clinical trial endpoints \nin Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study \nhas generated a large data set that can describe the contemporary natural \nhistory of DMD in 5-12.9-year-olds.\nMETHODS: Ninety-two corticosteroid-treated boys with DMD and 45 controls \nparticipated in this longitudinal study. Participants performed the 6-minute \nwalk test (6MWT) and timed function tests (TFT: 10-m walk/run, climbing 4 \nstairs, supine to stand).\nRESULTS: Boys with DMD had impaired functional performance even at 5-6.9 years \nold. Boys older than 7 had significant declines in function over 1 year for 10-m \nwalk/run and 6MWT. Eighty percent of participants could perform all functional \ntests at 9 years old. TFTs appear to be slightly more responsive and predictive \nof disease progression than the 6MWT in 7-12.9 year olds.\nDISCUSSION: This study provides insight into the contemporary natural history of \nkey functional endpoints in DMD. Muscle Nerve 58: 631-638, 2018.", "OBJECTIVE: Duchenne muscular dystrophy, an X-linked genetic disease, leads to \nprogressive muscle weakness mainly in the lower limbs. Motor function tests help \nto monitor disease progression. Can low-cost, simple assessments help in the \ndiagnostic suspicion of Duchenne muscular dystrophy? The authors aim to define \nthe sensitivity of time to rise from the floor, time to walk 10meters, and time \nto run 10meters, evaluating them as eventual diagnostic screening tools.\nMETHODS: This is an analytical, observational, retrospective (1998-2015), and \nprospective study (2015-2018). Cases were recruited from the database of the \npediatric neurology department and the healthy, from child care consultations, \nwith normal gait development (up to 15 months) and without other comorbidities \n(neuromuscular, pulmonary, heart diseases) from the same university hospital.\nRESULTS: 128 Duchenne muscular dystrophy patients and 344 healthy children were \nanalyzed, equally distributed in age groups. In Duchenne muscular dystrophy, \nthere is a progressive increase in the means of the times to perform the motor \ntests according to the age group, which accelerates very abruptly after 7 years \nof age. Healthy children acquire maximum motor capacity at 6 years and stabilize \ntheir times. The time to rise showed a p-value <0.05 and a strong association \n(effect size [ES] >0.8) in all age groups (except at 12 years), with time to \nwalk 10 meters from 9 years, and with time to run 10 meters , from 5 years. The \n100% sensitivity points were defined as follows: time to rise, at 2s; time to \nwalk 10 meters, 5s; time to run 10 meters, 4s.\nCONCLUSIONS: Time to rise is a useful and simple tool in the screening of \nneuromuscular disorders such as Duchenne muscular dystrophy, a previously \nincurable disease with new perspectives for treatment.", "OBJECTIVE: To describe the involvement of lower leg muscles in boys with \nDuchenne muscular dystrophy (DMD) by using MR imaging (MRI) and spectroscopy \n(MRS) correlated to indices of functional status.\nSUBJECTS AND METHODS: Nine boys with DMD (mean age, 11 years) and eight healthy \nage- and BMI-matched boys (mean age, 13 years) prospectively underwent lower leg \nMRI, 1H-MRS of tibialis anterior (TA) and soleus (SOL) for lipid fraction \nmeasures, and 31P-MRS for pH and high-energy phosphate measures. DMD subjects \nwere evaluated using the Vignos lower extremity functional rating, and tests \nincluding 6 min walk test (6MWT) and 10 m walk.\nRESULTS: DMD subjects had highest fatty infiltration scores in peroneal muscles, \nfollowed by medial gastrocnemius and soleus. Compared to controls, DMD boys \nshowed higher intramuscular fat (P = 0.04), lipid fractions of TA and SOL \n(P = 0.02 and 0.003, respectively), pH of anterior compartment (P = 0.0003), and \nlower phosphocreatine/inorganic phosphorus ratio of posterior compartment \n(P = 0.02). The Vignos rating correlated with TA (r = 0.79, P = 0.01) and SOL \n(r = 0.71, P = 0.03) lipid fractions. The 6MWT correlated with fatty \ninfiltration scores of SOL (r = -0.76, P = 0.046), medial (r = -0.80, P = 0.03) \nand lateral (r = -0.84, P = 0.02) gastrocnemius, intramuscular fat (r = -0.80, \nP = 0.03), and SOL lipid fraction (r = -0.89, P = 0.007). Time to walk 10 m \ncorrelated with anterior compartment pH (r = 0.78, P = 0.04).\nCONCLUSION: Lower leg muscles of boys with DMD show a distinct involvement \npattern and increased adiposity that correlates with functional status. Lower \nleg MRI and 1H-MRS studies may help to noninvasively demonstrate the severity of \nmuscle involvement.", "BACKGROUND AND PURPOSE: The aims of this study were to develop a clinical \nassessment scale to measure functional ability in ambulant boys with Duchenne \nmuscular dystrophy and to determine the reliability of the scale in multiple \ncentres in the UK.\nMETHODS: Focus groups and workshops were held with experienced paediatric \nneuromuscular physiotherapists to determine scale content. A manual was prepared \nwith accompanying videos, and training sessions were conducted. A total of 17 \nphysiotherapists from participating centres used the videos to determine \ninter-rater reliability. Five determined the intra-rater reliability.\nRESULTS: Strength of agreement for these groups based on total subject scores \nwas very good (0.95 and ≥ 0.93 for consistency and absolute agreement, \nrespectively). Test-retest ability was high, with perfect agreement between \noccasions for all but two items of the scale.\nCONCLUSIONS: Our study indicates that the North Star Ambulatory Assessment is \npractical and reliable. It takes only 10 minutes to perform and incorporates \nboth universally used timed tests as well as levels of activities, which allow \nassessment of high-functioning boys with Duchenne muscular dystrophy.", "PURPOSE: Duchenne muscular dystrophy can lead to upper extremity limitations, \npain and stiffness. In a previous study, these domains have been investigated \nusing extensive questionnaires, which are too time-consuming for clinical \npractice. This study aimed at gaining insight into the underlying dimensions of \nthese questionnaires, and to construct a short questionnaire that can be used \nfor clinical assessment.\nMETHODS: Exploratory factor analysis was performed on the responses of 213 \nparticipants to a web-based survey to find the underlying dimensions in the \nCapabilities of Upper Extremity questionnaire, the ABILHAND questionnaire, and \nquestionnaires regarding pain and stiffness. Based on these underlying \ndimensions, a stepwise approach was formulated. In addition, construct validity \nof the factors was investigated.\nRESULTS: In total, 14 factors were identified. All had high internal consistency \n(Cronbach's alpha >0.89) and explained 80-88% of the variance of the original \nquestionnaires. Construct validity was supported, because participants in the \nearly ambulatory stage performed significantly better (p< 0.001) than \nparticipants in the late non-ambulatory stage.\nCONCLUSION: The factors identified from the set of questionnaires provide a \nvalid representation of upper extremity function, pain and stiffness in Duchenne \nmuscular dystrophy. Based on the factor commonalities, the Upper Limb Short \nQuestionnaire was formulated. Implications for Rehabilitation New insights into \nthe underlying dimensions of upper extremity function, pain and stiffness in \nDuchenne muscular dystrophy are gained. Fourteen factors, with good internal \nconsistency and construct validity, are identified regarding upper extremity \nfunction, pain and stiffness in Duchenne muscular dystrophy. Based on these \nfactors, the Upper Limb Short Questionnaire is presented. The Upper Limb Short \nQuestionnaire can be used as an identifier of arm-hand limitations and the start \nof more thorough clinical investigation.", "Accelerometry provides information on habitual physical capability that may be \nof value in the assessment of function in Duchenne muscular dystrophy. This \npreliminary investigation describes the relationship between community \nambulation measured by the StepWatch activity monitor and the current standard \nof functional assessment, the 6-minute walk test, in ambulatory boys with \nDuchenne muscular dystrophy (n = 16) and healthy controls (n = 13). All \nparticipants completed a 6-minute walk test and wore the StepWatch™ monitor for \n5 consecutive days. Both the 6-minute walk test and StepWatch accelerometry \nidentified a decreased capacity for ambulation in boys with Duchenne compared to \nhealthy controls. There were strong, significant correlations between 6-minute \nwalk distance and all StepWatch parameters in affected boys only (r = \n0.701-0.804). These data proffer intriguing observations that warrant further \nexploration. Specifically, accelerometry outcomes may compliment the 6-minute \nwalk test in assessment of therapeutic interventions for Duchenne muscular \ndystrophy.", "BACKGROUND: Duchenne Muscular Dystrophy is a severe, incurable disorder caused \nby mutations in the dystrophin gene. The disease is characterized by decreased \nmuscle function, impaired muscle regeneration and increased inflammation. In a \nclinical context, muscle deterioration, is evaluated using physical tests and \nanalysis of muscle biopsies, which fail to accurately monitor the disease \nprogression.\nOBJECTIVES: This study aims to confirm and asses the value of blood protein \nbiomarkers as disease progression markers using one of the largest longitudinal \ncollection of samples.\nMETHODS: A total of 560 samples, both serum and plasma, collected at three \nclinical sites are analyzed using a suspension bead array platform to assess 118 \nproteins targeted by 250 antibodies in microliter amount of samples.\nRESULTS: Nine proteins are confirmed as disease progression biomarkers in both \nplasma and serum. Abundance of these biomarkers decreases as the disease \nprogresses but follows different trajectories. While carbonic anhydrase 3, \nmicrotubule associated protein 4 and collagen type I alpha 1 chain decline \nrather constantly over time, myosin light chain 3, electron transfer \nflavoprotein A, troponin T, malate dehydrogenase 2, lactate dehydrogenase B and \nnestin plateaus in early teens. Electron transfer flavoprotein A, correlates \nwith the outcome of 6-minutes-walking-test whereas malate dehydrogenase 2 \ntogether with myosin light chain 3, carbonic anhydrase 3 and nestin correlate \nwith respiratory capacity.\nCONCLUSIONS: Nine biomarkers have been identified that correlate with disease \nmilestones, functional tests and respiratory capacity. Together these biomarkers \nrecapitulate different stages of the disorder that, if validated can improve \ndisease progression monitoring.", "Duchenne muscular dystrophy (DMD) usually affects men. However, women are also \naffected in rare instances. Approximately 8% of female DMD carriers have muscle \nweakness and cardiomyopathy. The early identification of functional and motor \nimpairments can support clinical decision making.\nOBJECTIVE: To investigate the motor and functional impairments of 10 female \npatients with dystrophinopathy diagnosed with clinical, pathological, genetic \nand immunohistochemical studies.\nMETHODS: A descriptive study of a sample of symptomatic female carriers of DMD \nmutations. The studied variables were muscular strength and functional \nperformance.\nRESULTS: The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions \nwere found in seven patients. The age of onset of symptoms in female carriers of \nDMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness, \ncompensatory movements and longer timed performance on functional tasks were \nobserved in most of the cases. Differently from males with DMD, seven female \npatients showed asymmetrical muscular weakness. The asymmetric presentation of \nmuscle weakness was frequent and affected posture and functionality in some \ncases. The functional performance presents greater number of compensatory \nmovements. Time of execution of activities was not a good biomarker of \nfunctionality for this population, because it does not change in the same \nproportion as the number of movement compensations.\nCONCLUSION: Clinical manifestation of asymmetrical muscle weakness and \ncompensatory movements, or both can be found in female carriers of DMD \nmutations, which can adversely affect posture and functional performance of \nthese patients.", "Author information:\n(1)Division of Pediatric Neurology, University of Basel Children's Hospital, \nBasel, Switzerland; Department of Neurology, University of Basel Hospital, \nBasel, Switzerland.\n(2)Division of Pediatric Neurology, University of Basel Children's Hospital, \nBasel, Switzerland; Division of Neurology, Medical University Clinic, \nKantonsspital Baselland, Bruderholz, Switzerland.\n(3)Division of Pediatric Neurology, University of Basel Children's Hospital, \nBasel, Switzerland; Division of Pediatric Neurology, Lausanne University \nHospital, Lausanne, Switzerland; Division of Pediatric Neurology, University of \nBerne Hospital, Berne, Switzerland.\n(4)Division of Pediatric Neurology, University of Basel Children's Hospital, \nBasel, Switzerland.\n(5)Department of Pediatrics, Kaiser Franz Josef Hospital, Vienna, Austria.\n(6)Laboratoire de Génétique Médicale, INSERM 1112, Faculté de Médecine, \nStrasbourg, France.\n(7)Division of Pediatric Neurology, Lausanne University Hospital, Lausanne, \nSwitzerland.\n(8)Division of Pediatric Neurology, University of Berne Hospital, Berne, \nSwitzerland.\n(9)Division of Pediatric Neurology, Children's Hospital, Aarau, Switzerland.\n(10)Department of Radiology, Division of Radiological Physics, University of \nBasel Hospital, Basel, Switzerland.\n(11)Department of Clinical Research, Clinical Trial Unit, University of Basel \nHospital, Basel, Switzerland.\n(12)Division of Pediatric Neurology, University of Basel Children's Hospital, \nBasel, Switzerland; Department of Neurology, University of Basel Hospital, \nBasel, Switzerland; Division of Neurology, Medical University Clinic, \nKantonsspital Baselland, Bruderholz, Switzerland. Electronic address: \ndirk.fischer@ukbb.ch." ]	nan
55425615ed966d112c000003	[ 24273314, 19221094, 12217498, 20600808, 14743977, 15942025, 25425232, 23538833, 11677621, 20417622, 17532183, 21350489, 15823418, 22735706 ]	train	Are genes symmetrically distributed between leading and lagging DNA strand in bacteria?	yesno	In most bacteria, genes are preferentially encoded on the leading strand than on the lagging strand. This avoids the potentially detrimental head-on collisions that occur between the replication and transcription machineries when genes are encoded on the lagging strand. Head-on collisions are more deleterious than codirectional collisions, and may lead to replication fork arrest and genomic instability. Genes of some functional categories such as ribosome have higher preferences to be on the leading strands, while genes of other functional categories such as transcription factor have higher preferences on the lagging strands. Strand-biased gene distribution correlates with replication-associated purine asymmetry and the presence or absence of polC. Especially essential and highly transcribed genes and genes whose expression is important for fitness are more preferentially situated at the leading strand in bacteria.	no	[ "Genomic DNA is used as the template for both replication and transcription, \nwhose machineries may collide and result in mutagenesis, among other damages. \nBecause head-on collisions are more deleterious than codirectional collisions, \ngenes should be preferentially encoded on the leading strand to avoid head-on \ncollisions, as is observed in most bacterial genomes examined. However, why are \nthere still lagging strand encoded genes? Paul et al. recently proposed that \nthese genes take advantage of the increased mutagenesis resulting from head-on \ncollisions and are thus adaptively encoded on the lagging strand. We show that \nthe evidence they provided is invalid and that the existence of lagging strand \nencoded genes is explainable by a balance between deleterious mutations that \nbring genes from the leading to the lagging strand and purifying selection \npurging such mutants. Therefore, the adaptive hypothesis is neither \ntheoretically needed nor empirically supported.", "In this study, the factors driving genome-wide patterns of codon usages in \nLawsonia intracellularis genome are determined. For genes on the chromosome of \nthe bacterium, it is found that the most important source of variation results \nfrom strand-specific mutational biases. A lesser trend of variation is \nattributable to genes that are presumed as horizontally transferred. These \nputative alien genes are unusually GC richer than the other genes, whereas \nhorizontally transferred genes have been observed to be AT rich in bacteria with \nmedium and relatively low G + C contents. Hydropathy of encoded protein and \nexpression level are also found to influence codon usage. Therefore, codon usage \nin L. intracellularis chromosome is the result of a complex balance among the \ndifferent mutational and selectional factors. When analyzing genes in the \nlargest plasmid, for the first time it is found that the strand-specific \nmutational biases are responsible for the primary variation of codon usages in \nplasmid. Genes, particularly highly expressed genes of this plasmid, are mainly \nlocated on the leading strands and this supposed to be the effects exerted by \nreplicational-transcriptional selection. These facts suggest that this plasmid \nadopts the similar mechanism of replication as the chromosome in L. \nintracellularis. Common characters among the 10 bacteria in whose genomes the \nstrand-specific mutational biases are the primary source of variation of codon \nusage are also investigated. For example, it is found that genes dnaT and fis \nthat are involved in DNA replication initiation and re-initiation pathways are \nabsent in all of the 10 bacteria.", "Replication generates bacterial chromosomes with strands that differ in the \nnumber of genes and base composition. It has been suggested that in bacteria \nsuch as Bacillus subtilis, PolC is responsible for the synthesis of the leading \nstrand and DnaE for the lagging strand, whereas in many other bacteria DnaE is \nresponsible for the synthesis of both strands. Here, I show that the possession \nof PolC correlates with leading strands that contain an average of 78% of genes \ncompared with 58% for genomes that do not contain PolC. This suggests that \nasymmetrical replication forks could have a major role in defining and \nconstraining the structure of the bacterial chromosome. The presence of PolC is \nnot correlated with compositional strand bias, suggesting that the two biases \nresult from different types of structural asymmetry.", "We studied nucleotide usage biases in 4-fold degenerated sites of all the genes \nfrom leading and lagging strands of 30 bacterial genomes. The level of guanine \nin 4-fold degenerated sites (G4f) is significantly lower in genes from lagging \nstrands than in genes from leading strands, probably because of the faster rates \nof guanine oxidation in single-stranded DNA leading to G to T transversions. The \nrates of cytosine deamination causing C to T transitions are also higher in \nlagging strands. We showed that the level of codons able to form stop-codons by \nthe way of G to T transversions and C to T transitions is always higher than the \nlevel of codons able to form stop-codons by the way of C to A transversions and \nG to A transitions. This circumstance can be an explanation of the lower percent \nof ORFs in lagging strands of bacterial replichores than in leading strands.", "Many bacterial genomes are under asymmetric mutational pressure which introduces \ncompositional asymmetry into DNA molecule resulting in many biases in coding \nstructure of chromosomes. One of the processes affected by the asymmetry is \ntranslocation changing the position of the coding sequence on chromosome in \nrespect to the orientation on the leading and lagging DNA strand. When analysing \nsets of paralogs in 50 genomes, we found that the number of observed genes which \nswitched their positions on DNA strand is lowest for genomes with the highest \nDNA asymmetry. However, the number of orthologs which changed DNA strand \nincreases with the phylogenetic distance between the compared genomes. \nNevertheless, there is a fraction of coding sequences that stay on the leading \nstrand in all analysed genomes, whereas there are no sequences that stay always \non the lagging strand. Since sequences diverge very fast after switching the DNA \nstrand, this bias in mobility of sequences is responsible, in part, for higher \ndivergence rates among some of coding sequences located on the lagging DNA \nstrand.", "In bacteria, most genes are on the leading strand of replication, a phenomenon \nattributed to collisions between the DNA and RNA polymerases. In Escherichia \ncoli, these collisions slow the movement of the replication fork through \nactively transcribed genes only if they are coded on the lagging strand. For \ngenes on both strands, however, these collisions sever nascent transcripts and \ninterrupt gene expression. Based on these observations, we propose a new theory \nto explain strand bias: genes whose expression is important for fitness are \nselected to the leading strand because this reduces the duration of these \ninterruptions. Our theory predicts that multi-gene operons, which are subject to \nlonger interruptions, should be more strongly selected to the leading strand \nthan singleton transcripts. We show that this is true even after controlling for \nthe tendency for essential genes, which are strongly biased to the leading \nstrand, to occur in operons. Our theory also predicts that other factors that \nare associated with strand bias should have stronger effects for genes that are \nin operons. We find that expression level and phylogenetic ubiquity are \ncorrelated with strand bias for both essential and non-essential genes, but only \nfor genes in operons.", "The prokaryotic pangenome partitions genes into core and dispensable genes. The \norder of core genes, albeit assumed to be stable under selection in general, is \nfrequently interrupted by horizontal gene transfer and rearrangement, but how a \ncore-gene-defined genome maintains its stability or flexibility remains to be \ninvestigated. Based on data from 30 species, including 425 genomes from six \nphyla, we grouped core genes into syntenic blocks in the context of a pangenome \naccording to their stability across multiple isolates. A subset of the core \ngenes, often species specific and lineage associated, formed a core-gene-defined \ngenome organizational framework (cGOF). Such cGOFs are either single segmental \n(one-third of the species analyzed) or multisegmental (the rest). Multisegment \ncGOFs were further classified into symmetric or asymmetric according to segment \norientations toward the origin-terminus axis. The cGOFs in Gram-positive species \nare exclusively symmetric and often reversible in orientation, as opposed to \nthose of the Gram-negative bacteria, which are all asymmetric and irreversible. \nMeanwhile, all species showing strong strand-biased gene distribution contain \nsymmetric cGOFs and often specific DnaE (α subunit of DNA polymerase III) \nisoforms. Furthermore, functional evaluations revealed that cGOF genes are hub \nassociated with regard to cellular activities, and the stability of cGOF \nprovides efficient indexes for scaffold orientation as demonstrated by \nassembling virtual and empirical genome drafts. cGOFs show species specificity, \nand the symmetry of multisegmental cGOFs is conserved among taxa and constrained \nby DNA polymerase-centric strand-biased gene distribution. The definition of \nspecies-specific cGOFs provides powerful guidance for genome assembly and other \nstructure-based analysis.\nIMPORTANCE: Prokaryotic genomes are frequently interrupted by horizontal gene \ntransfer (HGT) and rearrangement. To know whether there is a set of genes not \nonly conserved in position among isolates but also functionally essential for a \ngiven species and to further evaluate the stability or flexibility of such \ngenome structures across lineages are of importance. Based on a large number of \nmulti-isolate pangenomic data, our analysis reveals that a subset of core genes \nis organized into a core-gene-defined genome organizational framework, or cGOF. \nFurthermore, the lineage-associated cGOFs among Gram-positive and Gram-negative \nbacteria behave differently: the former, composed of 2 to 4 segments, have their \nfragments symmetrically rearranged around the origin-terminus axis, whereas the \nlatter show more complex segmentation and are partitioned asymmetrically into \nchromosomal structures. The definition of cGOFs provides new insights into \nprokaryotic genome organization and efficient guidance for genome assembly and \nanalysis.", "Several mechanisms that increase the rate of mutagenesis across the entire \ngenome have been identified; however, how the rate of evolution might be \npromoted in individual genes is unclear. Most genes in bacteria are encoded on \nthe leading strand of replication. This presumably avoids the potentially \ndetrimental head-on collisions that occur between the replication and \ntranscription machineries when genes are encoded on the lagging strand. Here we \nidentify the ubiquitous (core) genes in Bacillus subtilis and determine that 17% \nof them are on the lagging strand. We find a higher rate of point mutations in \nthe core genes on the lagging strand compared with those on the leading strand, \nwith this difference being primarily in the amino-acid-changing (nonsynonymous) \nmutations. We determine that, overall, the genes under strong negative selection \nagainst amino-acid-changing mutations tend to be on the leading strand, \nco-oriented with replication. In contrast, on the basis of the rate of \nconvergent mutations, genes under positive selection for amino-acid-changing \nmutations are more commonly found on the lagging strand, indicating faster \nadaptive evolution in many genes in the head-on orientation. Increased gene \nlength and gene expression amounts are positively correlated with the rate of \naccumulation of nonsynonymous mutations in the head-on genes, suggesting that \nthe conflict between replication and transcription could be a driving force \nbehind these mutations. Indeed, using reversion assays, we show that the \ndifference in the rate of mutagenesis of genes in the two orientations is \ntranscription dependent. Altogether, our findings indicate that head-on \nreplication-transcription conflicts are more mutagenic than co-directional \nconflicts and that these encounters can significantly increase adaptive \nstructural variation in the coded proteins. We propose that bacteria, and \npotentially other organisms, promote faster evolution of specific genes through \norientation-dependent encounters between DNA replication and transcription.", "We have elaborated a method which has allowed us to estimate the direction of \ntranslocation of orthologs which have changed, during the phylogeny, their \npositions on chromosome in respect to the leading or lagging role of DNA \nstrands. We have shown that the relative number of translocations which have \nswitched positions of genes from the leading to the lagging DNA strand is lower \nthan the number of translocations which have transferred genes from the lagging \nstrand to the leading strand of prokaryotic genomes. This paradox could be \nexplained by assuming that the stronger mutation pressure and selection after \ninversion preferentially eliminate genes transferred from the leading to the \nlagging DNA strand.", "Essential genes, indispensable genes for an organism's survival, encode \nfunctions that are considered a foundation of life. Based on those \nexperimentally determined for 10 bacteria, we find that essential genes are more \npreferentially situated at the leading strand than at the lagging strand, for \nall the 10 genomes studied, confirming previous findings based on either smaller \ndatasets or putatively assigned ones by homology search. Furthermore, we find \nthat rather than all essential genes, only those with the COG functional \ncategory of information storage and process (J, K and L), and subcategories D \n(cell cycle control), M (cell wall biogenesis), O (posttranslational \nmodification), C (energy production and conversion), G (carbohydrate transport \nand metabolism), E (amino acid transport and metabolism) and F (nucleotide \ntransport and metabolism) are preferentially situated at the leading strand. In \ncontrast, the strand-bias for essential genes in other COG functional \nsubcategories is not statistically significant. These results suggest that the \nremarkable strand-bias of the distribution of essential genes is mainly relevant \nto the aforementioned functionalities, which, therefore, likely play a key role \nin shaping the gene strand-bias in bacterial genomes.", "Among prokaryotic genomes, the distribution of genes on the leading and lagging \nstrands of the replication fork is known to be biased. Several hypotheses \nexplaining this strand-biased gene distribution (SGD) have been proposed, but \nnone have been tested or supported by sufficient data analyses. In this work we \nhave analyzed 211 prokaryotic genomes in terms of compositional strand \nasymmetries and the presence or absence of polC and have found that SGD \ncorrelates not only with polC, but also with purine asymmetry (PAS). \nFurthermore, SGD, PAS, and polC are all features associated with a group of \nlow-GC, gram-positive bacteria (Firmicutes). We conclude that PAS is a \ncharacteristic of organisms with a heterodimeric DNA polymerase III \nalpha-subunit constituted by polC and dnaE, which may play a direct role in the \nmaintenance of SGD.", "Head-on encounters between the replication and transcription machineries on the \nlagging DNA strand can lead to replication fork arrest and genomic instability. \nTo avoid head-on encounters, most genes, especially essential and highly \ntranscribed genes, are encoded on the leading strand such that transcription and \nreplication are co-directional. Virtually all bacteria have the highly expressed \nribosomal RNA genes co-directional with replication. In bacteria, co-directional \nencounters seem inevitable because the rate of replication is about 10-20-fold \ngreater than the rate of transcription. However, these encounters are generally \nthought to be benign. Biochemical analyses indicate that head-on encounters are \nmore deleterious than co-directional encounters and that in both situations, \nreplication resumes without the need for any auxiliary restart proteins, at \nleast in vitro. Here we show that in vivo, co-directional transcription can \ndisrupt replication, leading to the involvement of replication restart proteins. \nWe found that highly transcribed rRNA genes are hotspots for co-directional \nconflicts between replication and transcription in rapidly growing Bacillus \nsubtilis cells. We observed a transcription-dependent increase in association of \nthe replicative helicase and replication restart proteins where head-on and \nco-directional conflicts occur. Our results indicate that there are \nco-directional conflicts between replication and transcription in vivo. \nFurthermore, in contrast to the findings in vitro, the replication restart \nmachinery is involved in vivo in resolving potentially deleterious encounters \ndue to head-on and co-directional conflicts. These conflicts probably occur in \nmany organisms and at many chromosomal locations and help to explain the \npresence of important auxiliary proteins involved in replication restart and in \nhelping to clear a path along the DNA for the replisome.", "Directional mutation pressure associated with replication processes is the main \ncause of the asymmetry between the leading and lagging DNA strands in bacterial \ngenomes. On the other hand, the asymmetry between sense and antisense strands of \nprotein coding sequences is a result of both mutation and selection pressures. \nThus, there are two different ways of superposition of the sense strand, on the \nleading or lagging strand. Besides many other implications of these two possible \nsituations, one seems to be very important - because of the asymmetric \nreplication-associated mutation pressure, the mutation rate of genes depends on \ntheir location. Using Monte Carlo methods, we have simulated, under \nexperimentally determined directional mutation pressure, the divergence rate and \nthe elimination rate of genes depending on their location in respect to the \nleading/lagging DNA strands in the asymmetric prokaryotic genome. We have found \nthat the best survival strategy for the majority of genes is to sometimes switch \nbetween DNA strands. Paradoxically, this strategy results in higher substitution \nrates but remains in agreement with observations in bacterial genomes that such \ninversions are very frequent and divergence rate between homologs lying on \ndifferent DNA strands is very high.", "The majority of bacterial genes are located on the leading strand, and the \npercentage of such genes has a large variation across different bacteria. \nAlthough some explanations have been proposed, these are at most partial \nexplanations as they cover only small percentages of the genes and do not even \nconsider the ones biased toward the lagging strand. We have carried out a \ncomputational study on 725 bacterial genomes, aiming to elucidate other factors \nthat may have influenced the strand location of genes in a bacterium. Our \nanalyses suggest that (i) genes of some functional categories such as ribosome \nhave higher preferences to be on the leading strands; (ii) genes of some \nfunctional categories such as transcription factor have higher preferences on \nthe lagging strands; (iii) there is a balancing force that tends to keep genes \nfrom all moving to the leading and more efficient strand and (iv) the percentage \nof leading-strand genes in an bacterium can be accurately explained based on the \nnumbers of genes in the functional categories outlined in (i) and (ii), genome \nsize and gene density, indicating that these numbers implicitly contain the \ninformation about the percentage of genes on the leading versus lagging strand \nin a genome." ]	['http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006273']
5c72768a7c78d6947100006c	[ 24023392, 17383248 ]	train	Are genes that escape X-chromosome inactivation related to mental impairment?	yesno	Yes. Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving.	yes	[ "In female mammals most X-linked genes are subject to X-inactivation. However, in \nhumans some X-linked genes escape silencing, these escapees being candidates for \nthe phenotypic aberrations seen in polyX karyotypes. These escape genes have \nbeen reported to be under stronger purifying selection than other X-linked \ngenes. Although it is known that escape from X-inactivation is much more common \nin humans than in mice, systematic assays of escape in humans have to date \nemployed only interspecies somatic cell hybrids. Here we provide the first \nsystematic next-generation sequencing analysis of escape in a human cell line. \nWe analyzed RNA and genotype sequencing data obtained from B lymphocyte cell \nlines derived from Europeans (CEU) and Yorubans (YRI). By replicated detection \nof heterozygosis in the transcriptome, we identified 114 escaping genes, \nincluding 76 not previously known to be escapees. The newly described escape \ngenes cluster on the X chromosome in the same chromosomal regions as the \npreviously known escapees. There is an excess of escaping genes associated with \nmental retardation, consistent with this being a common phenotype of polyX \nphenotypes. We find both differences between populations and between individuals \nin the propensity to escape. Indeed, we provide the first evidence for there \nbeing both hyper- and hypo-escapee females in the human population, consistent \nwith the highly variable phenotypic presentation of polyX karyotypes. \nConsidering also prior data, we reclassify genes as being always, never, and \nsometimes escape genes. We fail to replicate the prior claim that genes that \nescape X-inactivation are under stronger purifying selection than others.", "Mental retardation affects 2 to 3% of the population and is marked by \nsignificant etiological heterogeneity, including genetic and non genetic causes. \nFRAXA (FMR1) trinucleotide expansion is widely searched in routine screening, \nbut found in only about 2% of the patients tested. Mutations of the MECP2 \n(methyl-CpG-binding protein) gene mainly cause Rett syndrome but were also shown \nto be involved in mental retardation. This study aimed to estimate the frequency \nof MECP2 gene mutations in a large group of mentally retarded patients without \nFRAXA expansion. Screening by heteroduplex analysis and SSCP followed by DNA \nsequencing of shifted bands were performed on 613 patients, including 442 males \nand 171 females. Eleven sequence variants were found, including nine \npolymorphisms. The two others may be pathogenetic. The first one, the double \nnucleotide substitution c.1162_1163delinsTA leading to a premature stop codon \n(p.Pro388X) was found in a female patient with random X-inactivation, presenting \nwith borderline mental impairment without any features of Rett syndrome. The \nsecond one, the c.679C>G substitution, changing a glutamine to a glutamate in \nthe transcriptional repression functional domain (p.Gln227Glu), was found in a \nfemale patient with a moderately biased X-chromosome inactivation profile and \npresenting with mild intellectual delay and minor psychotic features. The low \nmutation rate suggests that a large-scale routine screening for MECP2 in \nmentally retarded subjects is not cost-effective in clinical practice. Screening \nmay be improved by a pre-selection based on clinical features that remain to be \nestablished." ]	nan
5e4946bf6d0a277941000005	[ 28874668 ]	train	Are genomic regulatory blocks (GRBs) any different than TADs?	yesno	No, clusters of CNEs (GRBs) strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.	no	[ "Developmental genes in metazoan genomes are surrounded by dense clusters of \nconserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of \nsequence conservation, with many acting as developmental long-range enhancers. \nClusters of CNEs define the span of regulatory inputs for many important \ndevelopmental regulators and have been described previously as genomic \nregulatory blocks (GRBs). Their function and distribution around important \nregulatory genes raises the question of how they relate to 3D conformation of \nthese loci. Here, we show that clusters of CNEs strongly coincide with \ntopological organisation, predicting the boundaries of hundreds of topologically \nassociating domains (TADs) in human and Drosophila. The set of TADs that are \nassociated with high levels of noncoding conservation exhibit distinct \nproperties compared to TADs devoid of extreme noncoding conservation. The close \ncorrespondence between extreme noncoding conservation and TADs suggests that \nthese TADs are ancient, revealing a regulatory architecture conserved over \nhundreds of millions of years.Metazoan genomes contain many clusters of \nconserved noncoding elements. Here, the authors provide evidence that these \nclusters coincide with distinct topologically associating domains in humans and \nDrosophila, revealing a conserved regulatory genomic architecture." ]	nan
5e48e0e0f8b2df0d49000001	[ 30459840, 30430918, 30343431 ]	train	Are gut microbiota profiles altered by irradiation?	yesno	Yes, Irradiation profoundly impacted gut microbiota profiles	yes	[ "The sterile insect technique (SIT) as an eco-friendly and reliable strategy has \nbeen used to control populations of insect pests of agricultural, veterinary and \nhuman health importance. Successful applications of SIT rely on the high-level \necological fitness of sterile males. A suitable and stable gut microbiome can \ncontribute to the ecological fitness of insect by influencing their \nphysiology, biochemistry and development processes. Here, we show that a shift \nin the gut bacterial composition and structure by sterilizing irradiation, \ncharacterized by a decrease in the major gut microbiota community \nEnterobacteriaceae, an expansion of the minor members (e.g., Bacillaceae) and a \nhigher richness and diversity, is tightly linked to radiation-induced ecological \nfitness (male mating competitiveness, flight capacity, survival rate and life \nspan) decline in Bactrocera dorsalis (Hendel) sterile males. Function prediction \nof gut microbiota indicated that changes in microbiome taxonomy tend to drive \nmicrobiome functional shifts. A higher nutrient consumption of the flourishing \nminor gut microbiota may cause a decline in nutrients and energy metabolic \nactivity of host and then result in the reduced ecological fitness of irradiated \nflies. Furthermore, we found that a gut bacterial strain Klebsiella oxytoca \n(BD177) can restore ecological fitness by improving food intake and increasing \nhaemolymph sugar and amino acid levels of irradiated B. dorsalis flies. Our \nfindings suggest that gut symbiont-based probiotics can be used as agents for \nreversing radiation-induced ecological fitness decrease.", "The development of effective biomarkers for detecting the magnitude of radiation \nexposure and resiliency of host response is crucial to identifying appropriate \ntreatment strategies after radiation exposure. We hypothesized that the \ngastrointestinal resident bacteria would demonstrate predictable, dose-dependent \nchanges after radiation exposure across two large animal models of acute \nradiation syndrome. Here, Göttingen minipigs (GMP) (n = 50) and rhesus macaques \n(n = 48) were exposed to five dose levels (resulting in mortality rates of \n33-100% and 25-68.7%, respectively). Fecal samples taken prior to and after \nirradiation (day 0 for GMP; day 0, 3 and 14 for macaques) were used for 16S rRNA \ngene sequence amplicon high-throughput sequencing. Baseline gut microbiota \nprofiles were dissimilar between GMP and macaques, however, radiation appeared \nto have similar effect at the phylum level, resulting in Bacteroidetes decrease \nand Firmicutes increase in both models. The abundance of the main Bacteroidetes \ngenus ( Bacteroides for GMP, Prevotella for macaques) was profoundly decreased \nby irradiation. Intracellular symbionts [Elusimicrobia in GMP, Treponema \n(Spirochaetes) in macaques] consistently increased after irradiation, suggesting \ntheir use as potential biomarkers of intestinal injury, and potential negative \neffect on health. Prevotella, Lactobacillus, Clostridium XIVa, Oscillibacter and \nElusimicrobium/ Treponema abundances were found to be very significantly \ncorrelated with radiation intensity. Furthermore, Prevotella, Enterorhabdus and \nRuminococcus and Enterorhabdus maintenance was strongly associated with survival \nin GMP, while Prevotella, Oscillibacter and Treponema were strongly associated \nwith survival and Streptococcus with death in macaques. Overall, we found that a \nwide range of gut bacterial genera known to be abundant in the human gut \nmicrobiota are excellent biomarkers of radiation intensity and resilience in \nanimal models, and that detrimental effects can be monitored, and potentially \nprevented, by targeting selected genera.", "In rodent studies, the gut microbiota has been implicated in facilitating both \nradioresistance, by protecting the epithelium from apoptotic responses and \nradiosensitivity, inducing endothelial apoptotic responses. Despite the \nobservation that large animal models, such as the Chinese Rhesus macaque and the \nGottingen Minipig, demonstrate similarity to human physiologic responses to \nradiation, little is known about radiation-induced changes of the gut microbiome \nin these models. To compare the two models, we used bioequivalent radiation \ndoses which resulted in an LD50 for Gottingen Minipigs and Chinese Rhesus \nmacaques, 1.9 Gy and 6.8 Gy, respectively. Fecal samples taken prior and 3 days \npost-radiation were used for 16S rRNA gene sequence amplicon high throughput \nsequencing (Illumina MiSeq). Baseline gut microbiota profiles were dissimilar \nbetween minipigs and rhesus macaques. Irradiation profoundly impacted gut \nmicrobiota profiles in both animals. Significant increases of intracellular \nsymbionts were common to both models and to reported changes in rodents \nsuggesting universality of these findings post-radiation. Remarkably, opposite \ndynamics were observed for the main phyla, with increase of Firmicutes and \ndecrease of Bacteroidetes and Proteobacteria in minipigs but with enrichment of \nBacteroidetes in rhesus macaques. Minipig changes in magnitude and in variety of \nspecies affected were more extensive than those observed in rhesus macaques. \nThis pilot study provides an important first step in comparing the \nradiosensitive pig model to the comparatively more radioresistant macaque model, \nfor the identification of microbial elements which may influence \nradiosensitivity." ]	nan
58e3d1743e8b6dc87c000001	[ 22787202, 3023620, 8649399, 8380890, 1337883, 21331901 ]	train	Are hepadnaviral minichromosomes free of nucleosomes?	yesno	Nucleosomes along viral cccDNA in the minichromosomes are not random but sequence-specifically positioned.	no	[ "Hepadnaviral covalently closed circular DNA (cccDNA) exists as an episomal \nminichromosome in the nucleus of virus-infected hepatocytes, and serves as the \ntranscriptional template for the synthesis of viral mRNAs. To obtain insight on \nthe structure of hepadnaviral cccDNA minichromosomes, we utilized ducks infected \nwith the duck hepatitis B virus (DHBV) as a model and determined the in vivo \nnucleosome distribution pattern on viral cccDNA by the micrococcal nuclease \n(MNase) mapping and genome-wide PCR amplification of isolated mononucleosomal \nDHBV DNA. Several nucleosome-protected sites in a region of the DHBV genome \n[nucleotides (nt) 2000 to 2700], known to harbor various cis transcription \nregulatory elements, were consistently identified in all DHBV-positive liver \nsamples. In addition, we observed other nucleosome protection sites in DHBV \nminichromosomes that may vary among individual ducks, but the pattern of MNase \nmapping in those regions is transmittable from the adult ducks to the newly \ninfected ducklings. These results imply that the nucleosomes along viral cccDNA \nin the minichromosomes are not random but sequence-specifically positioned. \nFurthermore, we showed in ducklings that a significant portion of cccDNA \npossesses a few negative superhelical turns, suggesting the presence of \nintermediates of viral minichromosomes assembled in the liver, where dynamic \nhepatocyte growth and cccDNA formation occur. This study supplies the initial \nframework for the understanding of the overall complete structure of \nhepadnaviral cccDNA minichromosomes.", "The structure of replicating simian virus 40 (SV40) minichromosomes was studied \nby DNA crosslinking with trimethyl-psoralen. The procedure was used both in \nvitro with extracted SV40 minichromosomes as well as in vivo with SV40-infected \ncells. Both procedures gave essentially the same results. Mature SV40 \nminichromosomes are estimated to contain about 27 nucleosomes (error +/- 2), \nexcept for those molecules with a nucleosome-free gap, which are interpreted to \ncontain 25 nucleosomes (error +/- 2). In replicative intermediates, nucleosomes \nare present in the unreplicated parental stem with the replication fork possibly \npenetrating into the nucleosomal DNA before the histone octamer is removed. \nNucleosomes reassociate on the newly replicated DNA branches at distances from \nthe branch point of 225 ( +/- 145) nucleotides on the leading strand and of 285( \n+/- 120) nucleotides on the lagging strand. In the presence of cycloheximide, \ndaughter duplexes contained unequal numbers of nucleosomes, supporting \ndispersive and random segregation of parental nucleosomes. These were arranged \nin clusters with normal nucleosome spacing. We detected a novel type of \ninterlocked dimer comprising two fully replicated molecules connected by a \nsingle-stranded DNA bridge. We cannot decide whether these dimers represent \nhemicatenanes or whether the two circles are joined by a Holliday-type \nstructure. The joining site maps within the replication terminus. We propose \nthat these dimers represent molecules engaged in strand segregation.", "Simian virus 40 minichromosomes were treated with trypsin to specifically remove \nthe amino-terminal histone domains (tails). Trypsin treatment does not affect \nthe spacing and the number of nucleosomes on minichromosomes but indices a more \nextended conformation, as shown by the reduced sedimentation coefficient of \ntrypsinized minichromosomes compared with the untreated controls. Trypsinized \nminichromosomes replicate more efficiently than control minichromosomes in in \nvitro replication assays. The increased template efficiency appears to be due to \nhigher rates of replicative fork movement. In vitro replication in the presence \nof protein-free competitor DNA shows that replicating trypsinized \nminichromosomes do not lose nucleosomes and replicating competitor DNA does not \ngain nucleosomes. This finding suggests that tailless nucleosomes are \ntransferred from the unreplicated prefork stem to replicated DNA branches and \nexcludes a participation of the basic histone domains in nucleosome transfer.", "Using in vitro replication assays, we compared native with salt-treated simian \nvirus 40 minichromosomes isolated from infected cell nuclei. Minichromosomes \nfrom both preparations contain the full complement of nucleosomes, but salt \ntreatment removes histone H1 and a fraction of nonhistone chromatin proteins. \nBoth types of minichromosomes served well as templates for in vitro replication, \nbut the structures of the replication products were strikingly different. \nReplicated salt-treated minichromosomes contained, on average, about half the \nnormal number of nucleosomes as previously shown (T. Krude and R. Knippers, Mol. \nCell. Biol. 11:6257-6267, 1991). In contrast, the replicated untreated \nminichromosomes were found to be densely packed with nucleosomes, indicating \nthat an assembly of new nucleosomes occurred during in vitro replication. \nBiochemical and immunological data showed that the fraction of nonhistone \nchromatin proteins associated with native minichromosomes includes a nucleosome \nassembly activity that appears to be closely related to chromatin assembly \nfactor I (S. Smith and B. W. Stillman, Cell 58:15-25, 1989). Furthermore, this \nminichromosome-bound nucleosome assembly factor is able to exert its activity in \ntrans to replicating protein-free competitor DNA. Thus, native chromatin itself \ncontains the activities required for an ordered assembly of nucleosomes during \nthe replication process.", "We operationally define two forms of SV40 minichromosomes, a 75S-form, prepared \nat low salt concentration, referred to as native minichromosomes, and a \n50S-form, obtained after treatment with 0.5 M potassium acetate, the \nsalt-treated minichromosomes. Both preparations of minichromosomes serve well as \ntemplates for replication in vitro. Their respective replication products are \nstrikingly different: replicated native minichromosomes contain a densely packed \narray of the maximal number of nucleosomes whereas replicated salt-treated \nminichromosomes carry, on average, half of the maximal number. We conclude that \nin both cases parental nucleosomes are transferred to progeny DNA, and, in \naddition, that an assembly of new nucleosomes occurs during the replication of \nnative minichromosomes. This is apparently due to the presence of a nucleosome \nassembly factor as a constituent of native minichromosomes that dissociates upon \ntreatment with salt. We further show that preparations of minichromosomes \nusually contain significant amounts of copurifying hnRNP particles and SV40 \nvirion precursor particles. However, these structures do not detectably affect \nthe replication and the chromatin assembly reactions.", "Amajor reason for treatment failure during antiviral therapy of chronic \nhepatitis B infection is thought to be the persistence of the key replicative \nintermediate, the viral covalently closed circular (CCC) or supercoiled DNA \n(1,2). Investigators studying the structure and function of hepadnaviral CCC DNA \n(3) have provided evidence that suggests that this structure exists in the \nnucleus of infected hepatocytes as a heterogeneous population of viral \nminichromosomes, which range from half to fully chromatinized, thought to be \nowing to their association with variable numbers of nucleosomes." ]	nan
530cf4c54a5037880c000002	[ 23114244, 23782410, 21563154, 23143331, 22518179, 21682982, 22964658, 24106935, 23955516, 23903677, 17989697, 23260098, 24225220, 22958022, 22173399, 23947111, 11331690, 19762171, 21276671 ]	train	Are high-flow nasal cannulae effective for treatment of preterm infants?	yesno	Yes. The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure for noninvasive respiratory support of preterm infants after extubation. However, the use of high-flow nasal cannulae in preterm infants was shown to be associated with a higher rate of reintubation, increased exposure to oxygen and longer duration of respiratory support. High-flow nasal cannulae are also effective for treatment of apnea of prematurity.	yes	[ "BACKGROUND: Heated, humidified, high-flow nasal cannula oxygen therapy (HHHFNC) \nhas been used to improve ventilation in preterm infants. There are no data on \nairway pressures generated and efficacy in bronchiolitis.\nOBJECTIVE: The objective of this study was to determine nasopharyngeal (NP) \npressures generated with HHHFNC therapy in bronchiolitis.\nMETHODS: We conducted a prospective, observational study to measure NP pressures \nat varying flow rates of HHHFNC therapy in moderate to severe bronchiolitis. \nVital signs, bronchiolitis severity scores, and oxygen saturation were also \nnoted.\nRESULTS: Twenty-five patients were enrolled (mean, 78.1 [SD, 30.9] days; weight, \n5.3 [SD, 1.1] kg). Nasopharyngeal pressures increased linearly with flow rates \nup to 6 L/min. Beyond 6 L/min, pressure increase was linear but less \naccelerated. On average, NP pressure increased by 0.45 cm H2O for each 1-L/min \nincrease in flow rate. There were significant differences between pressures in \nopen- and closed-mouth states for flow rates up to 6 L/min. At 6 L/min, the \npressure in open-mouth state was 2.47 cm H2O and that in closed-mouth state was \n2.74 cm H2O (P < 0.001). Linear regression analysis revealed that only flow (not \nweight or gender) had an effect on generated pressure. Bronchiolitis severity \nscores improved significantly with HHHFNC therapy (pre: 14.5 [SD, 1.4], post: \n10.4 [SD, 1.2]; P < 0.001).\nCONCLUSIONS: Increasing flow rates of HHHFNC therapy are associated with linear \nincreases in NP pressures in bronchiolitis patients. Larger studies are needed \nto assess the clinical efficacy of HHHFNC therapy in bronchiolitis.", "AIMS: This study aims to determine if there is a difference in the pharyngeal \npressure, measured as a surrogate for continuous positive distending airway \npressure, delivered to premature infants between two commonly used heated, \nhumidified high-flow nasal cannulae (HHHFNC) devices: Fisher & Paykel Healthcare \nHHHFNC and Vapotherm 2000i.\nMETHODS: Pharyngeal pressure measurements were taken from stable premature \ninfants receiving HHHFNC for respiratory support. Flow rates of 2-8 L/min were \nstudied.\nRESULTS: Nine infants had pharyngeal pressure measurements recorded with both \nHHHFNC devices at flow rates of 2-8 L/min. There was no difference in pharyngeal \npressures recorded between devices at flow rates of 2-6 L/min; measured pressure \nwas linearly associated with flow (R(2) = 0.9). At flow rates of 7 L/min, \nVapotherm delivered a mean (standard deviation) pharyngeal pressure of 4.7 (2.2) \ncmH2 O compared with 4.23 (2.2) cmH2 O by the Fisher & Paykel device (P = 0.04). \nAt a flow of 8 L/min, the mean pharyngeal pressure via Vapotherm was 4.9 (2.2) \ncmH2 O compared with 4.1 (2.3) cmH2 O with the Fisher & Paykel device (P = \n0.05).\nCONCLUSIONS: Both HHHFNC delivered similar pharyngeal pressures at flow rates of \n2-6 L/min. The pressure limiter valve of the Fisher & Paykel device attenuated \nthe pharyngeal pressures at flows of 7 and 8 L/min. Vapotherm trended towards \nhigher delivered pharyngeal pressure at flow rates 7 and 8 L/min, but the \nclinical significance of the difference remains unclear.", "BACKGROUND: High flow nasal cannulae (HFNC) are small, thin, tapered cannulae \nused to deliver oxygen or blended oxygen and air at flow rates of > 1 L/min. \nHFNC can be used to provide high concentrations of oxygen and may deliver \npositive end-expiratory pressure.\nOBJECTIVES: To compare the safety and efficacy of HFNC with other forms of \nnon-invasive respiratory support in preterm infants.\nSEARCH STRATEGY: The strategy included searches of the Cochrane Central Register \nof Controlled Trials (CENTRAL) (The Cochrane Library 2010), MEDLINE, CINAHL, \nEMBASE and abstracts from conference proceedings.\nSELECTION CRITERIA: Randomised or quasi-randomised trials comparing HFNC with \nother non-invasive forms of respiratory support in preterm infants immediately \nafter birth or following extubation.\nDATA COLLECTION AND ANALYSIS: Data were extracted and analysed by the authors. \nRelative risk, risk difference and number needed to treat were calculated.\nMAIN RESULTS: Four studies were identified for inclusion in the review. The \nstudies differed in the interventions compared (nasal continuous positive airway \npressure (CPAP), humidified HFNC, non-humidified HFNC), the flow rates provided \nand the indications for respiratory support. Meta-analysis and subgroup analysis \nwere not possible. When used as primary respiratory support after birth, one \ntrial found similar rates of treatment failure in infants treated with HFNC and \nnasal CPAP. Following extubation, one trial found that infants treated with HFNC \nhad a significantly higher rate of reintubation than those treated with nasal \nCPAP. Another trial found similar rates of reintubation for humidified and \nnon-humidified HFNC, and the fourth trial found no difference between two \ndifferent models of equipment used to deliver humidified HFNC.\nAUTHORS' CONCLUSIONS: There is insufficient evidence to establish the safety or \neffectiveness of HFNC as a form of respiratory support in preterm infants. When \nused following extubation, HFNC may be associated with a higher rate of \nreintubation than nasal CPAP. Further adequately powered randomised controlled \ntrials should be undertaken in preterm infants comparing HFNC with nasal CPAP \nand with other means of respiratory support; or of support following extubation. \nThese trials should measure clinically important outcomes.", "BACKGROUND: High flow nasal cannula (HFNC) systems utilize higher gas flow rates \nthan standard nasal cannulae. The use of HFNC as a respiratory support modality \nis increasing in the infant, pediatric, and adult populations as an alternative \nto non-invasive positive pressure ventilation.\nOBJECTIVES: This critical review aims to: (1) appraise available evidence with \nregard to the utility of HFNC in neonatal, pediatric, and adult patients; (2) \nreview the physiology of HFNC; (3) describe available HFNC systems (online \nsupplement); and (4) review ongoing and planned trials studying the utility of \nHFNC in various clinical settings.\nRESULTS: Clinical neonatal studies are limited to premature infants. Only a few \npediatric studies have examined the use of HFNC, with most focusing on this \nmodality for viral bronchiolitis. In critically ill adults, most studies have \nfocused on acute respiratory parameters and short-term physiologic outcomes with \nlimited investigations focusing on clinical outcomes such as duration of therapy \nand need for escalation of ventilatory support. Current evidence demonstrates \nthat HFNC generates positive airway pressure in most circumstances; however, the \npredominant mechanism of action in relieving respiratory distress is not well \nestablished.\nCONCLUSION: Current evidence suggests that HFNC is well tolerated and may be \nfeasible in a subset of patients who require ventilatory support with \nnon-invasive ventilation. However, HFNC has not been demonstrated to be \nequivalent or superior to non-invasive positive pressure ventilation, and \nfurther studies are needed to identify clinical indications for HFNC in patients \nwith moderate to severe respiratory distress.", "Children with congenital heart disease (CHD) are at risk for increased morbidity \nfrom viral lower respiratory tract infections because of anatomical cardiac \nlesions than can worsen an already compromised respiratory status. Respiratory \nsyncytial virus (RSV) remains an important pathogen in contributing toward the \nmorbidity in this population. Although the acute treatment of RSV largely \nremains supportive, the development of monoclonal antibodies, such as \npalivuzumab, has reduced the RSV-related hospitalization rate in children with \nCHD. This review highlights the specific cardiac complications of RSV infection, \nthe acute treatment of bronchiolitis in patients with CHD, and the search for \nnew therapies against RSV, including an effective vaccine, because of the high \ncost associated with immunoprophylaxis and its lack of reducing RSV-related \nmortality.", "BACKGROUND: Limited data are available to describe the CPAP effects that can be \nexpected when using high flow with a traditional nasal cannula.\nOBJECTIVE: To describe the relationship between the pressure generated at the \nairway opening and flow through a nasal cannula using a simulated infant model. \nWe hypothesized that positive pressure generated by a standard cannula at flows \n> 2 L/min would be minimal and clinically unimportant.\nMETHODS: Nares were simulated with holes drilled in a plastic fixture. A nares \ntemplate for CPAP prongs served as a sizing template for the holes. Small, \nmedium, and large nares fixtures were constructed and connected to a lung \nsimulator that simulated spontaneous breathing. Respiratory muscle pressure was \nsimulated by setting a waveform and adjusting the amplitude to deliver a range \nof tidal volumes (V(T)) from 3 mL to 12 mL. Lung compliance and resistance were \nset at 0.5 mL/cm H(2)O and 125 cm H(2)O/L/s, respectively. Nasal cannulas were \ninserted in the model nares. We assured that the prong occlusion of the nares \ndid not exceed 50%. Cannula flow was adjusted from 2-6 L/min in 1-L/min \nincrements. Data were averaged over 20 breaths. Mean airway pressure and percent \nchange in V(T) were recorded.\nRESULTS: The greatest effect on V(T) (mean ± SD 0.16 ± 0.10 mL) and pressure \nchange (mean ± SD 0.7 ± 0.5 cm H(2)O) occurred with the premature cannula. The \nleast effect on pressure (mean ± SD 0.3 ± 0.22 cm H(2)O) and V(T) change (mean ± \nSD 0.01 ± 0.02 mL) occurred with the infant cannula.\nCONCLUSIONS: Clinically important pressures were not generated by high flows \nwith a standard nasal cannula. The differences in spontaneous V(T) across all \nflows were negligible.", "BACKGROUND: High-flow nasal cannulae (HFNC) are gaining in popularity as a form \nof non-invasive respiratory support for preterm infants in neonatal intensive \ncare units around the world. They are proposed as an alternative to nasal \ncontinuous positive airway pressure (NCPAP) in a variety of clinical situations, \nincluding post-extubation support, primary therapy from birth and 'weaning' from \nNCPAP.\nOBJECTIVES: To present and discuss the available evidence for the use of HFNC in \nthe preterm population.\nMETHODS: An internet-based literature search for relevant, original research \narticles (both randomised studies and not) on the use of HFNC in preterm infants \nwas undertaken.\nRESULTS: A total of 19 studies were included in the review. Distending pressure \ngenerated by HFNC in preterm infants increases with increasing flow rate and \ndecreasing infant size and varies according to the amount of leak around the \nprongs. HFNC may be as effective as NCPAP at improving respiratory parameters \nsuch as tidal volume and work of breathing in preterm infants, but probably only \nat flow rates >2 litres/min. The efficacy and safety of HFNC in preterm infants \nremain to be determined.\nCONCLUSIONS: There is growing evidence of the feasibility of HFNC as an \nalternative to other forms of non-invasive ventilation in preterm infants. \nHowever, there remains uncertainty about the efficacy and safety of HFNC in this \npopulation. Until the results of larger randomised trials are known, widespread \nuse of HFNC to treat preterm infants cannot be recommended.", "BACKGROUND: The use of high-flow nasal cannulae is an increasingly popular \nalternative to nasal continuous positive airway pressure (CPAP) for noninvasive \nrespiratory support of very preterm infants (gestational age, <32 weeks) after \nextubation. However, data on the efficacy or safety of such cannulae in this \npopulation are lacking.\nMETHODS: In this multicenter, randomized, noninferiority trial, we assigned 303 \nvery preterm infants to receive treatment with either high-flow nasal cannulae \n(5 to 6 liters per minute) or nasal CPAP (7 cm of water) after extubation. The \nprimary outcome was treatment failure within 7 days. Noninferiority was \ndetermined by calculating the absolute difference in the risk of the primary \noutcome; the margin of noninferiority was 20 percentage points. Infants in whom \ntreatment with high-flow nasal cannulae failed could be treated with nasal CPAP; \ninfants in whom nasal CPAP failed were reintubated.\nRESULTS: The use of high-flow nasal cannulae was noninferior to the use of nasal \nCPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the \nnasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk \ndifference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). \nAlmost half the infants in whom treatment with high-flow nasal cannulae failed \nwere successfully treated with CPAP without reintubation. The incidence of nasal \ntrauma was significantly lower in the nasal-cannulae group than in the CPAP \ngroup (P=0.01), but there were no significant differences in rates of serious \nadverse events or other complications.\nCONCLUSIONS: Although the result for the primary outcome was close to the margin \nof noninferiority, the efficacy of high-flow nasal cannulae was similar to that \nof CPAP as respiratory support for very preterm infants after extubation. \n(Funded by the National Health and Medical Research Council; Australian New \nZealand Clinical Trials Network number, ACTRN12610000166077.).", "The objectives of this study were (1) to devise a nasal trauma score for preterm \ninfants receiving non-invasive respiratory support, (2) to compare the incidence \nof nasal trauma in preterm infants <32 weeks gestation randomised to either \nnasal continuous positive airway pressure (NCPAP) or heated humidified high-Flow \nnasal cannulae (HHHFNC), in the first 7 days post-extubation and (3) to assess \nthe effect of two different nasal dressings in those assigned to NCPAP. We \nrandomly assigned preterm ventilated infants to receive Vapotherm® HHHFNC or \nNCPAP post-extubation. Infants receiving HHHFNC were treated with Sticky \nWhiskers® and infants receiving NCPAP received either Sticky Whiskers® or \nCannualaide® nasal dressings. Bedside nursing staff scored six sites on each \ninfant's nose for erythema, bleeding or ulceration. Scores were recorded three \ntimes daily for the first 7 days post-extubation. The sum of these 21 scores was \nused as the summary measure of nasal trauma. The mean nasal trauma score for \ninfants assigned HHHFNC was 2.8 (SD 5.7) compared to 11.7 for NCPAP (SD 10.4), \np < 0.001. There was no difference in mean trauma score between infants on NCPAP \nassigned Sticky Whiskers® 14.4 (SD 12.5) or Cannualaide® 9.5 (SD 7.3), p = 0.06.\nCONCLUSION: HHHFNC resulted in significantly less nasal trauma in the first 7 \ndays post-extubation than NCPAP and was most significant in infants <28 weeks of \ngestation. The use of protective dressings was not associated with decreased \nnasal trauma for infants on NCPAP.", "BACKGROUND: High-flow nasal cannula (HFNC) is a safe, well-tolerated, and \nnoninvasive method of respiratory support that has seen increasing use in the \ncare of children with respiratory distress. High-flow nasal cannula may be able \nto prevent intubations in infants and children with respiratory distress.\nOBJECTIVE: The objective of this study was to determine the clinical and patient \ncharacteristics that predict success or failure of HFNC therapy in children \npresenting to the pediatric emergency department (PED) with respiratory \ndistress.\nDESIGN/METHODS: A retrospective cohort review was conducted of all children \nyounger than 2 years evaluated in 2 PEDs between June 2011 and September 2012 \nwho received HFNC therapy within 24 hours of initial triage. Data extraction \nincluded clinical variables, demographic variables, and patient outcomes. \nTherapy failure was defined as the clinical decision to intubate a patient after \nan antecedent trial of HFNC. Multivariable logistic regression was performed to \nidentify factors associated with intubation following HFNC.\nRESULTS: Four hundred ninety-eight cases meeting criteria for inclusion were \nidentified. The most common final diagnosis was acute bronchiolitis (n = 231, \n46%), followed by pneumonia (n = 138, 28%) and asthma (n = 38, 8%). Of the 498 \npatients, 42 (8%) of patients failed therapy and required intubation following \nHFNC trial. Risk factors associated with HFNC failure were triage respiratory \nrate greater than 90th percentile for age (odds ratio [OR], 2.11; 95% confidence \ninterval [CI], 1.01-4.43), initial venous PCO2 greater than 50 mm Hg (OR, 2.51; \n95% CI, 1.06-5.98), and initial venous pH less than 7.30 (OR, 2.53; 95% CI, \n1.12-5.74). A final diagnosis of bronchiolitis was observed to be protective \nwith respect to intubation (OR, 0.40; 95% CI, 0.17-0.96).\nCONCLUSIONS: In infants with all-cause respiratory distress presenting in the \nPED, triage respiratory rate greater than 90th percentile for age, initial \nvenous PCO2 greater than 50 mm Hg, and initial venous pH less than 7.30 were \nassociated with failure of HFNC therapy. A diagnosis of acute bronchiolitis was \nprotective with respect to intubation following HFNC. This finding may help \nguide clinicians who use HFNC by identifying a patient population at higher risk \nof failing therapy.", "OBJECTIVE: The aim of this study was to measure pharyngeal pressures in preterm \ninfants receiving high-flow nasal cannulae.\nSTUDY DESIGN: A total of 18 infants were studied (median gestational age 34 \nweeks, weight 1.619 kg). A catheter-tip pressure transducer was introduced into \nthe nasopharynx. Flow was sequentially increased to a maximum of 8 l min(-1) and \ndecreased to a minimum of 2 l min(-1).\nRESULT: There was a strong association between pharyngeal pressure and both flow \nrate and infant weight (P<0.001, r (2)=0.61), but not mouth closure. This \nrelationship could be expressed as pharyngeal pressure (cm H(2)O)=0.7+1.1 F \n(F=flow per kg in l min(-1) kg(-1)).\nCONCLUSION: High-flow nasal cannulae at flow rates of 2 to 8 l min(-1) can lead \nto clinically significant elevations in pharyngeal pressure in preterm infants. \nFlow rate and weight but not mouth closure are important determinants of the \npressure transmitted.", "OBJECTIVE: To determine whether postextubation respiratory support via heated, \nhumidified, high-flow nasal cannulae (HHHFNC) results in a greater proportion of \ninfants younger than 32 weeks' gestation being successfully extubated after a \nperiod of endotracheal positive pressure ventilation compared with conventional \nnasal continuous positive airway pressure (NCPAP).\nSTUDY DESIGN: We randomly assigned preterm ventilated infants to Vapotherm \nHHHFNC or NCPAP after extubation. The primary outcome, extubation failure, was \ndefined by prespecified failure criteria in the 7 days after extubation.\nRESULTS: A total of 132 ventilated infants younger than 32 weeks' gestation were \nrandomized to receive either HHHFNC (n = 67) or NCPAP (n = 65). Extubation \nfailure occurred in 15 (22%) of the HHHFNC group compared with 22 (34%) of the \nNCPAP group. There was no difference in the number of infants reintubated in the \nfirst week. Treatment with HHHFNC reduced the nasal trauma score 3.1 (SD 7.2) \nversus NCPAP 11.8 (SD 10.7), P < .001.\nCONCLUSIONS: HHHFNC and NCPAP produced similar rates of extubation failure.", "OBJECTIVE: To compare patient comfort in preterm infants treated with heated \nhumidified high flow nasal cannulae (HHHFNC) versus nasal continuous positive \nairway pressure (NCPAP).\nDESIGN: Randomised cross-over trial (2×24 h).\nSETTING: Single tertiary neonatal unit.\nPATIENTS: 20 infants less than 34 weeks postmenstrual age treated with NCPAP due \nto mild respiratory illness.\nINTERVENTIONS: After parental consent, infants were randomised to 24 h of \ntreatment with NCPAP or HHHFNC followed by 24 h of the alternate therapy.\nMAIN OUTCOME MEASURES: Primary outcome was patient comfort assessed by the EDIN \n(neonatal pain and discomfort) scale. Secondary outcomes were respiratory \nparameters (respiratory rate, FiO2, SpO2, TcPCO2), ambient noise, salivary \ncortisol and parental assessments of their child.\nRESULTS: We found no differences between HHHFNC and NCPAP in mean cumulative \nEDIN score (10.7 vs 11.1, p=0.25) or ambient noise (70 vs 74 dBa, p=0.18). \nParents assessed HHHFNC treatment as significantly better in the three domains, \n1) child satisfied, 2) parental contact and interaction and 3) possibility to \ntake part in care. Mean respiratory rate over 24 h was lower during HHHFNC than \nCPAP (41 vs 46, p=0.001). Other respiratory parameters were similar.\nCONCLUSIONS: Using EDIN scale, we found no difference in patient comfort with \nHHHFNC versus NCPAP. However, parents preferred HHHFNC, and during HHHFNC \nrespiratory rate was lower than during NCPAP.\nCLINICALTRIALSGOV, NUMBER: NCT01526226.", "Respiratory failure in the premature infants remains a difficult challenge. An \nalternative to the use of nasal continuous positive airway pressure (NCPAP) as a \nnon-invasive modality to support respiratory distress in premature infants has \nbeen the recent introduction of high flow nasal cannula (HFNC) devices in many \nneonatal units. There has been increased use of HFNC presumably because of \nanecdotal reports and experience that it is easy to use, and well tolerated by \nthe infants, while experiencing decreased nasal septumerosion. The paucity of \nevidence regarding its efficacy and safety, would support a caution approach to \nthe use of HFNC. Particular concern has focused on the imprecise regulation and \ngeneration of pressure that may occur at higher flows especially in the smallest \nof infants.", "Continuous positive airway pressure (CPAP) is widely used in neonatal units both \nas a primary mode of respiratory support and following extubation from \nmechanical ventilation. In this review, the evidence for CPAP use particularly \nin prematurely born infants is considered. Studies comparing methods of CPAP \ngeneration have yielded conflicting results, but meta-analysis of randomised \ntrials has demonstrated that delivering CPAP via short nasal prongs is most \neffective in preventing re-intubation. At present, there is insufficient \nevidence to establish the safety or efficacy of high flow nasal cannulae for \nprematurely born infants. Observational studies highlighted that early CPAP use \nrather than intubation and ventilation was associated with a lower incidence of \nbronchopulmonary dysplasia (BPD), but this has not been confirmed in three large \nrandomised trials. Meta-analysis of the results of randomised trials has \ndemonstrated that use of CPAP reduces extubation failure, particularly if a CPAP \nlevel of 5 cm H2O or more is used. Nasal injury can occur and is related to the \nlength of time CPAP is used; weaning CPAP by pressure rather than by \n\"time-cycling\" reduces the weaning time and may reduce BPD. In conclusion, \nfurther studies are required to identify the optimum mode of CPAP generation and \nit is important that prematurely born infants are weaned from CPAP as soon as \npossible.", "Despite of improved survival of premature infants, the incidence of long-term \npulmonary complications, mostly associated with ventilation-induced lung injury, \nremains high. Non invasive ventilation (NIV) is able to reduce the adverse \neffects of mechanical ventilation. Although nasal continuous positive airway \npressure (NCPAP) is an effective mode of NIV, traumatic nasal complications and \nintolerance of the nasal interface are common. Recently high flow nasal cannula \n(HFNC) is emerging as an efficient, better tolerated form of NIV, allowing \nbetter access to the baby's face, which may improve nursing, feeding and \nbonding. The aim of this review is to discuss the available evidence of \neffectiveness and safety of HFNC in preterm newborns with respiratory distress \nsyndrome (RDS). It is known that distending pressure generated by HFNC increases \nwith increasing flow rate and decreasing infant size and varies according to the \namount of leaks by nose and mouth. The effects of HFNC on lung mechanics, its \nclinical efficacy and safety are still insufficiently investigated. In \nconclusion, there is a growing evidence of the feasibility of HFNC as an \nalternative mode of NIV. However, further larger randomized trials are required, \nbefore being able to recommend HFNC in the treatment of moderate respiratory \ndistress of preterm infants.", "Apnea of prematurity (AOP) is frequently managed with nasal continuous positive \nairway pressure (NCPAP). Nasal cannula (NC) are used at low flows (<0.5 L/min) \nto deliver supplemental oxygen to neonates. A number of centers use high-flow \nnasal cannula (HFNC) in the management of AOP without measuring the positive \ndistending pressure (PDP) generated. Objective. To determine the NC flow \nrequired to generate PDP equal to that provided by NCPAP at 6 cm H(2)O and to \nassess the effectiveness of HFNC as compared NCPAP in the management of AOP. \nMethod. Forty premature infants, gestation 28.7 +/- 0.4 weeks (mean +/- standard \nerror of mean), postconceptual age at study 30.3 +/- 0.6 weeks, birth weight \n1256 +/- 66 g, study weight 1260 +/- 63 g who were being managed with \nconventional NCPAP for at least 24 hours for clinically significant apnea of \nprematurity, were enrolled in a trial of ventilator-generated conventional NCPAP \nversus infant NC at flows of up to 2.5 L/min. End expiratory esophageal pressure \nwas measured on NCPAP and on NC, and the gas flow on NC was adjusted to generate \nan end expiratory esophageal pressure equal to that measured on NCPAP. Two \n6-hour periods were continuously recorded and the data were stored on computer. \nResults. The flow required to generate a comparable PDP with NC varied with the \ninfant's weight and was represented by the equation: flow (L/min) = 0.92 + \n0.68x, x = weight in kg, R = 0.72. There was no difference in the frequency and \nduration of apnea, bradycardia or desaturation per recording between the 2 \nsystems. Conclusion. NC at flows of 1 to 2.5 L/min can deliver PDP in premature \nneonates. HFNC is as effective as NCPAP in the management of AOP.", "The management of endotracheal tubes and nasal cannulae covers a large part of \nwork time of nurses involved in the care of very preterm infants. These \nprocedures, although continuously performed, have not yet been scientifically \ndemonstrated. In fact, there is limited evidence regarding several points such \nas the frequency of endotracheal suctioning, the level of suction pressure, the \nduration of suctioning, the depth of catheter insertion, the sterility, and the \nuse of normal saline during endotracheal suction. With regard to the nasal \ncannulae, there is a more recent use of this device consisting in delivering \nend-expiratory pressure or gas flow to reduce the frequency of apneas and \ndesaturations in preterm infants or for the management of RDS. This approach is \ndefined high-flow nasal cannulae (HFNC). In this article, we review the \nliterature on the airway management of intubated patients as well as of infants \nmanaged with nasal-CPAP or nasal cannulae. Potential fields of research on this \ntopic are suggested.", "OBJECTIVE: To determine the better approach for weaning preterm infants from \nnasal continuous positive airway pressure (NCPAP) with or without transitioning \nto nasal cannula (NC).\nDESIGN/METHODS: This is a randomized, open label, controlled trial. Preterm \ninfants born at ≥28 weeks gestation who were clinically stable on NCPAP of 5 cm \nH(2)O with FiO(2)<0.30 for at least 24 h were randomly assigned to one of 2 \ngroups. The no-NC group were kept on NCPAP until they were on FiO(2)=0.21 for 24 \nh, and then were weaned off NCPAP completely without any exposure to NC. If they \nmet failing criteria, NCPAP was re-instituted. The NC-group was weaned off NCPAP \nwhen FiO(2) was ≤0.30 to NC (2 L/min) followed by gradual weaning from oxygen. \nInfants who failed NC were supported back with NCPAP for 24 h before making a \nsecond attempt of NC.\nRESULTS: Sixty neonates were enrolled; 30 in each group. The two groups were \nsimilar in birthweight, gestational age, sex, antenatal steroids, mode of \ndelivery, use of surfactant and xanthines, and duration of mechanical \nventilation. After randomization, the no-NC group had fewer days on oxygen \n[median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and \nshorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, \np=0.03]. There were no differences between groups regarding success of weaning \nfrom NCPAP.\nCONCLUSIONS: Weaning preterm infants from NCPAP to NC is associated with \nincreased exposure to oxygen and longer duration of respiratory support." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D057785', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000281', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D007234']
517404878ed59a060a000023	[ 15800932, 19509253, 19789319, 21041383, 20884621, 21452015, 19417021, 10893438, 22038994, 22161747, 18981013, 22279574, 15318170, 18506586, 19861438, 22811583 ]	train	Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors?	yesno	Yes, some HDAC inhibitors, such as Vorinostat, are on trial for human treatment after proving successful in animal models. Combination with other drugs is likely to be needed to control metastasis.	yes	[ "AN-7, a prodrug of butyric acid, induced histone hyperacetylation and \ndifferentiation and inhibited proliferation of human prostate 22Rv1 cancer cells \nin vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN-7 \ngiven orally thrice a week led to inhibition of tumor growth and metastasis, \ntumor regression in >25% of animals and increased survival. Median time to the \nexperimental end point (tumor volume 2 cm3 or death) in the untreated was 52 \ndays, and average tumor volume was 0.8 +/- 0.18 cm3. At the same time, 94.4% of \nAN-7-treated mice survived and had average tumor volumes of 0.37 +/- 0.1 cm3. \nPSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable \nmetastases positively stained for PSA and limited air gaps were found in lungs \nof untreated mice. In animals treated with AN-7, lung morphology appeared \nnormal. Primary tumors of treated animals were highly positive for PSA and had \nan elevated level of p21 and the proapoptotic protein Bax. Sections taken from \nAN-7-treated animals, examined under an electron microscope, exhibited condensed \nchromatin and apoptotic bodies. PSA serum levels were higher in untreated \ncompared to treated animals and correlated with tumor volume. Since prolonged \noral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not \ncause adverse effects and the former exhibited significant anticancer activity, \nAN-7 is likely to display a high therapeutic index and may be beneficial for \nprostate cancer patients.", "Vorinostat (suberoylanilide hydroxamic acid), a histone deacetylase inhibitor, \nis currently undergoing clinical evaluation as therapy for cancer. We \ninvestigated the effects of vorinostat on tumor cell radiosensitivity in a \nbreast cancer brain metastasis model using MDA-MB-231-BR cells. In vitro \nradiosensitivity was evaluated using clonogenic assay. Cell cycle distribution \nand apoptosis was measured using flow cytometry. DNA damage and repair was \nevaluated using gammaH2AX. Mitotic catastrophe was measured by immunostaining. \nGrowth delay and intracranial xenograft models were used to evaluate the in vivo \ntumor radiosensitivity. Cells exposed to vorinostat for 16 hours before and \nmaintained in the medium after irradiation had an increase in radiosensitivity \nwith a dose enhancement factor of 1.57. gammaH2AX, as an indicator of \ndouble-strand breaks, had significantly more foci per cell in the vorinostat \nplus irradiation group. Mitotic catastrophe, measured at 72 hours, was \nsignificantly increased in cells receiving vorinostat plus irradiation. \nIrradiation of s.c. MDA-MB-231-BR tumors in mice treated with vorinostat \nresulted in an increase in radiation-induced tumor growth delay. Most \nimportantly, animals with intracranial tumor implants lived the longest after \ncombination treatment. These results indicate that vorinostat enhances tumor \ncell radiosensitivity in vitro and in vivo. There was a greater than additive \nimprovement in survival in our intracranial model. Combining vorinostat with \nradiation may be a potential treatment option for patients with breast cancer \nwho develop brain metastases.", "PURPOSE: As chemotherapy and molecular therapy improve the systemic survival of \nbreast cancer patients, the incidence of brain metastases increases. Few \ntherapeutic strategies exist for the treatment of brain metastases because the \nblood-brain barrier severely limits drug access. We report the pharmacokinetic, \nefficacy, and mechanism of action studies for the histone deactylase inhibitor \nvorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain \nmetastasis of triple-negative breast cancer.\nEXPERIMENTAL DESIGN: The 231-BR brain trophic subline of the MDA-MB-231 human \nbreast cancer cell line was injected into immunocompromised mice for \npharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone \nacetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo.\nRESULTS: Following systemic administration, uptake of [(14)C]vorinostat was \nsignificant into normal rodent brain and accumulation was up to 3-fold higher in \na proportion of metastases formed by 231-BR cells. Vorinostat prevented the \ndevelopment of 231-BR micrometastases by 28% (P = 0.017) and large metastases by \n62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated \non day 3 post-injection. The inhibitory activity of vorinostat as a single agent \nwas linked to a novel function in vivo: induction of DNA double-strand breaks \nassociated with the down-regulation of the DNA repair gene Rad52.\nCONCLUSIONS: We report the first preclinical data for the prevention of brain \nmetastasis of triple-negative breast cancer. Vorinostat is brain permeable and \ncan prevent the formation of brain metastases by 62%. Its mechanism of action \ninvolves the induction of DNA double-strand breaks, suggesting rational \ncombinations with DNA active drugs or radiation.", "Histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related \napoptosis-inducing ligand (TRAIL) show promise for the treatment of cancers. The \npurpose of this study was to examine the molecular mechanisms by which HDAC \ninhibitor MS-275 sensitizes TRAIL-resistant breast cancer cells in vivo, \ninhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal \ntransition (EMT). BALB/c nude mice were orthotopically implanted with \nTRAIL-resistant invasive breast cancer MDA-MB-468 cells and treated \nintravenously with MS-275, TRAIL, or MS-275 followed by TRAIL, 4 times during \nfirst 3 weeks. Treatment of mice with TRAIL alone had no effect on tumor growth, \nmetastasis, angiogenesis, and EMT. In comparison, MS-275 sensitized \nTRAIL-resistant xenografts by inducing apoptosis, inhibiting tumor cell \nproliferation, angiogenesis, metastasis, and reversing EMT. Treatment of nude \nmice with MS-275 resulted in downregulation of NF-κB and its gene products \n(cyclin D1, Bcl-2, Bcl-X(L), VEGF, HIF-1α, IL-6, IL-8, MMP-2, and MMP-9) and \nupregulation of DR4, DR5, Bax, Bak, and p21(/CIP1) in tumor cells. Furthermore, \nMS-275-treated mice showed significantly reduced tumor growth and decreased \ncirculating vascular VEGFR2-positive endothelial cells, CD31-positive or von \nWillebrand factor-positive blood vessels, and lung metastasis compared with \ncontrol mice. Interestingly, MS-275 caused \"cadherin switch\" and reversed EMT as \nshown by the upregulation of E-cadherin and downregulation of N-cadherin and \ntranscription factors Snail, Slug, and ZEB1. In conclusion, sequential \ntreatments of mice with MS-275 followed by TRAIL may target multiple pathways to \nreverse EMT and inhibit tumor progression, angiogenesis, and metastasis and \nrepresent a novel therapeutic approach to treat cancer.", "PURPOSE: Although histone deacetylase inhibitors (HDACi) are emerging as a new \nclass of anticancer agents, one of the most significant concerns is that \ninteractions with a wide array of substrates using these agents might initiate \nboth therapeutic and undesired protective responses. Here, we sought to identify \nthe potential protective reactions initiated by HDACi and determine whether \ntargeting these reactions would enhance the antitumoral activity of HDACi.\nEXPERIMENTAL DESIGN: Gene expression profiles were analyzed by cDNA microarray \nin Molt-4 cells before and after treatment of vorinostat. Induction of CD146 by \nvorinostat was examined in a wide range of tumors and nonmalignant cells. AA98, \nan anti-CD146 monoclonal antibody, was used to target CD146 function. \nSynergistic antitumoral and antiangiogenic effects between AA98 and vorinostat \nwere examined both in vitro and in vivo. The potential effect of combined AA98 \nand vorinostat treatment on the AKT pathway was determined by Western blotting.\nRESULTS: The induction of CD146 is a common phenomenon in vorinostat-treated \ncancer but not in nonmalignant cells. Targeting of CD146 with AA98 substantially \nenhanced vorinostat-induced killing via the suppression of activation of AKT \npathways in cancer cells. Moreover, AA98 in combination with vorinostat \nsignificantly inhibited angiogenesis. In vivo, AA98 synergized with vorinostat \nto inhibit tumor growth and metastasis.\nCONCLUSION: The present study provided the first evidence that an undesired \ninduction of CD146 could serve as a protective response to offset the antitumor \nefficacy of vorinostat. On the other hand, targeting CD146 in combination with \nvorinostat could be exploited as a novel strategy to more effectively kill \ncancer cells.", "The concept of molecular tumor targeting might provide new hope in the treatment \nof advanced prostate cancer. We evaluated metastasis blocking properties of the \nhistone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian \ntarget of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. \nRAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in \ncombination. Adhesion to vascular endothelium or to immobilized collagen, \nfibronectin or laminin was quantified. Migration and invasion were explored by a \nmodified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow \ncytometry, western blotting and RT-PCR. Effects of drug treatment on integrin \nrelated signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation \nwere also determined. Separate application of RAD001 or VPA distinctly reduced \ntumor cell adhesion, migration and invasion, accompanied by elevated Akt \nactivation and p70S6kinase de-activation. Integrin subtype expression was \naltered significantly by both compounds (VPA > RAD001). When both drugs were \nused in concert additive effects were observed on the migratory and invasive \nbehavior but not on tumor-endothelium and tumor-matrix interaction. Separate \nmTOR or HDAC inhibition slows processes related to tumor metastasis. The \nRAD001-VPA combination showed advantage over VPA monotreatment with particular \nrespect to migration and invasion. Ongoing studies are required to assess the \nrelevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell \nmotility.", "PURPOSE: Histone deactylase inhibitors (HDACi) are a promising new class of \nanticancer therapeutics; however, little is known about HDACi activity in soft \ntissue sarcoma (STS), a heterogeneous cohort of mesenchymal origin malignancies. \nConsequently, we investigated the novel HDACi PCI-24781, alone/in combination \nwith conventional chemotherapy, to determine its potential anti-STS-related \neffects and the underlying mechanisms involved.\nEXPERIMENTAL DESIGN: Immunoblotting was used to evaluate the effects of \nPCI-24781 on histone and nonhistone protein acetylation and expression of \npotential downstream targets. Cell culture-based assays were utilized to assess \nthe effects of PCI-24781 on STS cell growth, cell cycle progression, apoptosis, \nand chemosensitivity. Quantitative reverse transcription-PCR, chromatin \nimmunoprecipitation, and reporter assays helped elucidate molecular mechanisms \nresulting in PCI-24781-induced Rad51 repression. The effect of PCI-24781, alone \nor with chemotherapy, on tumor and metastatic growth was tested in vivo using \nhuman STS xenograft models.\nRESULTS: PCI-24781 exhibited significant anti-STS proliferative activity in \nvitro, inducing S phase depletion, G(2)/M cell cycle arrest, and increasing \napoptosis. Superior effects were seen when combined with chemotherapy. A \nPCI-24781-induced reduction in Rad51, a major mediator of DNA double-strand \nbreak homologous recombination repair, was shown and may be a mechanism \nunderlying PCI-24781 chemosensitization. We showed that PCI-24781 \ntranscriptionally represses Rad51 through an E2F binding-site on the Rad51 \nproximal promoter. Although single-agent PCI-24781 had modest effects on STS \ngrowth and metastasis, marked inhibition was observed when combined with \nchemotherapy.\nCONCLUSIONS: In light of these findings, this novel molecular-based combination \nmay be applicable to multiple STS histologic subtypes, and potentially merits \nrigorous evaluation in human STS clinical trials.", "Cancer metastasis represents the most important cause of cancer death and agents \nthat may inhibit tumor cell invasion have been extensively pursued. In the \npresent study, we have examined the anti-invasive effect of apicidin \n[cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl -L-2-amin \no-8-oxodecanoyl)], a fungal metabolite that was identified as an antiprotozoal \nagent known to inhibit parasite histone deacetylase (HDAC). We show that \napicidin significantly inhibits H-ras-induced invasive phenotype of MCF10A human \nbreast epithelial cells in parallel with a specific downregulation of matrix \nmetalloproteinase (MMP)-2, but not MMP-9. We also show that apicidin induces a \nmorphological reversal and growth inhibition of H-ras MCF10A cells similar to \nthat induced by other HDAC inhibitors. Taken in conjunction with the fact that \nuncontrolled ras activation is probably the most common genetic defect in human \ncancer cells, our data showing the anti-invasive and detransforming activities \nof apicidin in H-ras-transformed MCF10A cells may suggest a potential use of \nHDAC inhibitors for treatment of cancer.", "PURPOSE: Metastasis is responsible for the death of most cancer patients, yet \nfew therapeutic agents are available which specifically target the molecular \nevents that lead to metastasis. We recently showed that inactivating mutations \nin the tumor suppressor gene BAP1 are closely associated with loss of \nmelanocytic differentiation in uveal melanoma (UM) and metastasis. The purpose \nof this study was to identify therapeutic agents that reverse the phenotypic \neffects of BAP1 loss in UM.\nEXPERIMENTAL DESIGN: In silico screens were done to identify therapeutic \ncompounds predicted to differentiate UM cells using Gene Set Enrichment Analysis \nand Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, \nand suberoylanilide hydroxamic acid were evaluated for their effects on UM cells \nusing morphologic evaluation, MTS viability assays, bromodeoxyuridine \nincorporation, flow cytometry, clonogenic assays, gene expression profiling, \nhistone acetylation and ubiquitination assays, and a murine xenograft \ntumorigenicity model.\nRESULTS: Histone deacetylase (HDAC) inhibitors induced morphologic \ndifferentiation, cell-cycle exit, and a shift to a differentiated, melanocytic \ngene expression profile in cultured UM cells. VPA inhibited the growth of UM \ntumors in vivo.\nCONCLUSIONS: These findings suggest that HDAC inhibitors may have therapeutic \npotential for inducing differentiation and prolonged dormancy of micrometastatic \ndisease in UM.", "Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for \nchemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced \nby vinyl carbamate in strain A/J mice followed by 500 mg/kg SAHA, 60 or 180 \nmg/kg atorvastatin, and combinations containing SAHA and atorvastatin \nadministered in their diet. SAHA and both combinations, but not atorvastatin, \ndecreased the multiplicity of lung tumors, including large adenomas and \nadenocarcinomas with the combinations demonstrating the greatest efficacy. In \nExperiment 2, lung tumors were induced by \n4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol in strain A/J mice followed by \n180 mg/kg atorvastatin, 500 mg/kg SAHA, or both drugs administered in the diet. \nSAHA and the combination of both drugs, but not atorvastatin alone, decreased \nthe multiplicity of lung tumors and large tumors, with the combination \ndemonstrating greater efficacy. In Experiment 3, lung tumors were induced by \n1,2-dimethylhydrazine in Swiss-Webster mice followed by 160 mg/kg atorvastatin, \n400 mg/kg SAHA, or a combination of both drugs administered in the diet. SAHA \nand the combination, but not atorvastatin, decreased the multiplicity of lung \ntumors with the combination demonstrating greater efficacy. The multiplicity of \ncolon tumors was decreased by SAHA, atorvastatin, and the combination, without \nany significant difference in their efficacy. mRNA expression analysis of lung \ntumor bearing mice suggested that the enhanced chemopreventive activity of the \ncombination is related to atorvastatin modulation of DNA repair, SAHA modulation \nof angiogenesis, and both drugs modulating invasion and metastasis pathways. \nAtorvastatin demonstrated chemoprevention activity as indicated by the \nenhancement of the efficacy of SAHA to prevent mouse lung tumors.", "PURPOSE: The primary goal of this trial was to determine the response rate of \nsingle-agent vorinostat in patients with metastatic breast cancer. The secondary \ngoals included assessment of time to progression, evaluation of toxicities, and \noverall survival.\nEXPERIMENTAL DESIGN: From June 2005 to March 2006, 14 patients received \nvorinostat, 200 mg p.o., twice daily for 14 days of each 21 day cycle. Response \nand progression were evaluated using Response Evaluation Criteria in Solid \nTumors (RECIST) criteria.\nRESULTS: The median age for all patients was 60.5 years (range, 37-88). Eight \npatients were estrogen receptor and/or progesterone positive, four were Her-2 \npositive. Sites of metastatic disease included brain, liver, lungs, bones, \npelvis, pleura, chest wall, and distant lymph nodes. Patients received a median \nof 1.5 prior (range, 0-2) chemotherapeutic regimens for metastatic disease. \nFatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically \nsignificant adverse effects. The median number of cycles delivered was 2 (range, \n1-20). There were no complete or partial responses, and the study was terminated \nafter the first stage; however, 4 patients were observed with stable disease \nwith time to progression of 4, 8, 9, and 14 months. The median number of months \nthat patients received treatment on this study was 1.7 (range, 0.5-14).\nCONCLUSIONS: Although not meeting the RECIST response criteria for adequate \nsingle-agent activity, the observed tolerable toxicities and the potential for \nclinical benefit in terms of stable disease suggest that further assessment of \nvorinostat as a part of combination therapy with either chemotherapeutic or \ntargeted agents in metastatic breast might be undertaken.", "BACKGROUND: Compound targeting histone deacetylase (HDAC) represents a new era \nin molecular cancer therapeutics. However, effective HDAC inhibitors for the \ntreatment of solid tumors remain to be developed.\nMETHODOLOGY/PRINCIPAL FINDINGS: Here, we propose a novel HDAC inhibitor, \nN-Hydroxy-4-(4-phenylbutyryl-amino) benzamide (HTPB), as a potential \nchemotherapeutic drug for solid tumors. The HDAC inhibition of HTPB was \nconfirmed using HDAC activity assay. The antiproliferative and anti-migratory \nmechanisms of HTPB were investigated by cell proliferation, flow cytometry, DNA \nladder, caspase activity, Rho activity, F-actin polymerization, and \ngelatin-zymography for matrix metalloproteinases (MMPs). Mice with tumor \nxenograft and experimental metastasis model were used to evaluate effects on \ntumor growth and metastasis. Our results indicated that HTPB was a pan-HDAC \ninhibitor in suppressing cell viability specifically of lung cancer cells but \nnot of the normal lung cells. Upon HTPB treatment, cell cycle arrest was induced \nand subsequently led to mitochondria-mediated apoptosis. HTPB disrupted F-actin \ndynamics via downregulating RhoA activity. Moreover, HTPB inhibited activity of \nMMP2 and MMP9, reduced integrin-β1/focal adhesion complex formation and \ndecreased pericellular poly-fibronectin assemblies. Finally, intraperitoneal \ninjection or oral administration of HTPB efficiently inhibited A549 xenograft \ntumor growth in vivo without side effects. HTPB delayed lung metastasis of 4T1 \nmouse breast cancer cells. Acetylation of histone and non-histone proteins, \ninduction of apoptotic-related proteins and de-phosphorylation of focal adhesion \nkinase were confirmed in treated mice.\nCONCLUSIONS/SIGNIFICANCE: These results suggested that intrinsic apoptotic \npathway may involve in anti-tumor growth effects of HTPB in lung cancer cells. \nHTPB significantly suppresses tumor metastasis partly through inhibition of \nintegrin-β1/FAK/MMP/RhoA/F-actin pathways. We have provided convincing \npreclinical evidence that HTPB is a potent HDAC targeted inhibitor and is thus a \npromising candidate for lung cancer chemotherapy.", "Histone deacetylase (HDAC) inhibitors induce growth arrest and apoptosis in a \nvariety of human cancer cells. Sodium butyrate (NaB), a short chain fatty acid, \nis a HDAC inhibitor and is produced in the colonic lumen as a consequence of \nmicrobial degradation of dietary fibers. In order to dissect out the mechanism \nof NaB-induced growth inhibition of cancer cells, we carried out expression \nprofiling of a human lung carcinoma cell line (H460) treated with NaB using a \ncDNA microarray. Of the total 1728 genes analysed, there were 32 genes with a \nmean expression value of 2.0-fold and higher and 66 genes with a mean expression \nvalue 3.0-fold and lower in NaB-treated cells. For a few selected genes, we \ndemonstrate that their expression pattern by semiquantitative reverse \ntranscription-polymerase chain reaction (RT-PCR) analysis is matching with the \nresults obtained by microarray analysis. Closer view at the expression profile \nof NaB-treated cells revealed the downregulation of a total of 16 genes \nassociated with cytokine signaling, in particular, interferon gamma (IFNgamma) \npathway. In good correlation, NaB-pretreated cells failed to induce interferon \nregulatory factor 1, an INFgamma target gene, efficiently upon IFNgamma \naddition. These results suggest that NaB inhibits proinflammatory cytokine \nsignaling pathway, thus providing proof of mechanism for its anti-inflammatory \nactivity. We also found that NaB induced three genes, which are known metastatic \nsuppressors, and downregulated 11 genes, which have been shown to promote \nmetastasis. Upregulation of metastatic suppressor Kangai 1 (KAI1) by NaB in a \ntime-dependent manner was confirmed by RT-PCR analysis. The differential \nregulation of metastasis-associated genes by NaB provides explanation for the \nanti-invasive properties of NaB. Therefore, our study presents new evidence for \npathways regulated by NaB, thus providing evidence for the mechanism behind \nanti-inflammatory and antimetastatic activities of NaB.", "Histone deacetylase inhibitory prodrugs that are metabolized to butyric acid and \nformaldehyde possess antineoplastic properties and low toxicity. We sought to \ncharacterize the antiangiogenic and antimetastatic activities of two lead \nprodrugs, pivaloyloxymethyl butyrate (AN-9) and butyroyloxymethyl-diethyl \nphosphate (AN-7) in murine cancer models. In the sc implanted human colon \ncarcinoma HT-29 xenograft model AN-7, exhibited superior anticancer activity \ncompared to AN-9, as was evident by the significantly greater inhibition of \ntumor growth and reduction of serum CEA. AN-7 was also more effective in \nreducing mean vessel density (MVD) by 7-fold, bFGF, Ki-67 (7-fold) and \nHIF-1alpha in immunohistochemically stained tumor sections. Semi-quantitative \nevaluation of the levels of bFGF, HDAC1 and HIF-1alpha by Western blot analysis \nshowed a decrease in expression only in the tumors of mice treated with AN-7. \nThe level of bFGF was reduced 3-fold in the tumor and that of TIMP1 was elevated \n(by 3-fold) in the serum of AN-7 treated mice. In a 4T1 metastatic breast \ncarcinoma model, AN-7 inhibited the formation of lung lesions by 76% and AN-9 by \n47%, further demonstrating the greater efficacy of AN-7 compared to AN-9 \n(P<0.02). Both AN-7 and AN-9 exhibited antimetastatic and antiangiogenic \nactivities by reducing vascularization, bFGF expression and HIF-1alpha. Yet, \nAN-7 was more potent than AN-9.", "PURPOSE: Histone deacetylase (HDAC) inhibitors have shown promising clinical \nactivity in the treatment of hematologic malignancies, but their activity in \nsolid tumor indications has been limited. Most HDAC inhibitors in clinical \ndevelopment only transiently induce histone acetylation in tumor tissue. Here, \nwe sought to identify a \"second-generation\" class I HDAC inhibitor with \nprolonged pharmacodynamic response in vivo, to assess whether this results in \nsuperior antitumoral efficacy.\nEXPERIMENTAL DESIGN: To identify novel HDAC inhibitors with superior \npharmacodynamic properties, we developed a preclinical in vivo tumor model, in \nwhich tumor cells have been engineered to express fluorescent protein dependent \non HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the \ntumor response to HDAC inhibitors.\nRESULTS: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic \nacid analogues resulted in the identification of JNJ-26481585. Once daily oral \nadministration of JNJ-26481585 induced continuous histone H3 acetylation. The \nprolonged pharmacodynamic response translated into complete tumor growth \ninhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas \n5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of \nC170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin \nshowed modest activity. Further characterization revealed that JNJ-26481585 is a \npan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L).\nCONCLUSIONS: The potent antitumor activity as a single agent in preclinical \nmodels combined with its favorable pharmacodynamic profile makes JNJ-26481585 a \npromising \"second-generation\" HDAC inhibitor. The compound is currently in \nclinical studies, to evaluate its potential applicability in a broad spectrum of \nboth solid and hematologic malignancies.", "PURPOSE: Histone deacetylase inhibitors (HDACi) are actively explored as \nnew-generation epigenetic drugs but have low efficacy in cancer monotherapy. To \nreveal new mechanism for combination therapy, we show that HDACi induce cell \ndeath but simultaneously activate tumor-progressive genes to ruin therapeutic \nefficacy. Combined treatments to target tumorigenesis and HDACi-activated \nmetastasis with low toxic modalities could develop new strategies for long-term \ncancer therapy.\nEXPERIMENTAL DESIGN: Because metastasis is the major cause of cancer mortality, \nwe measured cell migration activity and profiled metastasis-related gene \nexpressions in HDACi-treated cancer cells. We developed low toxic combination \nmodalities targeting tumorigenesis and HDACi-activated metastasis for \npreclinical therapies in mice.\nRESULTS: We showed that cell migration activity was dramatically and dose \ndependently enhanced by various classes of HDACi treatments in 13 of 30 examined \nhuman breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was \nalso enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs \nand downstream substrates along with upregulated proapoptotic p21. For targeting \ntumorigenesis and metastasis with immediate clinical impact, we showed that new \nmodalities of HDACi combined drugs with PKC inhibitory agent, curcumin or \ntamoxifen, not only suppressed HDACi-activated tumor progressive proteins and \ncell migration in vitro but also inhibited tumor growth and metastasis in vivo.\nCONCLUSION: Treatments of different structural classes of HDACi simultaneously \ninduced cell death and promoted cell migration and metastasis in multiple cancer \ncell types. Suppression of HDACi-induced PKCs leads to development of low toxic \nand long-term therapeutic strategies to potentially treat cancer as a chronic \ndisease." ]	['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D056572']
5ac3699f0340b9f058000001	[ 28527813, 25635462, 24218635, 20023155, 21783031, 24097306 ]	train	Are human enhancers or promoters evolving faster?	factoid	Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. We report that rapid evolution of enhancers is a universal feature of mammalian genomes.	enhancers	[ "A central goal of evolutionary biology is to understand the genetic origin of \nmorphological novelties-i.e. anatomical structures unique to a taxonomic group. \nElaboration of morphology during development depends on networks of regulatory \ngenes that activate patterned gene expression through transcriptional enhancer \nregions. We summarize recent case studies and genome-wide investigations that \nhave uncovered diverse mechanisms though which new enhancers arise. We also \ndiscuss how these enhancer-originating mechanisms have clarified the history of \ngenetic networks underlying diversification of genital structures in flies, \nlimbs and neural crest in chordates, and plant leaves. These studies have \nidentified enhancers that were pivotal for morphological divergence and \nhighlighted how novel genetic networks shaping form emerged from pre-existing \nones.", "Author information:\n(1)University of Cambridge, Cancer Research UK Cambridge Institute, Robinson \nWay, Cambridge, CB2 0RE, UK.\n(2)European Molecular Biology Laboratory, European Bioinformatics Institute, \nWellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.\n(3)Department of Biological Sciences, University of Illinois at Chicago (UIC), \n845 West Taylor Street, Chicago, IL 60607, USA.\n(4)UK Cetacean Strandings Investigation Programme (CSIP) and Institute of \nZoology, Zoological Society of London, Outer Circle, Regent's Park, London NW1 \n4RY, UK.\n(5)School of Optometry and Vision Sciences, Cardiff University, Maindy Road, \nCardiff CF24 4HQ, UK.\n(6)UCLA Center for Neurobehavioral Genetics, 695 Charles E. Young Drive South, \nLos Angeles, CA 90095, USA.\n(7)Division of Stem Cell Biology and Developmental Genetics, MRC National \nInstitute for Medical Research, Mill Hill, London NW7 1AA, UK.\n(8)Center for Zoo and Wild Animal Health, Copenhagen Zoo, Roskildevej 38, \nDK-2000 Frederiksberg, Denmark.\n(9)Department of Veterinary Medicine, University of Cambridge, Madingley Road, \nCambridge CB3 0ES, UK.\n(10)European Molecular Biology Laboratory, European Bioinformatics Institute, \nWellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK; Wellcome Trust \nSanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, \nUK. Electronic address: flicek@ebi.ac.uk.\n(11)University of Cambridge, Cancer Research UK Cambridge Institute, Robinson \nWay, Cambridge, CB2 0RE, UK; Wellcome Trust Sanger Institute, Wellcome Trust \nGenome Campus, Hinxton, Cambridge, CB10 1SD, UK. Electronic address: \nduncan.odom@cruk.cam.ac.uk.", "The complex expression patterns observed for many genes are often regulated by \ndistal transcription enhancers. Changes in the nucleotide sequences of enhancers \nmay therefore lead to changes in gene expression, representing a central \nmechanism by which organisms evolve. With the development of the experimental \ntechnique of chromatin immunoprecipitation (ChIP), in which discrete regions of \nthe genome bound by specific proteins can be identified, it is now possible to \nidentify transcription factor binding events (putative cis-regulatory elements) \nin entire genomes. Comparing protein-DNA binding maps allows us, for the first \ntime, to attempt to identify regulatory differences and infer global patterns of \nchange in gene expression across species. Here, we review studies that used \ngenome-wide ChIP to study the evolution of enhancers. The trend is one of high \ndivergence of cis-regulatory elements between species, possibly compensated by \nextensive creation and loss of regulatory elements and rewiring of their target \ngenes. We speculate on the meaning of the differences observed and discuss that \nalthough ChIP experiments identify the biochemical event of protein-DNA \ninteraction, it cannot determine whether the event results in a biological \nfunction, and therefore more studies are required to establish the effect of \ndivergence of binding events on species-specific gene expression.", "Cis-regulatory modules are non-protein-coding regions of DNA essential for the \ncontrol of gene expression. One class of regulatory modules is embryonic \nenhancers, which drive gene expression during development as a result of \ntranscription factor protein binding at the enhancer sequences. Recent \ncomparative studies have begun to investigate the evolution of the sequence \narchitecture within enhancers. These analyses are illuminating the way that \ndevelopmental biologists think about enhancers by revealing their molecular \nmechanism of function.", "The sequences of some gene regulatory elements diverge considerably, even \nbetween closely related species. A detailed analysis of the fast-evolving \nsparkling enhancer in Drosophila now identifies key compensatory mechanisms and \n'grammar' elements that are critical for maintaining functional integrity.", "There is growing interest in models of regulatory sequence evolution. However, \nexisting models specifically designed for regulatory sequences consider the \nindependent evolution of individual transcription factor (TF)-binding sites, \nignoring that the function and evolution of a binding site depends on its \ncontext, typically the cis-regulatory module (CRM) in which the site is located. \nMoreover, existing models do not account for the gene-specific roles of \nTF-binding sites, primarily because their roles often are not well understood. \nWe introduce two models of regulatory sequence evolution that address some of \nthe shortcomings of existing models and implement simulation frameworks based on \nthem. One model simulates the evolution of an individual binding site in the \ncontext of a CRM, while the other evolves an entire CRM. Both models use a \nstate-of-the art sequence-to-expression model to predict the effects of \nmutations on the regulatory output of the CRM and determine the strength of \nselection. We use the new framework to simulate the evolution of TF-binding \nsites in 37 well-studied CRMs belonging to the anterior-posterior patterning \nsystem in Drosophila embryos. We show that these simulations provide accurate \nfits to evolutionary data from 12 Drosophila genomes, which includes statistics \nof binding site conservation on relatively short evolutionary scales and site \nloss across larger divergence times. The new framework allows us, for the first \ntime, to test hypotheses regarding the underlying cis-regulatory code by \ndirectly comparing the evolutionary implications of the hypothesis with the \nobserved evolutionary dynamics of binding sites. Using this capability, we find \nthat explicitly modeling self-cooperative DNA binding by the TF Caudal (CAD) \nprovides significantly better fits than an otherwise identical evolutionary \nsimulation that lacks this mechanistic aspect. This hypothesis is further \nsupported by a statistical analysis of the distribution of intersite spacing \nbetween adjacent CAD sites. Experimental tests confirm direct homodimeric \ninteraction between CAD molecules as well as self-cooperative DNA binding by \nCAD. We note that computational modeling of the D. melanogaster CRMs alone did \nnot yield significant evidence to support CAD self-cooperativity. We thus \ndemonstrate how specific mechanistic details encoded in CRMs can be revealed by \nmodeling their evolution and fitting such models to multispecies data." ]	nan
56cae51f5795f9a73e000025	[ 20406178, 7551976, 23881705, 17852013, 7595631, 21829620, 25904790, 24995608, 25199710 ]	train	Are immune cells affected in Amyotrophic Lateral Sclerosis?	yesno	In ALS T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it.	yes	[ "The immune system has been found to be involved with positive and negative \neffects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. \nIn general, T cells, B cells, NK cells, mast cells, macrophages, dendritic \ncells, microglia, antibodies, complement and cytokines participate in limiting \ndamage. Several mechanisms of action, such as production of neurotrophic growth \nfactors and interaction with neurons and glial cells, have been shown to \npreserve these latter from injury and stimulate growth and repair. The immune \nsystem also participates in proliferation of neural progenitor stem cells and \ntheir migration to sites of injury and this activity has been documented in \nvarious neurologic disorders including traumatic injury, ischemic and \nhemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative \ndiseases (Alzheimer's disease, Parkinson's disease and ALS). Many therapies have \nbeen shown to stimulate the protective and regenerative aspects of the immune \nsystem in humans, such as intravenous immunoglobulins, and other experimental \ninterventions such as vaccination, minocycline, antibodies and neural stem \ncells, have shown promise in animal models of ALS. Consequently, several \nimmunosuppressive and immunomodulatory therapies have been tried in ALS, \ngenerally with no success, in particular intravenous immunoglobulins. The \nmultiple aspects of the immune response in ALS are beginning to be appreciated, \nand their potential as pharmacologic targets in neurologic disease is being \nexplored.", "The intrathymic injection of donor spleen cells into antilymphocyte serum \n(ALS)-treated mice induces significant prolongation of donor skin grafts. The \nintrathymic route of antigen presentation in this model is superior to the \nintravenous route in achieving unresponsiveness. To elucidate possible \nmechanisms involved in the induction of unresponsiveness in ALS-treated mice \nafter intrathymic injection of donor spleen cells, we have analysed the \nreactivity of lymphoid cells from unresponsive mice in various ways. Deletion of \ndonor reactive cells has been studied using the Mls antigen system. Functional \ninactivation was analysed by a sequential study of the frequency of donor \nreactive cells. Suppressor cell activity was studied using an adoptive transfer \nassay. Deletion of donor reactive cells was partial and occurred largely in the \nspleen in both early and late stages of unresponsiveness. The frequency of donor \nreactive cytotoxic cells was suppressed in both spleen and lymph nodes from day \n+/- 13 until grafts were rejected, with the exception of a rebound period at day \n+/- 22. In contrast, donor reactive cells were not deleted or inactivated in the \nthymus. Suppressor cell activity could only be detected in mice bearing \nlong-term grafts. These results suggest that donor reactive cytotoxic cells are \nfunctionally inactivated in the spleen and nodes in the early and late stages of \nunresponsiveness after intrathymic injection of antigen. In contrast, donor \nreactive cells in the thymus do not appear to be affected.", "Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease \nwith selective loss of upper and lower motor neurons. At sites of motor neuron \ninjury, neuroinflammation is a prominent pathological finding and is \ncharacterized by microglial activation, astrogliosis, and infiltration of \nmonocytes and T-cells. Both innate and adaptive immune responses actively \ninfluence disease progression in animal models and in ALS patients, and promote \nneuroprotection or neurotoxicity at different stages of disease. The early \nimmune reaction to signals from injured motor neurons is to rescue and repair \ndamaged tissue. As disease accelerates, a shift occurs from beneficial immune \nresponses (involving M2 microglia and regulatory T-cells) to deleterious immune \nresponses (involving M1 microglia and Th1 cells). In this review, we underscore \nthe importance of immune-mediated mechanisms in the pathogenesis of ALS and \ndiscuss the alterations and distinct phenotypes of immune cells at the different \nstages of disease. The better we understand the dynamic changes that occur \nwithin the immune system over the course of disease, the better we will be able \nto develop effective therapeutic regimens in ALS.", "Immunological disturbances have been implicated in the pathogenesis of \namyotrophic lateral sclerosis (ALS). Chemokines are involved in the recruitment \nof immune cells. Regulated upon activation, normal T-cell expressed and secreted \n(RANTES) is a C-C beta-chemokine with strong chemo-attractant activity for \nT-lymphocytes and monocytes. We examined serum levels of RANTES in 20 patients \nwith amyotrophic lateral sclerosis (ALS), 14 patients with non-inflammatory \nneurological disorders (NIND) and 13 control subjects (CTRL) and cerebrospinal \nfluid (CSF) levels of RANTES in ALS and NIND group patients in order to \ninvestigate whether RANTES as index of immune activation is present in ALS \npatients. Patients with ALS had higher RANTES levels compared with the NIND \npatients and CTRL subjects (p = 0.005 and p = 0.02, respectively). CSF RANTES \nlevels were also higher compared with the NIND patients (p = 0.007). No \ncorrelation of serum and CSF RANTES levels with disease duration was found. \nThese results may suggest an activated microglia induced recruitment of \nperipheral inflammatory cells to sites of inflammation in ALS patients.", "Point mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1) are \nassociated with autosomal dominant familial amyotrophic lateral sclerosis \n(FALS). We have measured Cu,Zn SOD activity in lymphoblastoid cells from \naffected and at risk FALS patients carrying mutations in the SOD1 gene, FALS \npatients without mutations in the SOD1 gene, individuals affected by the \nsporadic form of the disease (SALS), normal controls and individuals with other \nneurological abnormalities. The results show a significant decrease in Cu,Zn SOD \nactivity in affected and at risk FALS individuals as compared to FALS patients \nwithout mutations, SALS individuals, normal and neurological controls. It is \nconcluded that decreased SOD activity may contribute, together with other as yet \nunknown factors, to motor neurone demise.", "Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal \nneurodegenerative disorder characterized by the selective death of motor neurons \n(MN) in the spinal cord, and is associated with local neuroinflammation. \nCirculating CD4(+) T cells are required for controlling the local detrimental \ninflammation in neurodegenerative diseases, and for supporting neuronal \nsurvival, including that of MN. T-cell deficiency increases neuronal loss, while \nboosting T cell levels reduces it. Here, we show that in the mutant superoxide \ndismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T \n(NKT) cells increased dramatically, and T-cell distribution was altered both in \nlymphoid organs and in the spinal cord relative to wild-type mice. The most \nsignificant elevation of NKT cells was observed in the liver, concomitant with \norgan atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 \ndecreased, while the expression of IGF binding protein (IGFBP)-1 was augmented \nby more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, \nhepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete \nsignificantly higher levels of cytokines when stimulated with an NKT ligand, \nex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl \nceramide (α-GalCer), in a specific regimen, diminished the number of these cells \nin the periphery, and induced recruitment of T cells into the affected spinal \ncord, leading to a modest but significant prolongation of life span of mSOD1 \nmice. These results identify NKT cells as potential players in ALS, and the \nliver as an additional site of major pathology in this disease, thereby \nemphasizing that ALS is not only a non-cell autonomous, but a non-tissue \nautonomous disease, as well. Moreover, the results suggest potential new \ntherapeutic targets such as the liver for immunomodulatory intervention for \nmodifying the disease, in addition to MN-based neuroprotection and systemic \ntreatments aimed at reducing oxidative stress.", "Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, \nfor which there is currently no cure or effective treatment. In this disease, \nlocal neuroinflammation develops along the disease course and contributes to its \nrapid progression. In several models of CNS pathologies, circulating immune \ncells were shown to display an indispensable role in the resolution of the \nneuroinflammatory response. The recruitment of such cells to the CNS involves \nactivation of the choroid plexus (CP) of the brain for leukocyte trafficking, \nthrough a mechanism that requires IFN-γ signaling. Here, we found that in the \nmutant SOD1(G93A) (mSOD1) mouse model of ALS, the CP does not support leukocyte \ntrafficking during disease progression, due to a local reduction in IFN-γ \nlevels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led \nto CP activation, and was followed by the accumulation of immunoregulatory \ncells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) \nregulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in \nthe diseased spinal cord parenchyma. The immunization resulted in the \nattenuation of disease progression and an increased life expectancy of the mSOD1 \nmice. Collectively, our results demonstrate that recruitment of immunoregulatory \ncells to the diseased spinal cord in ALS, needed for fighting off the pathology, \ncan be enhanced by transiently boosting peripheral immunity to myelin antigens.", "In a previous study, we reported that intrathecal injection of mesenchymal stem \ncells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 \ntransgenic mice. In this study, we found that intrathecal MSC administration \nvastly increased the infiltration of peripheral immune cells into the spinal \ncord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide \ndismutase1 transgenic). Thus, we investigated the immunomodulatory effect of \nMSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on \nregulatory T lymphocytes (Treg ; CD4(+) /CD25(high) /FoxP3(+) ) and the mRNA \nexpression of several cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, IL-13, and \nTGF-β). Peripheral blood samples were obtained from nine healthy controls (HC) \nand sixteen patients who were diagnosed with definite or probable ALS. Isolated \nPBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 \nor 72 h. Based on a fluorescence-activated cell sorting analysis, we found that \nco-culture with MSCs increased the Treg /total T-lymphocyte ratio in the PBMCs \nfrom both groups according to the co-culture duration. Co-culture of PBMCs with \nMSCs for 24 h led to elevated mRNA levels of IFN-γ and IL-10 in the PBMCs from \nboth groups. However, after co-culturing for 72 h, although the IFN-γ mRNA level \nhad returned to the basal level in co-cultured HC PBMCs, the IFN-γ mRNA level in \nco-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and \nTGF-β were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor \nmRNA, in both HC and ALS PBMCs co-cultured for 72 h. The elevated expression of \nthese cytokines in the co-culture supernatant was confirmed via ELISA. \nFurthermore, we found that the increased mRNA level of indoleamine \n2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase \nin Treg induction. These findings of Treg induction and increased \nanti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect \nevidence that MSCs may play a role in the immunomodulation of inflammatory \nresponses when MSC therapy is targeted to ALS patients. We propose the following \nmechanism for the effect of mesenchymal stem cells (MSCs) administered \nintrathecally in amyotrophic lateral sclerosis (ALS): MSCs increase infiltration \nof peripheral immune cells into CNS and skew the infiltrated immune cells toward \nregulatory T lymphocytes (Treg ) and Th2 lymphocytes. Treg and Th2 secret \nanti-inflammatory cytokines such as IL-4, IL-10, and TGF-β. A series of \nimmunomodulatory mechanism provides a new strategy for ALS treatment.", "Immune cell infiltration to the brain's territory was considered for decades to \nreflect a pathological process in which immune cells attack the central nervous \nsystem (CNS); such a process is observed in the inflammatory autoimmune disease, \nmultiple sclerosis (MS). As neuroinflammatory processes within the CNS \nparenchyma are also common to other CNS pathologies, regardless of their \netiology, including neurodegenerative disorders such as Alzheimer's disease (AD) \nand Amyotrophic lateral sclerosis (ALS), these pathologies have often been \ncompared to MS, a disease that benefits from immunosuppressive therapy. Yet, \nover the last decade, it became clear that autoimmunity has a bright side, and \nthat it plays a pivotal role in CNS repair following damage. Specifically, \nautoimmune T cells were found to facilitate CNS healing processes, such as in \nthe case of sterile mechanical injuries to the brain or the spinal cord, mental \nstress, or biochemical insults. Even more intriguingly, autoimmune T cells were \nfound to be involved in supporting fundamental processes of brain functional \nintegrity, such as in the maintenance of life-long brain plasticity, including \nspatial learning and memory, and neurogenesis. Importantly, autoimmune T cells \nare part of a cellular network which, to operate efficiently and safely, \nrequires tight regulation by other immune cell populations, such as regulatory T \ncells, which are indispensable for maintenance of immunological self-tolerance \nand homeostasis. Here, we suggest that dysregulation of the balance between \nperipheral immune suppression, on one hand, and protective autoimmunity, on the \nother, is an underlying mechanism in the emergence and progression of the \nneuroinflammatory response associated with chronic neurodegenerative diseases \nand brain aging. Mitigating chronic neuroinflammation under these conditions \nnecessitates activation, rather than suppression, of the peripheral immune \nresponse directed against self. Accordingly, we propose that fighting off acute \nand chronic neurodegenerative conditions requires breaking peripheral immune \ntolerance to CNS self-antigens, in order to boost protective autoimmunity. \nNevertheless, the optimal approach to fine tune such immune response must be \nindividually explored for each condition." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012598', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D000690', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D002477', 'http://www.disease-ontology.org/api/metadata/DOID:230']
5cf4dec0a49efeb44c00000c	[ 22120008, 29517398, 28525751 ]	train	Are lamina-associated domains (LADs) associated with transcriptional activation?	yesno	Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression.	no	[ "Extensive changes in DNA methylation are common in cancer and may contribute to \noncogenesis through transcriptional silencing of tumor-suppressor genes. \nGenome-scale studies have yielded important insights into these changes but have \nfocused on CpG islands or gene promoters. We used whole-genome bisulfite \nsequencing (bisulfite-seq) to comprehensively profile a primary human colorectal \ntumor and adjacent normal colon tissue at single-basepair resolution. Regions of \nfocal hypermethylation in the tumor were located primarily at CpG islands and \nwere concentrated within regions of long-range (>100 kb) hypomethylation. These \nhypomethylated domains covered nearly half of the genome and coincided with late \nreplication and attachment to the nuclear lamina in human cell lines. We \nconfirmed the confluence of hypermethylation and hypomethylation within these \ndomains in 25 diverse colorectal tumors and matched adjacent tissue. We propose \nthat widespread DNA methylation changes in cancer are linked to silencing \nprograms orchestrated by the three-dimensional organization of chromatin within \nthe nucleus.", "The nuclear lamina contributes to the regulation of gene expression and to \nchromatin organization. Mutations in A-type nuclear lamins cause laminopathies, \nsome of which are associated with a loss of heterochromatin at the nuclear \nperiphery. Until recently however, little if any information has been provided \non where and how lamin A interacts with the genome and on how disease-causing \nlamin A mutations may rearrange genome conformation. Here, we review aspects of \nnuclear lamin association with the genome. We highlight recent evidence of \nreorganization of lamin A-chromatin interactions in cellular models of \nlaminopathies, and implications on the 3-dimensional rearrangement of chromatin \nin these models, including patient cells. We discuss how a hot-spot \nlipodystrophic lamin A mutation alters chromatin conformation and epigenetic \npatterns at an anti-adipogenic locus, and conclude with remarks on links between \nlamin A, Polycomb and the pathophysiology of laminopathies. The recent findings \npresented here collectively argue towards a deregulation of large-scale and \nlocal spatial genome organization by a subset of lamin A mutations causing \nlaminopathies.", "Author information:\n(1)Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, \nthe Netherlands; Department of Cell Biology, Erasmus University Medical Center, \n3015 CE Rotterdam, the Netherlands. Electronic address: b.v.steensel@nki.nl.\n(2)Department of Cell and Developmental Biology, University of Illinois at \nUrbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic \nBiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. \nElectronic address: asbel@illinois.edu." ]	nan
51757bbb8ed59a060a00002e	[ 22708672, 23028352, 20624288, 20587619, 21622663, 21112873, 20428234, 23454638, 22707570, 22955988, 23467124, 23463798, 22844254 ]	train	Are long non coding RNAs as conserved in sequence as protein coding genes?	yesno	No. Most long non coding RNAs (lncRNAs) are under lower sequence constraints than protein-coding genes.	no	[ "BACKGROUND: The HOX gene clusters are thought to be highly conserved amongst \nmammals and other vertebrates, but the long non-coding RNAs have only been \nstudied in detail in human and mouse. The sequencing of the kangaroo genome \nprovides an opportunity to use comparative analyses to compare the HOX clusters \nof a mammal with a distinct body plan to those of other mammals.\nRESULTS: Here we report a comparative analysis of HOX gene clusters between an \nAustralian marsupial of the kangaroo family and the eutherians. There was a \nstrikingly high level of conservation of HOX gene sequence and structure and \nnon-protein coding genes including the microRNAs miR-196a, miR-196b, miR-10a and \nmiR-10b and the long non-coding RNAs HOTAIR, HOTAIRM1 and HOXA11AS that play \ncritical roles in regulating gene expression and controlling development. By \nmicroRNA deep sequencing and comparative genomic analyses, two conserved \nmicroRNAs (miR-10a and miR-10b) were identified and one new candidate microRNA \nwith typical hairpin precursor structure that is expressed in both fibroblasts \nand testes was found. The prediction of microRNA target analysis showed that \nseveral known microRNA targets, such as miR-10, miR-414 and miR-464, were found \nin the tammar HOX clusters. In addition, several novel and putative miRNAs were \nidentified that originated from elsewhere in the tammar genome and that target \nthe tammar HOXB and HOXD clusters.\nCONCLUSIONS: This study confirms that the emergence of known long non-coding \nRNAs in the HOX clusters clearly predate the marsupial-eutherian divergence 160 \nMa ago. It also identified a new potentially functional microRNA as well as \nconserved miRNAs. These non-coding RNAs may participate in the regulation of HOX \ngenes to influence the body plan of this marsupial.", "Tinkering with pre-existing genes has long been known as a major way to create \nnew genes. Recently, however, motherless protein-coding genes have been found to \nhave emerged de novo from ancestral non-coding DNAs. How these genes originated \nis not well addressed to date. Here we identified 24 hominoid-specific de novo \nprotein-coding genes with precise origination timing in vertebrate phylogeny. \nStrand-specific RNA-Seq analyses were performed in five rhesus macaque tissues \n(liver, prefrontal cortex, skeletal muscle, adipose, and testis), which were \nthen integrated with public transcriptome data from human, chimpanzee, and \nrhesus macaque. On the basis of comparing the RNA expression profiles in the \nthree species, we found that most of the hominoid-specific de novo \nprotein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or \nchimpanzee with a similar transcript structure and correlated tissue expression \nprofile. According to the rule of parsimony, the majority of these \nhominoid-specific de novo protein-coding genes appear to have acquired a \nregulated transcript structure and expression profile before acquiring coding \npotential. Interestingly, although the expression profile was largely \ncorrelated, the coding genes in human often showed higher transcriptional \nabundance than their non-coding counterparts in rhesus macaque. The major \nfindings we report in this manuscript are robust and insensitive to the \nparameters used in the identification and analysis of de novo genes. Our results \nsuggest that at least a portion of long non-coding RNAs, especially those with \nactive and regulated transcription, may serve as a birth pool for protein-coding \ngenes, which are then further optimized at the transcriptional level.", "BACKGROUND: Long considered to be the building block of life, it is now apparent \nthat protein is only one of many functional products generated by the eukaryotic \ngenome. Indeed, more of the human genome is transcribed into noncoding sequence \nthan into protein-coding sequence. Nevertheless, whilst we have developed a deep \nunderstanding of the relationships between evolutionary constraint and function \nfor protein-coding sequence, little is known about these relationships for \nnon-coding transcribed sequence. This dearth of information is partially \nattributable to a lack of established non-protein-coding RNA (ncRNA) orthologs \namong birds and mammals within sequence and expression databases.\nRESULTS: Here, we performed a multi-disciplinary study of four highly conserved \nand brain-expressed transcripts selected from a list of mouse long intergenic \nnoncoding RNA (lncRNA) loci that generally show pronounced evolutionary \nconstraint within their putative promoter regions and across exon-intron \nboundaries. We identify some of the first lncRNA orthologs present in birds \n(chicken), marsupial (opossum), and eutherian mammals (mouse), and investigate \nwhether they exhibit conservation of brain expression. In contrast to \nconventional protein-coding genes, the sequences, transcriptional start sites, \nexon structures, and lengths for these non-coding genes are all highly variable.\nCONCLUSIONS: The biological relevance of lncRNAs would be highly questionable if \nthey were limited to closely related phyla. Instead, their preservation across \ndiverse amniotes, their apparent conservation in exon structure, and \nsimilarities in their pattern of brain expression during embryonic and early \npostnatal stages together indicate that these are functional RNA molecules, of \nwhich some have roles in vertebrate brain development.", "Experimental evidence suggests that half or more of the mammalian transcriptome \nconsists of noncoding RNA. Noncoding RNAs are divided into short noncoding RNAs \n(including microRNAs) and long noncoding RNAs (lncRNAs). We defined \ncomplementary DNAs (cDNAs) lacking any positive-strand open reading frames \n(ORFs) longer than 30 amino acids, as well as cDNAs lacking any evidence of \ninterspecies conservation of their longer-than-30-amino acid ORFs, as noncoding. \nWe have identified 5446 lncRNA genes in the human genome from approximately \n24,000 full-length cDNAs, using our new ORF-prediction pipeline. We combined \nthem nonredundantly with lncRNAs from four published sources to derive 6736 \nlncRNA genes. In an effort to distinguish standalone and antisense lncRNA genes \nfrom database artifacts, we stratified our catalog of lncRNAs according to the \ndistance between each lncRNA gene candidate and its nearest known protein-coding \ngene. We concurrently examined the protein-coding capacity of known genes \noverlapping with lncRNAs. Remarkably, 62% of known genes with \"hypothetical \nprotein\" names actually lacked protein-coding capacity. This study has greatly \nexpanded the known human lncRNA catalog, increased its accuracy through manual \nannotation of cDNA-to-genome alignments, and revealed that a large set of \nhypothetical-protein genes in GenBank lacks protein-coding capacity. In \naddition, we have developed, independently of existing NCBI tools, command-line \nprograms with high-throughput ORF-finding and BLASTP-parsing functionality, \nsuitable for future automated assessments of protein-coding capacity of novel \ntranscripts.", "MOTIVATION: Long non-coding RNAs (lncRNAs) resemble protein-coding mRNAs but do \nnot encode proteins. Most lncRNAs are under lower sequence constraints than \nprotein-coding genes and lack conserved secondary structures, making it hard to \npredict them computationally.\nRESULTS: We introduce an approach to predict spliced lncRNAs in vertebrate \ngenomes combining comparative genomics and machine learning. It is based on \ndetecting signatures of characteristic splice site evolution in vertebrate whole \ngenome alignments. First, we predict individual splice sites, then assemble \ncompatible sites into exon candidates, and finally predict multi-exon \ntranscripts. Using a novel method to evaluate typical splice site substitution \npatterns that explicitly takes the species phylogeny into account, we show that \nindividual splice sites can be accurately predicted. Since our approach relies \nonly on predicted splice sites, it can uncover both coding and non-coding exons. \nWe show that our predicted exons and partial transcripts are mostly non-coding \nand lack conserved secondary structures. These exons are of particular interest, \nsince existing computational approaches cannot detect them. Transcriptome \nsequencing data indicate tissue-specific expression patterns of predicted exons \nand there is evidence that increasing sequencing depth and breadth will validate \nadditional predictions. We also found a significant enrichment of predicted \nexons that form multi-exon transcript parts, and we experimentally validate such \na novel multi-exon gene. Overall, we obtain 336 novel multi-exon transcript \npredictions from human intergenic regions. Our results indicate the existence of \nnovel human transcripts that are conserved in evolution and our approach \ncontributes to the completion of the human transcript catalog.\nAVAILABILITY AND IMPLEMENTATION: Predicted human splice sites, exons and gene \nstructures together with a Perl implementation of the tree-based log-odds \nscoring and a supplementary PDF file containing additional figures and tables \nare available at: \nhttp://www.bioinf.uni-leipzig.de/publications/supplements/10-010. The five \nexperimentally confirmed partial transcript isoforms have been deposited in \nGenBank under accession numbers HM587422-HM587426.", "Large numbers of long RNAs with little or no protein-coding potential [long \nnoncoding RNAs (lncRNAs)] are being identified in eukaryotes. In parallel, \nincreasing data describing the expression profiles, molecular features and \nfunctions of individual lncRNAs in a variety of systems are accumulating. To \nenable the systematic compilation and updating of this information, we have \ndeveloped a database (lncRNAdb) containing a comprehensive list of lncRNAs that \nhave been shown to have, or to be associated with, biological functions in \neukaryotes, as well as messenger RNAs that have regulatory roles. Each entry \ncontains referenced information about the RNA, including sequences, structural \ninformation, genomic context, expression, subcellular localization, \nconservation, functional evidence and other relevant information. lncRNAdb can \nbe searched by querying published RNA names and aliases, sequences, species and \nassociated protein-coding genes, as well as terms contained in the annotations, \nsuch as the tissues in which the transcripts are expressed and associated \ndiseases. In addition, lncRNAdb is linked to the UCSC Genome Browser for \nvisualization and Noncoding RNA Expression Database (NRED) for expression \ninformation from a variety of sources. lncRNAdb provides a platform for the \nongoing collation of the literature pertaining to lncRNAs and their association \nwith other genomic elements. lncRNAdb can be accessed at: \nhttp://www.lncrnadb.org/.", "BACKGROUND: The role of long non-coding RNAs (lncRNAs) in controlling gene \nexpression has garnered increased interest in recent years. Sequencing projects, \nsuch as Fantom3 for mouse and H-InvDB for human, have generated abundant data on \ntranscribed components of mammalian cells, the majority of which appear not to \nbe protein-coding. However, much of the non-protein-coding transcriptome could \nmerely be a consequence of 'transcription noise'. It is therefore essential to \nuse bioinformatic approaches to identify the likely functional candidates in a \nhigh throughput manner.\nPRINCIPAL FINDINGS: We derived a scheme for classifying and annotating likely \nfunctional lncRNAs in mammals. Using the available experimental full-length cDNA \ndata sets for human and mouse, we identified 78 lncRNAs that are either \nsyntenically conserved between human and mouse, or that originate from the same \nprotein-coding genes. Of these, 11 have significant sequence homology. We found \nthat these lncRNAs exhibit: (i) patterns of codon substitution typical of \nnon-coding transcripts; (ii) preservation of sequences in distant mammals such \nas dog and cow, (iii) significant sequence conservation relative to their \ncorresponding flanking regions (in 50% cases, flanking regions do not have \nhomology at all; and in the remaining, the degree of conservation is \nsignificantly less); (iv) existence mostly as single-exon forms (8/11); and, (v) \npresence of conserved and stable secondary structure motifs within them. We \nfurther identified orthologous protein-coding genes that are contributing to the \npool of lncRNAs; of which, genes implicated in carcinogenesis are significantly \nover-represented.\nCONCLUSION: Our comparative mammalian genomics approach coupled with \nevolutionary analysis identified a small population of conserved long \nnon-protein-coding RNAs (lncRNAs) that are potentially functional across \nMammalia. Additionally, our analysis indicates that amongst the orthologous \nprotein-coding genes that produce lncRNAs, those implicated in cancer \npathogenesis are significantly over-represented, suggesting that these lncRNAs \ncould play an important role in cancer pathomechanisms.", "The genomic architecture of several functional elements in animals and plants, \nsuch as microRNAs and tRNA, has been better characterized. As yet, there is very \nlittle known about genomic organization and structure of lncRNA in animals and \nplants. Here, we conducted a genome-wide systematic computational analysis of \ngenomic architecture of lncRNAs, and further provided a more comprehensive \ncomparative view of genomic organization between lncRNAs and several other \nfunctional elements in the human genome. Our study not only provides \ncomprehensive knowledge for further studies into the correlations between the \ngenomic architecture of lncRNAs and their important functional roles in diverse \ncellular processes and in disease, but also will be valuable for understanding \nthe origin and evolution of lncRNAs.", "Thousands of long noncoding RNAs (lncRNAs) have been found in vertebrate \nanimals, a few of which have known biological roles. To better understand the \ngenomics and features of lncRNAs in invertebrates, we used available RNA-seq, \npoly(A)-site, and ribosome-mapping data to identify lncRNAs of Caenorhabditis \nelegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or \nmultiexonic structures that did not overlap protein-coding transcripts, and \nabout sixty antisense lncRNAs (ancRNAs), which were complementary to \nprotein-coding transcripts. Compared to protein-coding genes, the lncRNA genes \ntended to be expressed in a stage-dependent manner. Approximately 25% of the \nnewly identified lincRNAs showed little signal for sequence conservation and \nmapped antisense to clusters of endogenous siRNAs, as would be expected if they \nserve as templates and targets for these siRNAs. The other 75% tended to be more \nconserved and included lincRNAs with intriguing expression and sequence features \nassociating them with processes such as dauer formation, male identity, sperm \nformation, and interaction with sperm-specific mRNAs. Our study provides a \nglimpse into the lncRNA content of a nonvertebrate animal and a resource for \nfuture studies of lncRNA function.", "The human genome contains many thousands of long noncoding RNAs (lncRNAs). While \nseveral studies have demonstrated compelling biological and disease roles for \nindividual examples, analytical and experimental approaches to investigate these \ngenes have been hampered by the lack of comprehensive lncRNA annotation. Here, \nwe present and analyze the most complete human lncRNA annotation to date, \nproduced by the GENCODE consortium within the framework of the ENCODE project \nand comprising 9277 manually annotated genes producing 14,880 transcripts. Our \nanalyses indicate that lncRNAs are generated through pathways similar to that of \nprotein-coding genes, with similar histone-modification profiles, splicing \nsignals, and exon/intron lengths. In contrast to protein-coding genes, however, \nlncRNAs display a striking bias toward two-exon transcripts, they are \npredominantly localized in the chromatin and nucleus, and a fraction appear to \nbe preferentially processed into small RNAs. They are under stronger selective \npressure than neutrally evolving sequences-particularly in their promoter \nregions, which display levels of selection comparable to protein-coding genes. \nImportantly, about one-third seem to have arisen within the primate lineage. \nComprehensive analysis of their expression in multiple human organs and brain \nregions shows that lncRNAs are generally lower expressed than protein-coding \ngenes, and display more tissue-specific expression patterns, with a large \nfraction of tissue-specific lncRNAs expressed in the brain. Expression \ncorrelation analysis indicates that lncRNAs show particularly striking positive \ncorrelation with the expression of antisense coding genes. This GENCODE \nannotation represents a valuable resource for future studies of lncRNAs.", "Novel, profound and unexpected roles of long non-coding RNAs (lncRNAs) are \nemerging in critical aspects of gene regulation. Thousands of lncRNAs have been \nrecently discovered in a wide range of mammalian systems, related to \ndevelopment, epigenetics, cancer, brain function and hereditary disease. The \nstructural biology of these lncRNAs presents a brave new RNA world, which may \ncontain a diverse zoo of new architectures and mechanisms. While structural \nstudies of lncRNAs are in their infancy, we describe existing structural data \nfor lncRNAs, as well as crystallographic studies of other RNA machines and their \nimplications for lncRNAs. We also discuss the importance of dynamics in RNA \nmachine mechanism. Determining commonalities between lncRNA systems will help \nelucidate the evolution and mechanistic role of lncRNAs in disease, creating a \nstructural framework necessary to pursue lncRNA-based therapeutics.", "Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years \nas a potentially new and crucial layer of biological regulation. lncRNAs of all \nkinds have been implicated in a range of developmental processes and diseases, \nbut knowledge of the mechanisms by which they act is still surprisingly limited, \nand claims that almost the entirety of the mammalian genome is transcribed into \nfunctional noncoding transcripts remain controversial. At the same time, a small \nnumber of well-studied lncRNAs have given us important clues about the biology \nof these molecules, and a few key functional and mechanistic themes have begun \nto emerge, although the robustness of these models and classification schemes \nremains to be seen. Here, we review the current state of knowledge of the lncRNA \nfield, discussing what is known about the genomic contexts, biological \nfunctions, and mechanisms of action of lncRNAs. We also reflect on how the \nrecent interest in lncRNAs is deeply rooted in biology's longstanding concern \nwith the evolution and function of genomes.", "A large proportion of functional sequence within mammalian genomes falls outside \nprotein-coding exons and can be transcribed into long RNAs. However, the roles \nin mammalian biology of long noncoding RNA (lncRNA) are not well understood. Few \nlncRNAs have experimentally determined roles, with some of these being \nlineage-specific. Determining the extent by which transcription of lncRNA loci \nis retained or lost across multiple evolutionary lineages is essential if we are \nto understand their contribution to mammalian biology and to lineage-specific \ntraits. Here, we experimentally investigated the conservation of lncRNA \nexpression among closely related rodent species, allowing the evolution of DNA \nsequence to be uncoupled from evolution of transcript expression. We generated \ntotal RNA (RNAseq) and H3K4me3-bound (ChIPseq) DNA data, and combined both to \nconstruct catalogues of transcripts expressed in the adult liver of Mus musculus \ndomesticus (C57BL/6J), Mus musculus castaneus, and Rattus norvegicus. We \nestimated the rate of transcriptional turnover of lncRNAs and investigated the \neffects of their lineage-specific birth or death. LncRNA transcription showed \nconsiderably greater gain and loss during rodent evolution, compared with \nprotein-coding genes. Nucleotide substitution rates were found to mirror the in \nvivo transcriptional conservation of intergenic lncRNAs between rodents: only \nthe sequences of noncoding loci with conserved transcription were constrained. \nFinally, we found that lineage-specific intergenic lncRNAs appear to be \nassociated with modestly elevated expression of genomically neighbouring \nprotein-coding genes. Our findings show that nearly half of intergenic lncRNA \nloci have been gained or lost since the last common ancestor of mouse and rat, \nand they predict that such rapid transcriptional turnover contributes to the \nevolution of tissue- and lineage-specific gene expression." ]	nan
535d292a9a4572de6f000003	[ 22955974, 21622663, 22707570, 22955988, 24285305, 24106460 ]	train	Are long non coding RNAs spliced?	yesno	Long non coding RNAs appear to be spliced through the same pathway as the mRNAs	yes	[ "Splicing remains an incompletely understood process. Recent findings suggest \nthat chromatin structure participates in its regulation. Here, we analyze the \nRNA from subcellular fractions obtained through RNA-seq in the cell line K562. \nWe show that in the human genome, splicing occurs predominantly during \ntranscription. We introduce the coSI measure, based on RNA-seq reads mapping to \nexon junctions and borders, to assess the degree of splicing completion around \ninternal exons. We show that, as expected, splicing is almost fully completed in \ncytosolic polyA+ RNA. In chromatin-associated RNA (which includes the RNA that \nis being transcribed), for 5.6% of exons, the removal of the surrounding introns \nis fully completed, compared with 0.3% of exons for which no intron-removal has \noccurred. The remaining exons exist as a mixture of spliced and fewer unspliced \nmolecules, with a median coSI of 0.75. Thus, most RNAs undergo splicing while \nbeing transcribed: \"co-transcriptional splicing.\" Consistent with \nco-transcriptional spliceosome assembly and splicing, we have found significant \nenrichment of spliceosomal snRNAs in chromatin-associated RNA compared with \nother cellular RNA fractions and other nonspliceosomal snRNAs. CoSI scores \ndecrease along the gene, pointing to a \"first transcribed, first spliced\" rule, \nyet more downstream exons carry other characteristics, favoring rapid, \nco-transcriptional intron removal. Exons with low coSI values, that is, in the \nprocess of being spliced, are enriched with chromatin marks, consistent with a \nrole for chromatin in splicing during transcription. For alternative exons and \nlong noncoding RNAs, splicing tends to occur later, and the latter might remain \nunspliced in some cases.", "MOTIVATION: Long non-coding RNAs (lncRNAs) resemble protein-coding mRNAs but do \nnot encode proteins. Most lncRNAs are under lower sequence constraints than \nprotein-coding genes and lack conserved secondary structures, making it hard to \npredict them computationally.\nRESULTS: We introduce an approach to predict spliced lncRNAs in vertebrate \ngenomes combining comparative genomics and machine learning. It is based on \ndetecting signatures of characteristic splice site evolution in vertebrate whole \ngenome alignments. First, we predict individual splice sites, then assemble \ncompatible sites into exon candidates, and finally predict multi-exon \ntranscripts. Using a novel method to evaluate typical splice site substitution \npatterns that explicitly takes the species phylogeny into account, we show that \nindividual splice sites can be accurately predicted. Since our approach relies \nonly on predicted splice sites, it can uncover both coding and non-coding exons. \nWe show that our predicted exons and partial transcripts are mostly non-coding \nand lack conserved secondary structures. These exons are of particular interest, \nsince existing computational approaches cannot detect them. Transcriptome \nsequencing data indicate tissue-specific expression patterns of predicted exons \nand there is evidence that increasing sequencing depth and breadth will validate \nadditional predictions. We also found a significant enrichment of predicted \nexons that form multi-exon transcript parts, and we experimentally validate such \na novel multi-exon gene. Overall, we obtain 336 novel multi-exon transcript \npredictions from human intergenic regions. Our results indicate the existence of \nnovel human transcripts that are conserved in evolution and our approach \ncontributes to the completion of the human transcript catalog.\nAVAILABILITY AND IMPLEMENTATION: Predicted human splice sites, exons and gene \nstructures together with a Perl implementation of the tree-based log-odds \nscoring and a supplementary PDF file containing additional figures and tables \nare available at: \nhttp://www.bioinf.uni-leipzig.de/publications/supplements/10-010. The five \nexperimentally confirmed partial transcript isoforms have been deposited in \nGenBank under accession numbers HM587422-HM587426.", "Thousands of long noncoding RNAs (lncRNAs) have been found in vertebrate \nanimals, a few of which have known biological roles. To better understand the \ngenomics and features of lncRNAs in invertebrates, we used available RNA-seq, \npoly(A)-site, and ribosome-mapping data to identify lncRNAs of Caenorhabditis \nelegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or \nmultiexonic structures that did not overlap protein-coding transcripts, and \nabout sixty antisense lncRNAs (ancRNAs), which were complementary to \nprotein-coding transcripts. Compared to protein-coding genes, the lncRNA genes \ntended to be expressed in a stage-dependent manner. Approximately 25% of the \nnewly identified lincRNAs showed little signal for sequence conservation and \nmapped antisense to clusters of endogenous siRNAs, as would be expected if they \nserve as templates and targets for these siRNAs. The other 75% tended to be more \nconserved and included lincRNAs with intriguing expression and sequence features \nassociating them with processes such as dauer formation, male identity, sperm \nformation, and interaction with sperm-specific mRNAs. Our study provides a \nglimpse into the lncRNA content of a nonvertebrate animal and a resource for \nfuture studies of lncRNA function.", "The human genome contains many thousands of long noncoding RNAs (lncRNAs). While \nseveral studies have demonstrated compelling biological and disease roles for \nindividual examples, analytical and experimental approaches to investigate these \ngenes have been hampered by the lack of comprehensive lncRNA annotation. Here, \nwe present and analyze the most complete human lncRNA annotation to date, \nproduced by the GENCODE consortium within the framework of the ENCODE project \nand comprising 9277 manually annotated genes producing 14,880 transcripts. Our \nanalyses indicate that lncRNAs are generated through pathways similar to that of \nprotein-coding genes, with similar histone-modification profiles, splicing \nsignals, and exon/intron lengths. In contrast to protein-coding genes, however, \nlncRNAs display a striking bias toward two-exon transcripts, they are \npredominantly localized in the chromatin and nucleus, and a fraction appear to \nbe preferentially processed into small RNAs. They are under stronger selective \npressure than neutrally evolving sequences-particularly in their promoter \nregions, which display levels of selection comparable to protein-coding genes. \nImportantly, about one-third seem to have arisen within the primate lineage. \nComprehensive analysis of their expression in multiple human organs and brain \nregions shows that lncRNAs are generally lower expressed than protein-coding \ngenes, and display more tissue-specific expression patterns, with a large \nfraction of tissue-specific lncRNAs expressed in the brain. Expression \ncorrelation analysis indicates that lncRNAs show particularly striking positive \ncorrelation with the expression of antisense coding genes. This GENCODE \nannotation represents a valuable resource for future studies of lncRNAs.", "NONCODE (http://www.bioinfo.org/noncode/) is an integrated knowledge database \ndedicated to non-coding RNAs (excluding tRNAs and rRNAs). Non-coding RNAs \n(ncRNAs) have been implied in diseases and identified to play important roles in \nvarious biological processes. Since NONCODE version 3.0 was released 2 years \nago, discovery of novel ncRNAs has been promoted by high-throughput RNA \nsequencing (RNA-Seq). In this update of NONCODE, we expand the ncRNA data set by \ncollection of newly identified ncRNAs from literature published in the last 2 \nyears and integration of the latest version of RefSeq and Ensembl. Particularly, \nthe number of long non-coding RNA (lncRNA) has increased sharply from 73 327 to \n210 831. Owing to similar alternative splicing pattern to mRNAs, the concept of \nlncRNA genes was put forward to help systematic understanding of lncRNAs. The 56 \n018 and 46 475 lncRNA genes were generated from 95 135 and 67 628 lncRNAs for \nhuman and mouse, respectively. Additionally, we present expression profile of \nlncRNA genes by graphs based on public RNA-seq data for human and mouse, as well \nas predict functions of these lncRNA genes. The improvements brought to the \ndatabase also include an incorporation of an ID conversion tool from RefSeq or \nEnsembl ID to NONCODE ID and a service of lncRNA identification. NONCODE is also \naccessible through http://www.noncode.org/.", "Long non-coding (lnc) RNAs are defined as non-protein coding RNAs distinct from \nhousekeeping RNAs such as tRNAs, rRNAs, and snRNAs, and independent from small \nRNAs with specific molecular processing machinery such as micro- or piwi-RNAs. \nRecent studies of lncRNAs across different species have revealed a diverse \npopulation of RNA molecules of differing size and function. RNA sequencing \nstudies suggest transcription throughout the genome, so there is a need to \nunderstand how sequence relates to functional and structural relationships \namongst RNA molecules. Our synthesis of recent studies suggests that neither \nsize, presence of a poly-A tail, splicing, direction of transcription, nor \nstrand specificity are of importance to lncRNA function. Rather, relative \ngenomic position in relation to a target is fundamentally important. In this \nreview, we describe issues of key importance in functional assessment of lncRNA \nand how this might apply to lncRNAs important in neurodevelopment." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012326', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D062085']
5a6e4814b750ff445500004a	[ 28985562 ]	train	Are loop domains preserved upon cohesin loss?	yesno	No. Degradation of cohesin leads to elimination of loop domains. Neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes.	no	[ "Author information:\n(1)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Molecular and Human Genetics, Baylor College of \nMedicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford \nUniversity School of Medicine, Stanford, CA 94305, USA.\n(2)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Molecular and Human Genetics, Baylor College of \nMedicine, Houston, TX 77030, USA.\n(3)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Molecular and Human Genetics, Baylor College of \nMedicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, \nRice University, Houston, TX 77030, USA.\n(4)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.\n(5)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.\n(6)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, \nTX 77030, USA; Department of Computer Science, Stanford University, Stanford, CA \n94305, USA.\n(7)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of \nPathology and Center for Cancer Research, Massachusetts General Hospital and \nHarvard Medical School, Boston, MA 02114, USA.\n(8)Department of Chemistry, New York University, New York, NY 10003, USA.\n(9)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Departments of Computer Science and Computational and Applied \nMathematics, Rice University, Houston, TX 77030, USA.\n(10)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Molecular and Human Genetics, Baylor College of \nMedicine, Houston, TX 77030, USA; Departments of Computer Science and \nComputational and Applied Mathematics, Rice University, Houston, TX 77030, USA; \nMedical Scientist Training Program, Baylor College of Medicine, Houston, TX \n77030, USA.\n(11)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Medicine, University of California, San Diego, La \nJolla, CA 92037, USA.\n(12)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; \nDepartment of Medicine, University of California, San Diego, La Jolla, CA 92037, \nUSA.\n(13)Department of Chemistry, New York University, New York, NY 10003, USA; \nCourant Institute of Mathematical Sciences, New York University, New York, NY \n10012, USA; NYU-ECNU Center for Computational Chemistry, NYU Shanghai, Shanghai \n200062, China.\n(14)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of \nCancer Research, NCI, NIH, Bethesda, MD 20892, USA.\n(15)Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of \nBiology, MIT, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard \nMedical School, Boston, MA 02115, USA.\n(16)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX \n77030, USA; Department of Molecular and Human Genetics, Baylor College of \nMedicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, \nRice University, Houston, TX 77030, USA; Broad Institute of MIT and Harvard, \nCambridge, MA 02139, USA; Departments of Computer Science and Computational and \nApplied Mathematics, Rice University, Houston, TX 77030, USA. Electronic \naddress: erez@erez.com." ]	nan
5cebf83ea49efeb44c00000a	[ 1958563, 18603021, 17108242, 25956531, 508371, 16549717, 22155196, 30394940 ]	train	Are male or female persons more prone to autoimmunity?	factoid	Sex hormones have long been implicated in autoimmune diseases because women account for 80% of cases.	Female	[ "The immune response of males and females is not identical but instead has been \nshown to be dimorphic in its nature, with females generally demonstrating a \ngreater overall response than males. This dimorphism extends to both the humoral \nand cell mediated systems and appears to be mechanistically based on the \ndifferences in type and concentration of sex steroids in males vs females. \nFurthermore, growth hormone and prolactin secretions which are different in \nmales and females may also be partly responsible for the observed dimorphism. \nBecause autoimmune disease results from a pathological perturbation of normal \nimmune function, it follows that expression of these diseases will also \ndemonstrate a dimorphic pattern. Examples of this autoimmune dimorphism include \n(but are not limited to) lupus, rheumatoid arthritis and multiple sclerosis with \nthe two former more prevalent in females than males and the latter more severe \nduring pregnancy. To explain autoimmune dimorphism it therefore becomes \nnecessary firstly to describe the cellular and hormonal interactions found in \nnormal immune regulation and thereafter extrapolate these to autoimmune \nphenomena.", "Autoimmune diseases include several conditions that cumulatively are estimated \nto affect over 5% of the US population with a striking female predominance \nreported for most of them. The cause and mechanisms of this sex bias remains \nunknown despite multiple proposed hypotheses. Indeed, it is well established in \nseveral experimental settings that the human immune system exhibits sexual \ndimorphism with basic immune responses differing between females and males. \nAmong candidate factors to explain these differences we note that particular \nattention has been primarily devoted to sex hormones, yet data have been \ninconclusive or have not been confirmed. The same seems to apply to the \nhypothesis of fetal microchimerism. Most recently, sex chromosome abnormalities \nand skewed X chromosome inactivation have been suggested as novel players, \nparticularly in later-onset diseases. We review herein the most recent data on \nthe mechanisms proposed for the female predominance. We also attempt to \ndetermine whether observed sex ratios are in fact the result of sex-biased \nawareness in case-finding studies.", "Sex hormones have long been implicated in autoimmune diseases because women \naccount for 80% of cases. The mechanism of hormonal action in autoimmunity is \nunknown. Drawing on genetic studies of autoimmune disease, this article \ndiscusses how both genes and sex hormones may exert their effects through the \nsame general mechanism, dysregulation of transcription factor NF-kappaB, an \nimmunoregulatory protein. Gene and hormone alterations of the NF-kappaB \nsignaling cascade provide a unifying hypothesis to explain the wide-ranging \nhuman and murine autoimmune disease phenotypes regulated by NF-kappaB, including \ncytokine balance, antigen presentation, lymphoid development, and lymphoid \nrepertoire selection by apoptosis.", "Autoimmune diseases like rheumatoid arthritis are multifactorial in nature, \nrequiring both genetic and environmental factors for onset. Increased \npredisposition of females to a wide range of autoimmune diseases points to a \ngender bias in the multifactorial etiology of these disorders. However, the \nexisting evidence to date has not provided any conclusive mechanism of \ngender-bias beyond the role of hormones and sex chromosomes. The gut microbiome, \nwhich impacts the innate and adaptive branches of immunity, not only influences \nthe development of autoimmune disorders but may interact with sex-hormones to \nmodulate disease progression and sex-bias. Here, we review the current \ninformation on gender bias in autoimmunity and discuss the potential of \nmicrobiome-derived biomarkers to help unravel the complex interplay between \ngenes, environment and hormones in rheumatoid arthritis.", "Investigators from this laboratory have been studying sex hormones in normal and \nautoimmune mice for the past 10 years. We have found that immune responses to \nDNa are influenced by sex hormones. Androgens reduce and estrogens increase both \nspontaneous and immunization-induced antibodies to single-stranded DNA in NZB X \nNZW, NZB X C3H, NZB X CBA, NZB X DBA mice. Treatment of female NZB/W mice with \ntestosterone or 5 alpha dihydrotestosterone retards the progress of \nautoimmunity. Castration is not necessary for this effect. In contrast, danazol \nhas no favorable effect on the disease process. Estrogens cause a marked \nacceleration of autoimmunity and a reduction in thymus weight. During the course \nof these studies, we found that a number of problems or variables arise in \nstudying sex hormone effects, including: 1) X-linked genes, 2) metabolism of \ntestosterone to estrogens, 3) dose of hormone, 4) age at which administration is \ninitiated, 5) differential effects of sex hormones on different autoantibodies \nand various immune responses.", "BACKGROUND: The sexually dimorphic prevalence of autoimmune disease remains one \nof the most intriguing clinical observations among this group of disorders. \nWhile sex hormones have long been recognized for their roles in reproductive \nfunctions, within the past 2 decades scientists have found that sex hormones are \nintegral signaling modulators of the mammalian immune system. Sex hormones have \ndefinitive roles in lymphocyte maturation, activation, and synthesis of \nantibodies and cytokines. Sex hormone expression is altered among patients with \nautoimmune disease, and this variation of expression contributes to immune \ndysregulation.\nOBSERVATIONS: English-language literature from the last 10 years was reviewed to \nexamine the relationship between sex hormones and the function of the mammalian \nimmune system. Approximately 50 publications were included in this review, and \nthe majority were controlled trials with investigator blinding that compared \nboth male and female diseased and normal subjects. The review provided basic \nknowledge regarding the broad impact of sex hormones on the immune system and \nhow abnormal sex hormone expression contributes to the development and \nmaintenance of autoimmune phenomena, with a focus on systemic lupus \nerythematosus, as models of \"lupus-prone\" mice are readily available.\nCONCLUSIONS: Sex hormones affect the function of the mammalian immune system, \nand sex hormone expression is different in patients with systemic lupus \nerythematosus than in healthy subjects. Sex hormones play a role in the genesis \nof autoimmunity. Future research may provide a therapeutic approach that is \ncapable of altering disease pathogenesis, rather than targeting disease \nsequelae.", "The number of human conditions that are currently considered to be autoimmune \ndiseases (AID) has been steadily growing over the past decades and it is now \nestimated that over 10 million people are affected in the United States. One of \nthe major shared features among AID is the predominance in the female sex which \nin some cases changes with the age at disease diagnosis. Numerous hypotheses \nhave been formulated based on intuitive scientific backgrounds to justify this \nsex imbalance, i.e. sex hormones and reproductive factors, fetal microchimerism, \nother sex-related environmental factors, a skewing of the X-chromosome \ninactivation patterns, and major defects in sex chromosomes. Nevertheless, none \nof these hypotheses has thus far gathered enough convincing evidence and in most \ncases data are conflicting, as well illustrated by the reports on fetal \nmicrochimerism in systemic sclerosis or primary biliary cirrhosis. The present \narticle will critically discuss the main hypotheses (loss of mosaicism, \nreactivation, and haploinsufficiency) that have been proposed based on findings \nin female patients with specific AID along with two additional mechanisms \n(X-chromosome vulnerability and X-linked polyamine genes) that have been \nobserved in AID models. Further, recent data have significantly shifted the \nparadigm of X chromosome inactivation by demonstrating that a large number of \ngenes can variably escape silencing on one or both chromosomes. As a result we \nmay hypothesize that more than one mechanism may contribute to the female \nsusceptibility to tolerance breakdown while the possibility that unknown factors \nmay indeed protect men from AID should not be overlooked.", "PURPOSE OF REVIEW: To give an overview of recently published articles addressing \nthe mechanisms underlying sex bias in autoimmune disease.\nRECENT FINDINGS: Recent studies investigating the origins of sex bias in \nautoimmune disease have revealed an extensive and interconnected network of \ngenetic, hormonal, microbial, and environmental influences. Investigation of sex \nhormones has moved beyond profiling the effects of hormones on activity and \nprevalence of immune cell types to defining the specific immunity-related genes \ndriving these changes. Deeper examination of the genetic content of the X and Y \nchromosomes and genetic escapees of X chromosome inactivation has revealed some \nkey drivers of female-biased autoimmunity. Animal studies are offering further \ninsights into the connections among microbiota, particularly that of the gut, \nand the immune system.\nSUMMARY: Sex bias in autoimmune disease is the manifestation of a complex \ninterplay of the sex chromosomes, sex hormones, the microbiota, and additional \nenvironmental and sociological factors." ]	nan
56d2ee61f22319765a000007	[ 24480744, 24768686, 25430002, 26458103, 25469751, 26121403, 25378335 ]	train	Are messenger RNA molecules epigenetically methylated?	yesno	Yes, methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts.	yes	[ "RNA methylation modifications have been found for decades of years, which occur \nat different RNA types of numerous species, and their distribution is \nspecies-specific. However, people rarely know their biological functions. There \nare several identified methylation modifications in eukaryotic messenger RNA \n(mRNA), such as N(7)-methylguanosine (m(7)G) at the cap, \nN(6)-methyl-2'-O-methyladenosine (m(6)Am), 2'-O-methylation (Nm) within the cap \nand the internal positions, and internal N(6)-methyladenosine (m(6)A) and \n5-methylcytosine (m(5)C). Among them, m(7)G cap was studied more clearly and \nfound to have vital roles in several important mRNA processes like mRNA \ntranslation, stability and nuclear export. m(6)A as the most abundant \nmodification in mRNA was found in the 1970s and has been proposed to function in \nmRNA splicing, translation, stability, transport and so on. m(6)A has been \ndiscovered as the first RNA reversible modification which is demethylated \ndirectly by human fat mass and obesity associated protein (FTO) and its homolog \nprotein, alkylation repair homolog 5 (ALKBH5). FTO has a special demethylation \nmechanism that demethylases m(6)A to A through two over-oxidative intermediate \nstates: N(6)-hydroxymethyladenosine (hm(6)A) and N(6)-formyladenosine (f(6)A). \nThe two newly discovered m(6)A demethylases, FTO and ALKBH5, significantly \ncontrol energy homeostasis and spermatogenesis, respectively, indicating that \nthe dynamic and reversible m(6)A, analogous to DNA and histone modifications, \nplays broad roles in biological kingdoms and brings us an emerging field \"RNA \nEpigenetics\". 5-methylcytosine (5mC) as an epigenetic mark in DNA has been \nstudied widely, but m(5)C in mRNA is seldom explored. The bisulfide sequencing \nshowed m(5)C is another abundant modification in mRNA, suggesting that it might \nbe another RNA epigenetic mark. This review focuses on the main methylation \nmodifications in mRNA to describe their formation, distribution, function and \ndemethylation from the current knowledge and to provide future perspectives on \nfunctional studies.", "Mammalian messenger RNA (mRNA) and long noncoding RNA (lncRNA) contain tens of \nthousands of posttranscriptional chemical modifications. Among these, the \nN(6)-methyl-adenosine (m(6)A) modification is the most abundant and can be \nremoved by specific mammalian enzymes. m(6)A modification is recognized by \nfamilies of RNA binding proteins that affect many aspects of mRNA function. \nmRNA/lncRNA modification represents another layer of epigenetic regulation of \ngene expression, analogous to DNA methylation and histone modification.", "Recent discoveries of reversible N(6)-methyladenosine (m(6)A) methylation on \nmessenger RNA (mRNA) and mapping of m(6)A methylomes in mammals and yeast have \nrevealed potential regulatory functions of this RNA modification. In plants, \ndefects in m(6)A methyltransferase cause an embryo-lethal phenotype, suggesting \na critical role of m(6)A in plant development. Here, we profile m(6)A \ntranscriptome-wide in two accessions of Arabidopsis thaliana and reveal that \nm(6)A is a highly conserved modification of mRNA in plants. Distinct from \nmammals, m(6)A in A. thaliana is enriched not only around the stop codon and \nwithin 3'-untranslated regions, but also around the start codon. Gene ontology \nanalysis indicates that the unique distribution pattern of m(6)A in A. thaliana \nis associated with plant-specific pathways involving the chloroplast. We also \ndiscover a positive correlation between m(6)A deposition and mRNA abundance, \nsuggesting a regulatory role of m(6)A in plant gene expression.", "The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine \n(m(6)A), which has broad roles in RNA biology. In mammalian cells, the \nasymmetric distribution of m(6)A along mRNAs results in relatively less \nmethylation in the 5' untranslated region (5'UTR) compared to other regions. \nHowever, whether and how 5'UTR methylation is regulated is poorly understood. \nDespite the crucial role of the 5'UTR in translation initiation, very little is \nknown about whether m(6)A modification influences mRNA translation. Here we show \nthat in response to heat shock stress, certain adenosines within the 5'UTR of \nnewly transcribed mRNAs are preferentially methylated. We find that the dynamic \n5'UTR methylation is a result of stress-induced nuclear localization of YTHDF2, \na well-characterized m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 \npreserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A \n'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in \nthe form of m(6)A promotes cap-independent translation initiation, providing a \nmechanism for selective mRNA translation under heat shock stress. Using Hsp70 \nmRNA as an example, we demonstrate that a single m(6)A modification site in the \n5'UTR enables translation initiation independent of the 5' end \nN(7)-methylguanosine cap. The elucidation of the dynamic features of 5'UTR \nmethylation and its critical role in cap-independent translation not only \nexpands the breadth of physiological roles of m(6)A, but also uncovers a \npreviously unappreciated translational control mechanism in heat shock response.", "miRNAs and DNA methylation are both critical regulators of gene expression. \nAberration in miRNA expression or DNA methylation is a causal factor for \nnumerous pathological conditions. DNA methylation can inhibit the transcription \nof miRNAs, just like coding genes, by methylating the CpG islands in the \npromoter regions of miRNAs. Conversely, certain miRNAs can directly target DNA \nmethyltransferases and bring about their inhibition, thereby affecting the whole \ngenome methylation pattern. Recently, methylation patterns have also been \nrevealed in mRNA. Surprisingly, the two most commonly studied methylation states \nin mRNA (m6A and m5C) are found to be enriched in 3'-UTRs (untranslated \nregions), the target site for the majority of miRNAs. Whereas m5C is reported to \nstabilise mRNA, m6A has a destabilising effect on mRNA. However, the effect of \nmRNA methylation on its interaction with miRNAs is largely unexplored. The \nreview highlights the complex interplay between microRNA and methylation at DNA \nand mRNA level.", "N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA \nand has been linked to diverse effects on mRNA fate. Current mapping approaches \nlocalize m6A residues to transcript regions 100-200 nt long but cannot identify \nprecise m6A positions on a transcriptome-wide level. Here we developed m6A \nindividual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) \nand used it to demonstrate that antibodies to m6A can induce specific mutational \nsignatures at m6A residues after ultraviolet light-induced antibody-RNA \ncross-linking and reverse transcription. We found that these antibodies \nsimilarly induced mutational signatures at N(6),2'-O-dimethyladenosine (m6Am), a \nmodification found at the first nucleotide of certain mRNAs. Using these \nsignatures, we mapped m6A and m6Am at single-nucleotide resolution in human and \nmouse mRNA and identified small nucleolar RNAs (snoRNAs) as a new class of \nm6A-containing non-coding RNAs (ncRNAs).", "Methyltranscriptome is an exciting new area that studies the mechanisms and \nfunctions of methylation in transcripts. The MethylTranscriptome DataBase \n(MeT-DB, http://compgenomics.utsa.edu/methylation/) is the first comprehensive \nresource for N6-methyladenosine (m(6)A) in mammalian transcriptome. It includes \na database that records publicaly available data sets from methylated RNA \nimmunoprecipitation sequencing (MeRIP-Seq), a recently developed technology for \ninterrogating m(6)A methyltranscriptome. MeT-DB includes ∼ 300 k m(6)A \nmethylation sites in 74 MeRIP-Seq samples from 22 different experimental \nconditions predicted by exomePeak and MACS2 algorithms. To explore this rich \ninformation, MeT-DB also provides a genome browser to query and visualize \ncontext-specific m(6)A methylation under different conditions. MeT-DB also \nincludes the binding site data of microRNA, splicing factor and RNA binding \nproteins in the browser window for comparison with m(6)A sites and for exploring \nthe potential functions of m(6)A. Analysis of differential m(6)A methylation and \nthe related differential gene expression under two conditions is also available \nin the browser. A global perspective of the genome-wide distribution of m(6)A \nmethylation in all the data is provided in circular ideograms, which also act as \na navigation portal. The query results and the entire data set can be exported \nto assist publication and additional analysis." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012333', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0080188', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0032259', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008745', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0036265', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0001510']
53636e727d100faa0900000d	[ 23229728, 24238656, 22710432, 23707524, 22715154, 19807731, 18677110, 23153241, 23658527 ]	train	Are microRNA (miR) regulated through DNA methylation of their promoters?	yesno	Dysregulation of miRNA expression involved in cancer and Alzheimer's disease can be triggered by multiple mechanisms including aberrant DNA methylation of the miRNA gene promoter. Epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM).	yes	[ "MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous \nsilencers of target genes. Some tumor-suppressive miRNAs are known to be \nepigenetically silenced by promoter DNA methylation in cancer. In the present \nstudy, we aimed to identify miRNA genes that are silenced by DNA \nhypermethylation in hepatocellular carcinoma (HCC). We screened for miRNA genes \nwith promoter DNA hypermethylation using a genome-wide methylation microarray \nanalysis in HCC cells. It was found that miR-335, which is harbored within an \nintron of its protein-coding host gene, MEST, was downregulated by aberrant \npromoter hypermethylation via further methylation assays, including \nmethylation-specific PCR, combined bisulfite and restriction analysis, bisulfite \nsequencing analysis and 5-aza-2'-deoxycytidine treatment. The expression levels \nof miR-335 significantly correlated with those of MEST, supporting the notion \nthat the intronic miR-335 is co-expressed with its host gene. The levels of \nmiR-335/MEST methylation were significantly higher in 18 (90%) out of 20 primary \nHCC tumors, compared to their non-tumor tissue counterparts (P<0.001). The \nexpression levels of miR-335 were significantly lower in 25 (78%) out of 32 \nprimary HCC tumors, compared to their non-tumor tissue counterparts (P=0.001). \nFurthermore, the expression levels of miR-335 were significantly lower in HCC \ntumors with distant metastasis compared to those without distant metastasis \n(P=0.02). In conclusion, our results indicate that expression of miR-335 is \nreduced by aberrant DNA methylation in HCC.", "Author information:\n(1)School for Mental Health and Neuroscience (MHeNS), Faculty of Health, \nMedicine, and Life Sciences, European Graduate School of Neuroscience (EURON), \nMaastricht University Medical Centre, Maastricht, the Netherlands; Division of \nMolecular Psychiatry, Department of Psychiatry, Psychosomatics, and \nPsychotherapy, University of Würzburg, Würzburg, Germany. Electronic address: \nd.vandenhove@maastrichtuniversity.nl.\n(2)School for Mental Health and Neuroscience (MHeNS), Faculty of Health, \nMedicine, and Life Sciences, European Graduate School of Neuroscience (EURON), \nMaastricht University Medical Centre, Maastricht, the Netherlands.\n(3)Institute of Psychiatry, King's College London, London, UK; Exeter Medical \nSchool, Exeter University, London, UK.\n(4)School for Mental Health and Neuroscience (MHeNS), Faculty of Health, \nMedicine, and Life Sciences, European Graduate School of Neuroscience (EURON), \nMaastricht University Medical Centre, Maastricht, the Netherlands; Division of \nMolecular Psychiatry, Department of Psychiatry, Psychosomatics, and \nPsychotherapy, University of Würzburg, Würzburg, Germany.\n(5)Center for Neuroscience, Swammerdam Institute for Life Sciences, University \nof Amsterdam, Amsterdam, the Netherlands.\n(6)VIB Center for the Biology of Disease, VIB, Leuven, Belgium; Center for Human \nGenetics, University of Leuven School of Medicine, Leuven, Belgium.", "Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of \nhematopoietic malignancies, including chronic lymphocytic leukemia (CLL). \nHowever, an understanding of the mechanisms that cause aberrant miRNA \ntranscriptional control is lacking. In this study, we comprehensively \ninvestigated the role and extent of miRNA epigenetic regulation in CLL. \nGenome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed \nglobal DNA methylation patterns upstream of miRNA sequences that distinguished \nmalignant from healthy cells and identified putative miRNA promoters. \nIntegration of DNA methylation and miRNA promoter data led to the identification \nof 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA \nhypomethylation accounted for more than 60% of all aberrant promoter-associated \nDNA methylation in CLL, and promoter DNA hypomethylation was restricted to \nwell-defined regions. Individual hyper- and hypomethylated promoters allowed \ndiscrimination of CLL samples from healthy controls. Promoter DNA methylation \npatterns were confirmed in an independent patient cohort, with 11 miRNAs \nconsistently showing an inverse correlation between DNA methylation status and \nexpression level. Together, our findings characterize the role of epigenetic \nchanges in the regulation of miRNA transcription and create a repository of \ndisease-specific promoter regions that may provide additional insights into the \npathogenesis of CLL.", "Epigenetics refers to the study of heritable changes in the pattern of gene \nexpression that is controlled by a mechanism specifically not due to changes the \nprimary DNA sequence. Well-known epigenetic mechanisms include DNA methylation, \npost-translational histone modifications and RNA-based mechanisms including \nthose controlled by small non-coding RNAs (miRNAs). Recent studies have shown \nthat epigenetic modifications orchestrate the hepatic stellate cell (HSC) \nactivation and liver fibrosis. In this review we focus on the aberrant \nmethylation of CpG island promoters of select genes is the prominent epigenetic \nmechanism to effectively silence gene transcription facilitating HSC activation \nand liver fibrosis. Furthermore, we also discuss epigenetic dysregulation of \ntumor-suppressor miRNA genes by promoter DNA methylation and the interaction of \nDNA methylation with miRNAs involved in the regulation of HSC activation and \nliver fibrosis. Recent advances in epigenetics alterations in the pathogenesis \nof liver fibrosis and their possible use as new therapeutic targets and \nbiomarkers.", "DNA methylation is one of the heritable epigenetic modifications, leading to \nrepressed gene expressions and consequent phenotypic alterations without \nchanging the DNA sequence. MicroRNA (miRNA) is a novel class of short non-coding \nRNA molecules regulating a wide range of cellular functions through \ntranslational repression of their target genes. Recently, epigenetic \ndysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has \nbeen implicated in human cancers, including multiple myeloma (MM). This article \npresents a brief overview of the pathogenesis of MM, the role of DNA methylation \nin cancer biology, methods of DNA methylation analysis, miRNA biology and \ndysregulation of miRNAs in MM and summaries the current data on the role of DNA \nmethylation of tumor-suppressive miRNAs in MM.", "Aberrant epigenetic regulation has recently been implicated in the \ndownregulation of tumour suppressor microRNAs (miRNAs). Histone modification and \nDNA methylation can have different roles in gene silencing in cancer. To \ninvestigate whether histone modifications would contribute to the dysregulation \nof miRNAs in acute lymphoblastic leukaemia (ALL), the effect of a histone \ndeacetylase inhibitor, trichostatin A (TSA), on miRNA expression profile was \nanalysed by microarray assay in a precursor B-cell ALL cell line NALM-6. A total \nof 10 miRNAs were downregulated and 31 were upregulated significantly following \nTSA treatment. Among TSA-upregulated miRNAs, MIR22 is an extronic miRNA and \nresides in the second exon of the non-coding transcript MGC14376. Upregulation \nof MIR22 transcription was found in both NALM-6 cells and primary human ALL \nmalignant cells treated with TSA. Whereas a CpG island was identified within the \npromoter element of MIR22, no promoter DNA methylation was detected in these \ncells. In contrast, accumulation of the repressive histone marker H3K27 \ntrimethylation (H3K27triM) was identified around the transcriptional start point \nof the gene, which was reduced by TSA treatment. Thus, accumulation of H3K27triM \nindependent of promoter DNA methylation may be a novel epigenetic mechanism for \nMIR22 silencing in ALL.", "The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 \nrepressor MDM2, varies widely among human cancer-derived cell types. Whereas \nHCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 \nleukemia cells undergo rapid apoptosis and other cell lines show an intermediate \nresponse. We found that the expression of the p53 target genes p21, 14-3-3sigma \nand the microRNA miR-34a correlates tightly with the cell fate choice adopted. \nAll three genes were strongly induced in arresting cells, but silenced in cells \nundergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target \ngenes were equally expressed in arresting and apoptotic cells. Interestingly, we \nestablish that miR-34a cooperates with p21 and 14-3-3sigma to override the \napoptotic signals generated by p53 activation. Strikingly, p53 binding to \nchromatin and p53-mediated recruitment of certain coactivators to all three \ntarget loci does not vary among cell types. Instead, the cell type-specific \nsilencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma \npromoter DNA methylation and reduced processing of the miR-34a primary \ntranscript. Thus, p53-independent events regulating expression of protein-coding \ngenes and microRNAs within the network can define the cellular outcome of p53 \nactivation.", "miRNAs are a group of small noncoding RNAs measuring 19-25 nucleotides. \nSequence-specific binding of miRNAs to the 3´ untranslated regions of target \ngenes leads to translational repressions. Dysregulation of miRNA expression \ninvolved in cancer can be triggered by multiple mechanisms including aberrant \nDNA methylation of the miRNA gene promoter. Of note, DNA methylation of tumor \nsuppressor miRNAs has been implicated in various human cancers. Moreover, miRNA \nsilencing mediated by aberrant promoter DNA methylation can potentially be \nreversed by hypomethylating agents, and hence may pose a new therapeutic target \nin cancer. In this review, the authors will focus on the aberrant methylation of \nmiRNAs in the pathogenesis of lymphoid malignancies including chronic \nlymphocytic leukemia, multiple myeloma and acute lymphoblastic leukemia.", "Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal \nand differentiation in mouse embryonic stem cells (ESCs). We have previously \nshown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor \ngene constitutively activates Wnt signaling in ESCs and inhibits their capacity \nto differentiate towards ecto-, meso-, and endodermal lineages. However, the \nunderlying molecular and cellular mechanisms through which Wnt regulates lineage \ndifferentiation in mouse ESCs remain to date largely unknown. To this aim, we \nhave derived and studied the gene expression profiles of several Apc-mutant ESC \nlines encoding for different levels of Wnt signaling activation. We found that \ndown-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the \ncontrol of self-renewal and pluripotency, represents a specific and primary \nresponse to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression \npartially restored the neural defects observed in Apc-mutant ESCs, suggesting \nthat Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression \nof neural differentiation. We found that Tcf3 down-regulation in the context of \nconstitutively active Wnt signaling does not result from promoter DNA \nmethylation but is likely to be caused by a plethora of mechanisms at both the \nRNA and protein level as shown by the observed decrease in activating histone \nmarks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel \nWnt-regulated microRNA that targets Tcf3 and attenuates early neural \ndifferentiation in mouse ESCs. Our data show for the first time that Wnt \nsignaling down-regulates Tcf3 expression, possibly at both the transcriptional \nand post-transcriptional levels, and thus highlight a novel mechanism through \nwhich Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse \nembryonic stem cells." ]	['http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012926', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D035683', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0006306', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D019175', 'http://amigo.geneontology.org/cgi-bin/amigo/term_details?term=GO:0044030', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004247']
58aa0a62396a458e50000007	[ 26227334, 25030760, 23973077, 26000474, 19700636, 25959773 ]	train	Are microtubules marked by glutamylation?	yesno	Yes, glutamylation is the most prevalent tubulin posttranslational modification and marks stable microtubules.	yes	[ "Microtubules have important functions ranging from maintenance of cell \nmorphology to subcellular transport, cellular signaling, cell migration, and \nformation of cell polarity. At the organismal level, microtubules are crucial \nfor various biological processes, such as viral entry, inflammation, immunity, \nlearning and memory in mammals. Microtubules are subject to various covalent \nmodifications. One such modification is tubulin acetylation, which is associated \nwith stable microtubules and conserved from protists to humans. In the past \nthree decades, this reversible modification has been studied extensively. In \nmammals, its level is mainly governed by opposing actions of α-tubulin \nacetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies \nof the mouse enzymes have yielded new insights into biological functions of \ntubulin acetylation. Abnormal levels of this modification are linked to \nneurological disorders, cancer, heart diseases and other pathological \nconditions, thereby yielding important therapeutic implications. This review \nsummarizes related studies and concludes that tubulin acetylation is important \nfor regulating microtubule architecture and maintaining microtubule integrity. \nTogether with detyrosination, glutamylation and other modifications, tubulin \nacetylation may form a unique 'language' to regulate microtubule structure and \nfunction.", "The cytoskeleton, mainly consisting of microtubules, intermediate filaments and \nmicrofilaments, along with cytoskeleton associated and interconnecting proteins \nas well as the centrosome, plays enormously important roles in all stages of \nembryogenesis and undergoes significant changes to accommodate a diversity of \ncellular functions during gametogenesis, oocyte maturation, fertilization and \npre-implantation embryo development. The varied functions of the cytoskeleton \ncan be accomplished on many different levels, among which are a diversity of \ndifferent posttranslational modifications (PTMs), chemical modifications that \nregulate activity, localization and interactions with other cellular molecules. \nPTMs of the cytoskeleton, including phosphorylation, glycosylation, \nubiquitination, detyrosination/tyrosination, (poly)glutamylation and \n(poly)glycylation, acetylation, sumoylation, and palmitoylation, will be \naddressed in this chapter. Focus will be on (1) Microtubules, microtubule \norganizing centers (centrosomes), intermediate filaments, microfilaments and \ntheir PTMs; (2) Cytoskeletal functions and cytoskeletal PTMs during \ngametogenesis and oocyte maturation; and (3) Cytoskeletal functions and \ncytoskeletal PTMs during fertilization and pre-implantation embryo development.", "Microtubules play highly diverse and essential roles in every eukaryotic cell. \nWhile built from conserved dimers of α- and β-tubulin, microtubules can be \ndiversified by posttranslational modifications in order to fulfill specific \nfunctions in cells. The tubulin posttranslational modifications: acetylation, \ndetyrosination, polyglutamylation, and polyglycylation play important roles in \nmicrotubule functions; however, only little functional and mechanistic insight \nhas been gained so far. The modification state of microtubules can be visualized \nwith specific antibodies. A drawback is that detailed information about the \nspecificities and limitations of these antibodies are not easily accessible in \nthe literature. We provide here a comprehensive description of the currently \navailable set of antibodies specific to tubulin modifications. Focusing on \nglutamylation antibodies, we discuss specific protocols that allow using these \nantibodies to gain semi-quantitative information on the levels and distribution \nof tubulin modifications in immunocytochemistry and immunoblot.", "Enzymes of the tubulin tyrosine ligase-like (TTLL) family posttranslationally \nmodify and thereby mark microtubules by glutamylation, generating specific \nrecognition sites for microtubule-interacting proteins. Garnham et al. report \nthe first structure of a TTLL protein alone and in complex with microtubules, \nelucidating their mechanism of action.", "In most eukaryotic cells, tubulin is subjected to posttranslational \nglutamylation, a conserved modification of unclear function. The glutamyl side \nchains form as branches of the primary sequence glutamic acids in two \nbiochemically distinct steps: initiation and elongation. The length of the \nglutamyl side chain is spatially controlled and microtubule type specific. Here, \nwe probe the significance of the glutamyl side chain length regulation in vivo \nby overexpressing a potent side chain elongase enzyme, Ttll6Ap, in Tetrahymena. \nOverexpression of Ttll6Ap caused hyperelongation of glutamyl side chains on the \ntubulin of axonemal, cortical, and cytoplasmic microtubules. Strikingly, in the \nsame cell, hyperelongation of glutamyl side chains stabilized cytoplasmic \nmicrotubules and destabilized axonemal microtubules. Our observations suggest \nthat the cellular outcomes of glutamylation are mediated by spatially restricted \ntubulin interactors of diverse nature.", "Glutamylation, the most prevalent tubulin posttranslational modification, marks \nstable microtubules and regulates recruitment and activity of microtubule- \ninteracting proteins. Nine enzymes of the tubulin tyrosine ligase-like (TTLL) \nfamily catalyze glutamylation. TTLL7, the most abundant neuronal glutamylase, \nadds glutamates preferentially to the β-tubulin tail. Coupled with ensemble and \nsingle-molecule biochemistry, our hybrid X-ray and cryo-electron microscopy \nstructure of TTLL7 bound to the microtubule delineates a tripartite microtubule \nrecognition strategy. The enzyme uses its core to engage the disordered anionic \ntails of α- and β-tubulin, and a flexible cationic domain to bind the \nmicrotubule and position itself for β-tail modification. Furthermore, we \ndemonstrate that all single-chain TTLLs with known glutamylase activity utilize \na cationic microtubule-binding domain analogous to that of TTLL7. Therefore, our \nwork reveals the combined use of folded and intrinsically disordered substrate \nrecognition elements as the molecular basis for specificity among the enzymes \nprimarily responsible for chemically diversifying cellular microtubules." ]	nan
534427f8aeec6fbd07000009	[ 22649506, 22893128, 19633228, 15946860, 23694700, 23935863, 22072984, 23015295, 23819581, 24147068, 23704925, 23799614, 23450047 ]	train	Are most driver gene mutations synonymous or non-synonymous?	factoid	A common goal of tumor sequencing projects is finding genes whose mutations are selected for during tumor development. This is accomplished by choosing genes that have more non-synonymous mutations than expected from an estimated background mutation frequency.	non-synonymous	[ "BACKGROUND: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal \ntract with little molecular characterization. We performed whole genome \nsequencing (WGS) on paired normal and tumor DNA from a patient with \nmetastatic-ONB to identify the somatic alterations that might be drivers of \ntumorigenesis and/or metastatic progression.\nMETHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA was isolated from fresh frozen \ntissue from a metastatic lesion and whole blood, followed by WGS at >30X depth, \nalignment and mapping, and mutation analyses. Sanger sequencing was used to \nconfirm selected mutations. Sixty-two somatic short nucleotide variants (SNVs) \nand five deletions were identified inside coding regions, each causing a \nnon-synonymous DNA sequence change. We selected seven SNVs and validated them by \nSanger sequencing. In the metastatic ONB samples collected several months prior \nto WGS, all seven mutations were present. However, in the original surgical \nresection specimen (prior to evidence of metastatic disease), mutations in KDR, \nMYC, SIN3B, and NLRC4 genes were not present, suggesting that these were \nacquired with disease progression and/or as a result of post-treatment effects.\nCONCLUSIONS/SIGNIFICANCE: This work provides insight into the evolution of ONB \ncancer cells and provides a window into the more complex factors, including \ntumor clonality and multiple driver mutations.", "Cancer cells evolve from normal cells by somatic mutations and natural \nselection. Comparing the evolution of cancer cells and that of organisms can \nelucidate the genetic basis of cancer. Here we analyse somatic mutations in >400 \ncancer genomes. We find that the frequency of somatic single-nucleotide \nvariations increases with replication time during the S phase much more \ndrastically than germ-line single-nucleotide variations and somatic large-scale \nstructural alterations, including amplifications and deletions. The ratio of \nnonsynonymous to synonymous single-nucleotide variations is higher for cancer \ncells than for germ-line cells, suggesting weaker purifying selection against \nsomatic mutations. Among genes with recurrent mutations only cancer driver genes \nshow evidence of strong positive selection, and late-replicating regions are \ndepleted of cancer driver genes, although enriched for recurrently mutated \ngenes. These observations show that replication timing has a prominent role in \nshaping the single-nucleotide variation landscape of cancer cells.", "Genetic variation for pathogen infectivity is an important driver of disease \nincidence and prevalence in both natural and managed systems. Here, we use the \ninteraction between the rust pathogen, Melampsora lini, and two host plants, \nLinum marginale and Linum usitatissimum, to examine how host-pathogen \ninteractions influence the maintenance of polymorphism in genes underlying \npathogen virulence. Extensive sequence variation at two effector loci (AvrP123, \nAvrP4) was found in M. lini isolates collected from across the native range of \nL. marginale in Australia, as well as in isolates collected from a second host, \nthe cultivated species L. usitatissimum. A highly significant excess of \nnonsynonymous compared with synonymous polymorphism was found at both loci, \nsuggesting that diversifying selection is important for the maintenance of the \nobserved sequence diversity. Agrobacterium-mediated transient transformation \nassays were used to demonstrate that variants of both the AvrP123 and AvrP4 \ngenes are differentially recognized by resistance genes in L. marginale. We \nfurther characterized patterns of nucleotide variation at AvrP123 and AvrP4 in \n10 local populations of M. lini infecting the wild host L. marginale. \nPopulations were significantly differentiated with respect to allelic \nrepresentation at the Avr loci, suggesting the possibility of local selection \nmaintaining distinct genetic structures between pathogen populations, whereas \nlimited diversity may be explained via selective sweeps and demographic \nbottlenecks. Together, these results imply that interacting selective and \nnonselective factors, acting across a broad range of scales, are important for \nthe generation and maintenance of adaptively significant variation in \npopulations of M. lini.", "This is the first report of an insect esterase efficiently expressed in the \nmethylotrophic yeast Pichia pastoris (so far insect esterases have been produced \nonly in the baculovirus system). Having isolated a Tribolium castaneum \ncarboxylesterase cDNA (TCE), we were initially unable to express it in \nEscherichia coli or P. pastoris despite significant transcription levels. As \ncodon usage bias is different in T. castaneum and P. pastoris, we assumed this \nwas a possible explanation for the translational barrier observed in yeast. \nAccordingly, we designed and constructed by recursive PCR a synthetic TCE gene \n(synTCE) optimized for heterologous expression in P. pastoris, i.e., a gene in \nwhich certain TCE codons are replaced with synonymous codons 'preferred' in P. \npastoris. When the altered gene was placed under the control of either the P. \npastoris glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter or the \ninducible alcohol oxidase (AOX1) promoter and introduced on an expression vector \ninto P. pastoris, its product was produced intracellularly. We also successfully \nexplored the possibility of obtaining a secreted product: P. pastoris cells \nexpressing an in-frame fusion of synTCE with the alpha-factor secretion signal \nunder the control of the GAP promoter were found to secrete the recombinant \nesterase into the external medium (to a concentration of 7 mg/L). In addition to \nthis demonstration of TCE production in yeast, our results suggest that the GAP \npromoter could advantageously replace the AOX1 promoter as a driver of synTCE \nexpression. TCE specific activity was approximately 5 U/mg when p-nitrophenyl \nacetate was used as substrate.", "A common goal of tumor sequencing projects is finding genes whose mutations are \nselected for during tumor development. This is accomplished by choosing genes \nthat have more non-synonymous mutations than expected from an estimated \nbackground mutation frequency. While this background frequency is unknown, it \ncan be estimated using both the observed synonymous mutation frequency and the \nnon-synonymous to synonymous mutation ratio. The synonymous mutation frequency \ncan be determined across all genes or in a gene-specific manner. This choice \nintroduces an interesting trade-off. A gene-specific frequency adjusts for an \nunderlying mutation bias, but is difficult to estimate given missing synonymous \nmutation counts. Using a genome-wide synonymous frequency is more robust, but is \nless suited for adjusting biases. Studying four evaluation criteria for \nidentifying genes with high non-synonymous mutation burden (reflecting \npreferential selection of expressed genes, genes with mutations in conserved \nbases, genes with many protein interactions, and genes that show loss of \nheterozygosity), we find that the gene-specific synonymous frequency is superior \nin the gene expression and protein interaction tests. In conclusion, the use of \nthe gene-specific synonymous mutation frequency is well suited for assessing a \ngene's non-synonymous mutation burden.", "We have developed a sequence conservation-based artificial neural network \npredictor called NetDiseaseSNP which classifies nsSNPs as disease-causing or \nneutral. Our method uses the excellent alignment generation algorithm of SIFT to \nidentify related sequences and a combination of 31 features assessing sequence \nconservation and the predicted surface accessibility to produce a single score \nwhich can be used to rank nsSNPs based on their potential to cause disease. \nNetDiseaseSNP classifies successfully disease-causing and neutral mutations. In \naddition, we show that NetDiseaseSNP discriminates cancer driver and passenger \nmutations satisfactorily. Our method outperforms other state-of-the-art methods \non several disease/neutral datasets as well as on cancer driver/passenger \nmutation datasets and can thus be used to pinpoint and prioritize plausible \ndisease candidates among nsSNPs for further investigation. NetDiseaseSNP is \npublicly available as an online tool as well as a web service: \nhttp://www.cbs.dtu.dk/services/NetDiseaseSNP.", "Previous genome-wide scans of positive natural selection in humans have \nidentified a number of non-neutrally evolving genes that play important roles in \nskin pigmentation, metabolism, or immune function. Recent studies have also \nshown that a genome-wide pattern of local adaptation can be detected by \nidentifying correlations between patterns of allele frequencies and \nenvironmental variables. Despite these observations, the degree to which natural \nselection is primarily driven by adaptation to local environments, and the role \nof pathogens or other ecological factors as selective agents, is still under \ndebate. To address this issue, we correlated the spatial allele frequency \ndistribution of a large sample of SNPs from 55 distinct human populations to a \nset of environmental factors that describe local geographical features such as \nclimate, diet regimes, and pathogen loads. In concordance with previous studies, \nwe detected a significant enrichment of genic SNPs, and particularly \nnon-synonymous SNPs associated with local adaptation. Furthermore, we show that \nthe diversity of the local pathogenic environment is the predominant driver of \nlocal adaptation, and that climate, at least as measured here, only plays a \nrelatively minor role. While background demography by far makes the strongest \ncontribution in explaining the genetic variance among populations, we detected \nabout 100 genes which show an unexpectedly strong correlation between allele \nfrequencies and pathogenic environment, after correcting for demography. \nConversely, for diet regimes and climatic conditions, no genes show a similar \ncorrelation between the environmental factor and allele frequencies. This result \nis validated using low-coverage sequencing data for multiple populations. Among \nthe loci targeted by pathogen-driven selection, we found an enrichment of genes \nassociated to autoimmune diseases, such as celiac disease, type 1 diabetes, and \nmultiples sclerosis, which lends credence to the hypothesis that some \nsusceptibility alleles for autoimmune diseases may be maintained in human \npopulation due to past selective processes.", "BACKGROUND: Gastric adenocarcinoma is a rare diagnosis in childhood. A \n14-year-old male patient presented with metastatic gastric adenocarcinoma, and a \nstrong family history of colon cancer. Clinical sequencing of CDH1 and APC were \nnegative. Whole exome sequencing was therefore applied to capture the majority \nof protein-coding regions for the identification of single-nucleotide variants, \nsmall insertion/deletions, and copy number abnormalities in the patient's \ngermline as well as primary tumor.\nMATERIALS AND METHODS: DNA was extracted from the patient's blood, primary \ntumor, and the unaffected mother's blood. DNA libraries were constructed and \nsequenced on Illumina HiSeq2000. Data were post-processed using Picard and \nSamtools, then analyzed with the Genome Analysis Toolkit. Variants were \nannotated using an in-house Ensembl-based program. Copy number was assessed \nusing ExomeCNV.\nRESULTS: Each sample was sequenced to a mean depth of coverage of greater than \n120×. A rare non-synonymous coding single-nucleotide variant (SNV) in TP53 was \nidentified in the germline. There were 10 somatic cancer protein-damaging \nvariants that were not observed in the unaffected mother genome. ExomeCNV \ncomparing tumor to the patient's germline, identified abnormal copy number, \nspanning 6,946 genes.\nCONCLUSION: We present an unusual case of Li-Fraumeni detected by whole exome \nsequencing. There were also likely driver somatic mutations in the gastric \nadenocarcinoma. These results highlight the need for more thorough and broad \nscale germline and cancer analyses to accurately inform patients of inherited \nrisk to cancer and to identify somatic mutations.", "BACKGROUND: It is a great challenge of modern biology to determine the \nfunctional roles of non-synonymous Single Nucleotide Polymorphisms (nsSNPs) on \ncomplex phenotypes. Statistical and machine learning techniques establish \ncorrelations between genotype and phenotype, but may fail to infer the \nbiologically relevant mechanisms. The emerging paradigm of Network-based \nAssociation Studies aims to address this problem of statistical analysis. \nHowever, a mechanistic understanding of how individual molecular components work \ntogether in a system requires knowledge of molecular structures, and their \ninteractions.\nRESULTS: To address the challenge of understanding the genetic, molecular, and \ncellular basis of complex phenotypes, we have, for the first time, developed a \nstructural systems biology approach for genome-wide multiscale modeling of \nnsSNPs--from the atomic details of molecular interactions to the emergent \nproperties of biological networks. We apply our approach to determine the \nfunctional roles of nsSNPs associated with hypoxia tolerance in Drosophila \nmelanogaster. The integrated view of the functional roles of nsSNP at both \nmolecular and network levels allows us to identify driver mutations and their \ninteractions (epistasis) in H, Rad51D, Ulp1, Wnt5, HDAC4, Sol, Dys, GalNAc-T2, \nand CG33714 genes, all of which are involved in the up-regulation of Notch and \nGurken/EGFR signaling pathways. Moreover, we find that a large fraction of the \ndriver mutations are neither located in conserved functional sites, nor \nresponsible for structural stability, but rather regulate protein activity \nthrough allosteric transitions, protein-protein interactions, or protein-nucleic \nacid interactions. This finding should impact future Genome-Wide Association \nStudies.\nCONCLUSIONS: Our studies demonstrate that the consolidation of statistical, \nstructural, and network views of biomolecules and their interactions can provide \nnew insight into the functional role of nsSNPs in Genome-Wide Association \nStudies, in a way that neither the knowledge of molecular structures nor \nbiological networks alone could achieve. Thus, multiscale modeling of nsSNPs may \nprove to be a powerful tool for establishing the functional roles of sequence \nvariants in a wide array of applications.", "Neuroblastoma is one of the most genomically heterogeneous childhood malignances \nstudied to date, and the molecular events that occur during the course of the \ndisease are not fully understood. Genomic studies in neuroblastoma have showed \nonly a few recurrent mutations and a low somatic mutation burden. However, none \nof these studies has examined the mutations arising during the course of \ndisease, nor have they systemically examined the expression of mutant genes. \nHere we performed genomic analyses on tumors taken during a 3.5 years disease \ncourse from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal \nprimary tumor taken at surgical resection, and a liver metastasis at autopsy). \nWhole genome sequencing of the index liver metastasis identified 44 \nnon-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large \nhemizygous deletion in the ATRX gene which has been recently reported in \nneuroblastoma. Of these 45 somatic alterations, 15 were also detected in the \nprimary tumor and bone marrow biopsy, while the other 30 were unique to the \nindex tumor, indicating accumulation of de novo mutations during therapy. \nFurthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of \nthe 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of \nexpression of the mutant alleles, suggesting potential oncogenic driver roles of \nthese mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 \nwas highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant \ndemonstrated a significantly increased motility through elevated Rho signaling, \nbut had no effect on growth. Therefore, this study highlights the need for \nmultiple biopsies and sequencing during progression of a cancer and \ncombinatorial DNA and RNA sequencing approach for systematic identification of \nexpressed driver mutations.", "Cutaneous malignant melanoma is the most fatal skin cancer and although improved \ncomprehension of its pathogenic pathways allowed to realize some effective \nmolecular targeted therapies, novel targets and drugs are still needed. Aiming \nto add genetic information potentially useful for novel targets discovery, we \nperformed an extensive genomic characterization by whole-exome sequencing and \nSNP array profiling of six cutaneous melanoma cell lines derived from metastatic \npatients. We obtained a total of 3,325 novel coding single nucleotide variants, \nincluding 2,172 non-synonymous variants. We catalogued the coding mutations \naccording to Sanger COSMIC database and to a manually curated list including \ngenes involved in melanoma pathways identified by mining recent literature. \nBesides confirming the presence of known melanoma driver mutations (BRAF(V600E), \nNRAS(Q61R) ), we identified novel mutated genes involved in signalling pathways \ncrucial for melanoma pathogenesis and already addressed by current targeted \ntherapies (such as MAPK and glutamate pathways). We also identified mutations in \nfour genes (MUC19, PAICS, RBMXL1, KIF23) never reported in melanoma, which might \ndeserve further investigations. All data are available to the entire research \ncommunity in our Melanoma Exome Database (at https://155.253.6.64/MExDB/). In \nsummary, these cell lines are valuable biological tools to improve the genetic \ncomprehension of this complex cancer disease and to study functional relevance \nof individual mutational events, and these findings could provide insights \npotentially useful for identification of novel therapeutic targets for cutaneous \nmalignant melanoma.", "Squamous cell lung cancer is a major histotype of non-small cell lung cancer \n(NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome \nsequencing to identify novel non-synonymous somatic mutations in squamous cell \nlung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 \nnon-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs \ncausing frameshifts. We also found four SNVs located within splicing sites. We \nverified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) \nand 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the \nmutated genes were also mutated in at least one patient with a different type of \nlung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. \nFour genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the \nsamples in the COSMIC database. We identified two missense mutations in \nC10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the \nCOSMIC database. We found another somatic mutation in EP300 that was mutated in \n4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, \nour results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as \npotential driver genes of squamous cell lung cancer.", "CONTEXT: The tumorigenic role of genetic abnormalities in sporadic pituitary \nnonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, \nis unknown.\nOBJECTIVE: The objective of the study was to identify somatic genetic \nabnormalities in sporadic pituitary NFAs.\nDESIGN: Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and \nleukocyte samples obtained from the same patients. Somatic variants were \nconfirmed by dideoxynucleotide sequencing, and candidate driver genes were \nassessed in an additional 24 pituitary NFAs.\nRESULTS: Whole-exome sequencing achieved a high degree of coverage such that \napproximately 97% of targeted bases were represented by more than 10 base reads; \n24 somatic variants were identified and confirmed in the discovery set of 7 \npituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of \nvariants occurred as missense single nucleotide variants and the remainder were \nsynonymous changes or small frameshift deletions. Each of the 24 mutations \noccurred in independent genes with no recurrent mutations. Mutations were not \nobserved in genes previously associated with pituitary tumorigenesis, although \nsomatic variants in putative driver genes including platelet-derived growth \nfactor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper \nsterile-α-motif kinase (ZAK) were identified; however, DNA sequence analysis of \nthese in the validation set of 24 pituitary NFAs did not reveal any mutations \nindicating that these genes are unlikely to contribute significantly in the \netiology of sporadic pituitary NFAs.\nCONCLUSIONS: Pituitary NFAs harbor few somatic mutations consistent with their \nlow proliferation rates and benign nature, but mechanisms other than somatic \nmutation are likely involved in the etiology of sporadic pituitary NFAs." ]	['http://www.disease-ontology.org/api/metadata/DOID:162', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009369', 'http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009154']
5a89537cfcd1d6a10c000002	[ 7606923, 6177004, 8896561, 9177778, 100785, 2767161, 3248380, 6538846 ]	train	Are mouse chromosomes acrocentric?	yesno	yes	yes	[ "Physical gene mapping by in situ hybridization is a difficult task in an \nall-acrocentric mouse karyotype, because all of the chromosomes are \nmorphologically very similar. These difficulties can be overcome by using the \nmany different metacentric Robertsonian translocation (Rb) chromosomes derived \nfrom wild mice. Here we describe the establishment of two Moloney murine \nleukemia virus-transformed suspension cell lines, WMP-1 and WMP-2, derived from \nwild mice of the strain WMP/WMP. These mice carry nine pairs of metacentric Rb \nchromosomes containing chromosomes 1 to 18. Chromosome 19 and the sex \nchromosomes are the only acrocentric chromosomes. Furthermore, a heterozygous \nreciprocal translocation between chromosomes 13 and 17 involved in two Rb \nchromosomes is present in this stock and provides additional marker chromosomes. \nThe chromosome designation of these mice is Rb(10.17)9Mpl Rb(13.15)10Mpl \nT(13.17)1Lub.", "We have assigned the gene (B2m) coding for murine beta 2-microglobulin (B2M) to \nmouse chromosome 2 by using a novel panel of Chinese hamster-mouse somatic cell \nhybrid clones. Because of 35 independent primary hybrids used in this study were \nderived from two types of feral mice, each with a different combination of \nRobertsonian translocation chromosomes, as well as from mice with a normal \ncomplement of acrocentric chromosomes, analysis of 16 selected mouse enzyme \nmarkers provided data on the segregation of all 20 mouse chromosomes in these \nhybrids. Mouse B2M was identified in cell hybrids by immunoprecipitation with a \nspecies-specific anti-mouse B2M antiserum followed by two-dimensional \npolyacrylamide gel electrophoresis of the immunoprecipitated polypeptides. \nEnzyme analysis of the segregant clones excluded all chromosomes for B2m \nassignment except mouse chromosome 2, and karyotype analysis of nine informative \nhybrid clones confirmed the assignment of B2m to this chromosome. These results \ndemonstrate that, in the mouse, as in man, B2m is not linked to the major \nhistocompatibility or immunoglobulin loci.", "Murine models of human carcinogenesis are exceedingly valuable tools to \nunderstand genetic mechanisms of neoplastic growth. The identification of \nrecurrent chromosomal rearrangements by cytogenetic techniques serves as an \ninitial screening test for tumour specific aberrations. In murine models of \nhuman carcinogenesis, however, karyotype analysis is technically demanding \nbecause mouse chromosomes are acrocentric and of similar size. Fluorescence in \nsitu hybridization (FISH) with mouse chromosome specific painting probes can \ncomplement conventional banding analysis. Although sensitive and specific, FISH \nanalyses are restricted to the visualization of only a few mouse chromosomes at \na time. Here we apply a novel imaging technique that we developed recently for \nthe visualization of human chromosomes to the simultaneous discernment of all \nmouse chromosomes. The approach is based on spectral imaging to measure \nchromosome-specific spectra after FISH with differentially labelled mouse \nchromosome painting probes. Utilizing a combination of Fourier spectroscopy, \nCCD-imaging and conventional optical microscopy, spectral imaging allows \nsimultaneous measurement of the fluorescence emission spectrum at all sample \npoints. A spectrum-based classification algorithm has been adapted to karyotype \nmouse chromosomes. We have applied spectral karyotyping (SKY) to chemically \ninduced plasmocytomas, mammary gland tumours from transgenic mice overexpressing \nthe c-myc oncogene and thymomas from mice deficient for the ataxia \ntelangiectasia (Atm) gene. Results from these analyses demonstrate the potential \nof SKY to identify complex chromosomal aberrations in mouse models of human \ncarcinogenesis.", "Genome mapping in the dog is in its early stages. Here we illustrate an approach \nto combined physical and linkage mapping of type 1 anchor (gene) loci in the dog \nusing information on syntenic homology from human and mouse, an interbreed \ncross/backcross, and a strategy for isolation of dog genomic clones containing \nboth gene-specific sequences and simple sequence repeat polymorphisms. Eleven \ngene loci from human chromosome 17q (HSA17q) were mapped to the centromeric \ntwo-thirds of dog chromosome 9 (CFA9), an acrocentric chromosome of medium size: \nP4HB, GALK1, TK1, GH1, MYL4, BRCA1, RARA, THRA1, MPO, NF1, and CRYBA1. Eight of \nthese were also positioned on a linkage map spanning 38.6 cM. Based on combined \nfluorescence in situ hybridization and linkage mapping, the gene order on CFA9 \nis similar to that of the homologous genes on HSA17q and mouse chromosome 11 \n(MMU11), but in the dog the gene order is inverted with respect to the \ncentromere. Canine loci, GALK1, TK1, GH1, MYL4, THRA1, and RARA constitute a \nclosely linked group near the centromeric end of CFA9, spanning a genetic \ndistance of only 4.7 cM. Canine NF1 and CRYBA1 lie distally, near the lower \nborder of the Giemsa band adjacent to the distal one-third of CFA9. NF1 and \nCRYBA1 are loosely linked to the more centromeric group (31.2 cM). No HSA17 \ngenes were found on the telomeric one-third of CFA9. Painting of dog chromosomes \nwith a human whole chromosome 17 probe showed hybridization with only the \nproximal two-thirds of CFA9, consistent with the conclusion that the distal \none-third corresponds to a segment or segments of other human chromosomes. Two \nloci, GLUT4 and PMP22, located on HSA17p, were mapped by FISH to dog chromosome \n5 in a region also identified by the whole human chromosome 17 paint, indicating \ndisruption of HSA17 syntenic homology at the centromere.", "Using somatic cell hybrids from fusions of lymphocytes of two different mouse \nstocks with the myeloma cell line X63-Ag8, we have assigned genes for the \nimmunoglobulin heavy and kappa-type light chains to chromosomes 12 and 6, \nrespectively. The two mouse stocks exhibit karyotypes consisting of nine pairs \nof metacentric chromosomes as a result of centric fusions of acrocentric \nchromosomes in different combinations. In the hybrid cells these metacentric \nchromosomes can be distinguished from the acrocentric chromosomes of myeloma \norigin, permitting correlation of Ig chain expression with mitotic loss of \nindividual metacentric chromosomes.", "The mouse genome contains a major and a minor satellite DNA family of repetitive \nDNA sequences. The use of 5-azacytidine has allowed us to demonstrate that these \nsatellite DNAs are organized in two separate domains at the centromeres of mouse \nchromosomes. The minor satellite is closer to the short arms of the acrocentric \nchromosomes than the major satellite. The major satellite is farther away, \nflanking the minor satellite and adjacent to the euchromatic long arm of each \nmouse chromosome. At the level of resolution afforded by the in situ \nhybridization technique it would appear that the organization of the centromeric \ndomain of the mouse is similar to that in man. That is, both contain two \nrepetitive DNA sequence families arranged in major blocks.", "Genes for fibronectin, gamma crystallin, and isocitrate dehydrogenase-1 are \nsyntenic in mouse, man, and cow. In an effort to physically locate this \nconserved chromosome region in the genomes of the respective species, we have \nlocalized the fibronectin and gamma crystallin genes to mouse chromosome 1, \nregion C1-5 by in situ hybridization. In situ hybridization was conducted on \nmetaphase chromosomes of bone marrow preparations of Rb 1.7 mice. These cells \ncontain Robertsonian translocated chromosomes 1 and 7 as the only submetacentric \nchromosome in an otherwise acrocentric genome. Physically mapping these genes to \nmouse chromosome 1 now enables comparisons of the genetic map and the physical \nmap on the proximal half of this chromosome. Genes in this conserved region of \nmouse chromosome 1 are also involved in resistance to intracellular pathogens, \nand the chromosomal localization of this region may facilitate the \nidentification of homologous genes in other species.", "While analysis and sorting of human chromosomes by flow cytometry has been \nwidely used, isolation of a pure mouse chromosome remains very difficult, since \nmost murine chromosomes are quite similar in size. To overcome this problem, we \nhave analysed mouse cell lines having either Robertsonian translocations or \nisochromosomes. The resulting metacentric chromosomes are very different in size \nand in morphology from normal mouse acrocentric chromosomes. These \ncharacteristics have been analysed by computer-monitored flow cytometry, \nfacilitated by improvements in the chromosome extraction procedure. Signals \ncharacteristic of the iso-lq chromosome in cell line PCC4 azaR1, and of the \nnormal X chromosome in the mouse strain 22CD have thus been obtained. These \nchromosomes have been sorted and can be easily recognized by fluorescence \nmicroscopy when collected onto serum-albumin-coated microscope slides. The \ntechnical modifications made, coupled with the existence of a great diversity of \nmetacentric chromosomes resulting from Robertsonian translocations, should allow \nthe purification of a number of different mouse chromosomes." ]	nan
604906ed1cb411341a000163	[ 33300069, 32195770, 31729101, 31837357 ]	train	Are mucin overexpression associated with disease?	yesno	Yes, mucins are overexpressed in various malignancies and inflammations.	yes	[ "Hepatolithiasis is a common disease that represents a serious health threat to \nthe Chinese population. The pathological mechanism underlying hepatolithiasis is \nclosely related to bacterial infections of the intrahepatic bile duct, followed \nby chronic inflammation and the overexpression of mucin 5AC (MUC5AC). However, \nthe exact mechanism responsible for the lipopolysaccharide (LPS)‑induced \nupregulation of MUC5AC has yet to be elucidated. Specificity protein 1 (Sp1) is \na ubiquitous transcription factor that plays a vital role in the regulation of a \nnumber of genes that are responsible for normal cellular function. \nmicroRNA (miR/miRNA)‑130b is a member of the miRNA family. miRNAs can bind to \nthe 3'‑untralsated region (3'‑UTR) of a target gene and influence its expression \nlevels. The present study found that LPS increases the expression of MUC5AC by \ninfluencing Sp1 secretion. Chromatin immunoprecipitation‑quantitative PCR \nexperiments further verified three Sp1 binding sites in the MUC5AC promoter \nsequence that can regulate the expression of MUC5AC. Further analysis \ndemonstrated that Sp1 expression was regulated by miR‑130b. Luciferase \nexperiments identified one miR‑130b binding site in the Sp1 3'‑UTR region. \nIn vivo experiments also confirmed the role of the miR‑130b‑Sp1‑MUC5AC signaling \npathway in the formation of biliary stones and indicated that this pathway may \nprovide targeted therapeutic strategies for the treatment of intrahepatic bile \nduct stones.", "BACKGROUND: MUC1-glycoprotein is expressed at low levels and in fully \nglycosylated form on epithelial cells. Inflammation causes MUC1 overexpression \nand hypoglycosylation. We hypothesized that overexpression of hypoglycosylated \nMUC1 would be found in postoperative Crohn's disease (CD) recurrence and could \nbe considered an additional biomarker of recurrence severity.\nMETHODS: We examined archived neo-terminal ileum biopsies from patients with \nprior ileocecal resection who had postoperative endoscopic assessment of CD \nrecurrence and given a Rutgeerts ileal recurrence score. Consecutive tissue \nsections were stained using 2 different anti-MUC1 antibodies, HMPV that \nrecognizes all forms of MUC1 and 4H5 that recognizes only \ninflammation-associated hypoglycosylated MUC1.\nRESULTS: A total of 71 postoperative CD patients were evaluated. There was \nsignificant increase in MUC1 expression of both glycosylated/normal (P<0.0001) \nand hypoglycosylated/abnormal (P<0.0001) forms in patients with severe \nendoscopic CD recurrence (i3+i4), ileal score i2, compared with patients in \nendoscopic remission (i0+i1). Results were similar regardless of anti-TNF-α use. \nAlthough MUC1 expression and Rutgeerts scores were in agreement when \ncharacterizing the majority of cases, there were a few exceptions where MUC1 \nexpression was characteristic of more severe recurrence than implied by \nRutgeerts score.\nCONCLUSIONS: MUC1 is overexpressed and hypoglycosylated in neo-terminal ileum \ntissue of patients with postoperative CD recurrence. Increased levels are \nassociated with more severe endoscopic recurrence scores, and this is not \ninfluenced by anti-TNF-α use. Discrepancies found between Rutgeerts scores and \nMUC1 expression suggest that addition of MUC1 as a biomarker of severity of \npostoperative CD recurrence may improve categorization of recurrence status and \nconsequently treatment decisions.", "MUC1 is a membrane glycoprotein, which in adenocarninomas is overexpressed and \nexhibits truncated O-glycosylation. Overexpression and altered glycosylation \nmake MUC1 into a candidate for immunotherapy. Monoclonal antibodies directed \nagainst MUC1 frequently bind an immunodominant epitope that contains a single \nsite for O-glycosylation. Glycosylation with tumor carbohydrate antigens such as \nthe Tn-antigen (GalNAc-O-Ser/Thr) results in antibodies binding with higher \naffinity. One proposed model to explain the enhanced affinity of antibodies for \nthe glycosylated antigen is that the addition of a carbohydrate alters the \nconformational properties, favoring a binding-competent state. The \nconformational effects associated with Tn glycosylation of the MUC1 antigen was \ninvestigated using solution-state NMR and molecular dynamics. NMR experiments \nrevealed distinct substructures of the glycosylated MUC1 peptides compared with \nthe unglycosylated peptide. Molecular dynamics simulations of the MUC1 \nglycopeptide and peptide revealed distinguishing differences in their \nconformational preferences. Furthermore, the glycopeptide displayed a smaller \nconformational sampling compared with the peptide, suggesting that the \nglycopeptide sampled a narrower conformational space and is less dynamic. A \ncomparison of the computed ensemble of conformations assuming random \ndistribution, NMR models, and molecular dynamics simulations indicated that the \nMUC1 glycopeptide and aglycosylated peptide sampled structurally distinctly \nensembles and that these ensembles were different from that of the random coil. \nTogether, these data support the hypothesis that that conformational \npre-selection could be an essential feature of these peptides that dictates the \nbinding affinities to MUC1 specific antibodies.", "BACKGROUND & AIMS: Mucin 13 (MUC13) is reportedly overexpressed in human \nmalignancies. However, the clinicopathological and biological significance of \nMUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of \nthis study was to define the role of MUC13 in the progression of iCCA.\nMETHODS: Expression levels of MUC13 in human iCCA samples were evaluated by \nimmunohistochemistry, western blot, and real-time PCR. In vitro and in vivo \nexperiments were used to assess the effect of MUC13 on iCCA cell growth and \nmetastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by \nmolecular methods. The upstream regulatory effects of MUC13 were evaluated by \nLuciferase and DNA methylation assays.\nRESULTS: MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 \noverexpression positively correlated with clinicopathological characteristics of \niCCA, such as vascular invasion and lymph node metastasis, and was independently \nassociated with poor survival. Results from loss-of-function and \ngain-of-function experiments suggested that knockdown of MUC13 attenuated, while \noverexpression of MUC13 enhanced, the proliferation, motility, and invasiveness \nof iCCA cells in vitro and in vivo. Mechanistically, we found that the \nphosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, \nsuch as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, \nwere required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with \nepidermal growth factor receptor (EGFR) and subsequently activated the \nEGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing \nEGFR internalization. We also found that MUC13 was directly regulated by \nmiR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in \nthe promoter area.\nCONCLUSIONS: These findings suggest that aberrant hypermethylation-induced \ndownregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading \nto metastasis via activation of the EGFR/PI3K/AKT signaling pathway.\nLAY SUMMARY: Mucin 13 overexpression has been implicated in the development of \nmalignancies, although its role in intrahepatic cholangiocarcinoma has not been \nstudied. Herein, we show that mucin 13 plays a critical role in intrahepatic \ncholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic \nmarker and as a treatment target." ]	nan
604903551cb411341a000162	[ 31907968, 31908009, 31904283 ]	train	Are mucins glycosylated proteins?	yesno	Yes, Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion.	yes	[ "Mucin is a glycoprotein that is the primary component of the mucus overlaying \nthe epithelial tissues. Because mucin functions as a first line of the innate \nimmune system, Pseudomonas aeruginosa appears to require interaction with mucin \nto establish infection in the host. However, the interactions between P. \naeruginosa and mucin have been poorly understood. In this study, using in vivo \nexpression technology (IVET), we attempted to identify mucin-inducible promoters \nthat are likely to be involved in the establishment of P. aeruginosa infection. \nThe IVET analysis revealed that the genes encoding glycosidases, sulfatases, and \npeptidases that are thought to be required for the utilization of mucin as a \nnutrient are present in 13 genes downstream of the identified promoters. Our \nresults indicated that, among them, sdsA1 encoding a secreted sulfatase plays a \ncentral role in the degradation of mucin. It was then demonstrated that \ndisruption of sdsA1 leads to a decreased release of sulfate from mucin and \nsulfated sugars. Furthermore, the sdsA1 mutant showed a reduction in the ability \nof mucin gel penetration and an attenuation of virulence in leukopenic mice \ncompared with the wild-type strain. Collectively, these results suggest that \nSdsA1 plays an important role as a virulence factor of P. aeruginosa.", "Many members of the mucin family are evolutionarily conserved and are often \naberrantly expressed and glycosylated in various benign and malignant \npathologies leading to tumor invasion, metastasis, and immune evasion. The large \nsize and extensive glycosylation present challenges to study the mucin structure \nusing traditional methods, including crystallography. We offer the hypothesis \nthat the functional versatility of mucins may be attributed to the presence of \nintrinsically disordered regions (IDRs) that provide dynamism and flexibility \nand that the IDRs offer potential therapeutic targets. Herein, we examined the \nlinks between the mucin structure and function based on IDRs, posttranslational \nmodifications (PTMs), and potential impact on their interactome. Using \nsequence-based bioinformatics tools, we observed that mucins are predicted to be \nmoderately (20%-40%) to highly (>40%) disordered and many conserved mucin \ndomains could be disordered. Phosphorylation sites overlap with IDRs throughout \nthe mucin sequences. Additionally, the majority of predicted O- and N- \nglycosylation sites in the tandem repeat regions occur within IDRs and these \nIDRs contain a large number of functional motifs, that is, molecular recognition \nfeatures (MoRFs), which directly influence protein-protein interactions (PPIs). \nThis investigation provides a novel perspective and offers an insight into the \ncomplexity and dynamic nature of mucins.", "Mucin-type O-linked glycosylation, a posttranslational modification affecting \nthe stability and biophysical characteristics of proteins, requires C1GalT1 (T \nsynthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 \nmutations cause renal failure via not yet established mechanisms. We hypothesize \nthat impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to \ncause disease. Podocyte-specific Cosmc knockout mice were generated and \nphenotyped to test this hypothesis. Female heterozygous mice displaying mosaic \ninactivation of Cosmc in podocytes due to random X-linked inactivation were also \nexamined. Mice with podocyte-specific Cosmc deletion develop profound \nalbuminuria, foot process effacement, glomerular sclerosis, progressive renal \nfailure, and impaired survival. Glomerular transcriptome analysis reveals early \nchanges in cell adhesion, extracellular matrix organization, and \nchemokine-mediated signaling pathways, coupled with podocyte loss. Expression of \nthe O-glycoprotein podoplanin was lost, while Tn antigen, representing immature \nO-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous \nmale and homozygous female animals, heterozygous female mosaic animals developed \nonly mild albuminuria, focal foot process effacement, and nonprogressive kidney \ndisease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive \nfoot processes interdigitating with those of normal podocytes but not with other \nCosmc-deficient cells. This suggests a cell nonautonomous mechanism for \nmucin-type O-glycoproteins in maintaining podocyte function. In summary, our \nfindings demonstrated an essential and likely cell nonautonomous role for \nmucin-type O-glycosylation for podocyte function." ]	nan
58e11bf76fddd3e83e00000c	[ 22366791, 22892647, 22300873, 23053135, 27632209, 24442578, 22228244, 27619540, 24064469, 23934648, 22673113, 26303227, 24521566 ]	train	Are mutations in the C9orf72 gene associated with macular degeneration?	yesno	Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS.	no	[ "An expanded hexanucleotide repeat in the C9ORF72 gene has recently been \nidentified as a major cause of familial frontotemporal lobar degeneration and \nmotor neuron disease, including cases previously identified as linked to \nchromosome 9. Here we present a detailed retrospective clinical, neuroimaging \nand histopathological analysis of a C9ORF72 mutation case series in relation to \nother forms of genetically determined frontotemporal lobar degeneration \nascertained at a specialist centre. Eighteen probands (19 cases in total) were \nidentified, representing 35% of frontotemporal lobar degeneration cases with \nidentified mutations, 36% of cases with clinical evidence of motor neuron \ndisease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 \ncases had no identified relevant family history. Families showed wide variation \nin clinical onset (43-68 years) and duration (1.7-22 years). The most common \npresenting syndrome (comprising a half of cases) was behavioural variant \nfrontotemporal dementia, however, there was substantial clinical heterogeneity \nacross the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical \nfeatures consistent with motor neuron disease during the period of follow-up. \nAnxiety and agitation and memory impairment were prominent features (between a \nhalf to two-thirds of cases), and dominant parietal dysfunction was also \nfrequent. Affected individuals showed variable magnetic resonance imaging \nfindings; however, relative to healthy controls, the group as a whole showed \nextensive thinning of frontal, temporal and parietal cortices, subcortical grey \nmatter atrophy including thalamus and cerebellum and involvement of long \nintrahemispheric, commissural and corticospinal tracts. The neuroimaging profile \nof the C9ORF72 expansion was significantly more symmetrical than progranulin \nmutations with significantly less temporal lobe involvement than \nmicrotubule-associated protein tau mutations. Neuropathological examination in \nsix cases with C9ORF72 mutation from the frontotemporal lobar degeneration \nseries identified histomorphological features consistent with either type A or B \nTAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR \nDNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus \nand cerebellum were a consistent feature of these cases, in contrast to the \nsimilar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control \ncases with frontotemporal lobar degeneration-TAR DNA-binding protein. These \nfindings corroborate the clinical importance of the C9ORF72 mutation in \nfrontotemporal lobar degeneration, delineate phenotypic and neuropathological \nfeatures that could help to guide genetic testing, and suggest hypotheses for \nelucidating the neurobiology of a culprit subcortical network.", "Frontotemporal lobar degeneration (FTLD) is a genetically heterogenous syndrome \nand has been associated most recently with a hexanucleotide repeat expansion \nwithin the C9ORF72 gene. Pathogenic TDP-43 gene (TARDBP) mutations have been \nidentified in amyotrophic lateral sclerosis, but the role of TARDBP mutations in \nFTLD is more contradictory. To investigate the role of TARDBP mutations in a \nclinical series of Finnish FTLD patients, we sequenced TARDBP exons 1 to 6 in 77 \nFTLD patients. No evident pathogenic mutations were found. We identified a novel \nheterozygous c.876_878delCAG sequence variant in 2 related patients with \nbehavioral variant frontotemporal dementia without amyotrophic lateral \nsclerosis. The variant is predicted to cause an amino acid deletion of serine at \nposition 292 (p.Ser292del). However, p.Ser292del was also found in 1 healthy \nmiddle-aged control. Interestingly, both patients carried the C9ORF72 expansion. \nTherefore, the TARDBP variant p.Ser292del might be considered a rare \npolymorphism and the C9ORF72 repeat expansion the actual disease-causing \nmutation in the family. Our results suggest that TARDBP mutations are a rare \ncause of FTLD. However, the interaction of several genetic factors needs to be \ntaken into account when investigating neurodegenerative diseases.", "The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as \nthe cause of chromosome 9-linked frontotemporal dementia and motor neuron \ndisease offers the opportunity for greater understanding of the relationship \nbetween these disorders and other clinical forms of frontotemporal lobar \ndegeneration. In this study, we screened a cohort of 398 patients with \nfrontotemporal dementia, progressive non-fluent aphasia, semantic dementia or \nmixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron \ndisease was present in 55 patients (14%). We identified 32 patients with C9ORF72 \nmutations, representing 8% of the cohort. The patients' clinical phenotype at \npresentation varied: nine patients had frontotemporal dementia with motor neuron \ndisease, 19 had frontotemporal dementia alone, one had mixed semantic dementia \nwith frontal features and three had progressive non-fluent aphasia. There was, \nas expected, a significant association between C9ORF72 mutations and presence of \nmotor neuron disease. Nevertheless, 46 patients, including 22 familial, had \nmotor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the \npatients with C9ORF72 mutations presented with psychosis, with a further 28% \nexhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation \nbearers presented similarly. The presence of psychosis dramatically increased \nthe odds that patients carried the mutation. Mutation bearers showed a low \nincidence of motor stereotypies, and relatively high incidence of complex \nrepetitive behaviours, largely linked to patients' delusions. They also showed a \nlower incidence of acquired sweet food preference than patients without C9ORF72 \nmutations. Post-mortem pathology in five patients revealed transactive response \nDNA-binding protein 43 pathology, type A in one patient and type B in three. \nHowever, one patient had corticobasal degeneration pathology. The findings \nindicate that C9ORF72 mutations cause some but not all cases of frontotemporal \ndementia with motor neuron disease. Other mutations remain to be discovered. \nC9ORF72 mutations are associated with variable clinical presentations and \npathology. Nevertheless, the findings highlight a powerful association between \nC9ORF72 mutations and psychosis and suggest that the behavioural characteristics \nof patients with C9ORF72 mutations are qualitatively distinct. Mutations in the \nC9ORF72 gene may be a major cause not only of frontotemporal dementia with motor \nneuron disease but also of late onset psychosis.", "An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic \ncause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration \nassociated with TDP-43 pathology (FTLD-TDP). In addition to TDP-43-positive \nneuronal and glial inclusions, C9ORF72-linked FTLD-TDP has characteristic \nTDP-43-negative neuronal cytoplasmic and intranuclear inclusions as well as \ndystrophic neurites in the hippocampus and cerebellum. These lesions are \nimmunopositive for ubiquitin and ubiquitin-binding proteins, such as \nsequestosome-1/p62 and ubiquilin-2. Studies examining the frequency of the \nC9ORF72 mutation in clinically probable Alzheimer's disease (AD) have found a \nsmall proportion of AD cases with the mutation. This prompted us to \nsystematically explore the frequency of Alzheimer-type pathology in a series of \n17 FTLD-TDP cases with mutations in C9ORF72 (FTLD-C9ORF72). We identified four \ncases with sufficient Alzheimer-type pathology to meet criteria for \nintermediate-to-high-likelihood AD. We compared AD pathology in the 17 \nFTLD-C9ORF72 to 13 cases of FTLD-TDP linked to mutations in the gene for \nprogranulin (FTLD-GRN) and 36 cases of sporadic FTLD (sFTLD). FTLD-C9ORF72 cases \nhad higher Braak neurofibrillary tangle stage than FTLD-GRN. Increased tau \npathology in FTLD-C9ORF72 was assessed with thioflavin-S fluorescent \nmicroscopy-based neurofibrillary tangle counts and with image analysis of tau \nburden in temporal cortex and hippocampus. FTLD-C9ORF72 had significantly more \nneurofibrillary tangles and higher tau burden compared with FTLD-GRN. The \ndifferences were most marked in limbic regions. On the other hand, sFTLD and \nFTLD-C9ORF72 had a similar burden of tau pathology. These results suggest \nFTLD-C9ORF72 has increased propensity for tau pathology compared to FTLD-GRN, \nbut not sFTLD. The accumulation of tau as well as lesions immunoreactive for \nubiquitin and ubiquitin-binding proteins (p62 and ubiquilin-2) suggests that \nmutations in C9ORF72 may involve disrupted protein degradation that favors \naccumulation of multiple different proteins.", "'Microtubule-associated protein tau' (MAPT), 'granulin' (GRN) and 'chromosome 9 \nopen reading frame72' (C9ORF72) gene mutations are the major known genetic \ncauses of frontotemporal dementia (FTD). Recent studies suggest that mutations \nin these genes may also be associated with other forms of dementia. Therefore we \ninvestigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors \nto dementia in a random, unselected Turkish cohort of dementia patients. A \ncombination of whole-exome sequencing, Sanger sequencing and fragment \nanalysis/Southern blot was performed in order to identify pathogenic mutations \nand novel variants in these genes as well as other FTD-related genes such as the \n'charged multivesicular body protein 2B' (CHMP2B), the 'FUS RNA binding protein' \n(FUS), the 'TAR DNA binding protein' (TARDBP), the 'sequestosome1' (SQSTM1), and \nthe 'valosin containing protein' (VCP). We determined one pathogenic MAPT \nmutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). \nIn GRN we identified a probably pathogenic TGAG deletion in the splice donor \nsite of exon 6. Three patients were found to carry the GGGGCC expansions in the \nnon-coding region of the C9ORF72 gene. In summary, a complete screening for \nmutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of \npathogenic mutations in a random cohort of 93 Turkish index patients with \ndementia.", "Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) \nhave recently been linked to frontotemporal lobar degeneration (FTLD) and \namyotrophic lateral sclerosis, and may be the most common genetic cause of both \nneurodegenerative diseases. Genetic variants at TMEM106B influence risk for the \nmost common neuropathological subtype of FTLD, characterized by inclusions of \nTAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that \nTMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) \nmutations, with the major (risk) allele of rs1990622 associating with earlier \nage at onset of disease. Here, we report that rs1990622 genotype affects age at \ndeath in a single-site discovery cohort of FTLD patients with C9orf72 expansions \n(n = 14), with the major allele correlated with later age at death (p = 0.024). \nWe replicate this modifier effect in a 30-site international neuropathological \ncohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that \nthe major allele associates with later age at death (p = 0.016), as well as \nlater age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect \nage at onset or death in 241 FTLD-TDP cases negative for GRN mutations or \nC9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 \nexpansions. Intriguingly, the genotype that confers increased risk for \ndeveloping FTLD-TDP (major, or T, allele of rs1990622) is associated with later \nage at onset and death in C9orf72 expansion carriers, providing an example of \nsign epistasis in human neurodegenerative disease.", "Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a \nnon-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as \nthe cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and \nfrontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we \nidentified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) \ncases. Patients with the mutation presented with typical motor features of ALS, \nalthough subjects with the C9ORF72 mutation had more frequent bulbar onset, \ncompared to those without this mutation. Dementia was significantly more common \nin ALS patients and families with the C9ORF72 mutation and was usually \nearly-onset FTD. There was striking clinical heterogeneity among the members of \nindividual families with the mutation. The associated neuropathology was a \ncombination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to \nTDP-43-immunoreactive pathology, a consistent and specific feature of cases with \nthe C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative \ninclusions in a variety of neuroanatomical regions, such as the cerebellar \ncortex. These findings support the C9ORF72 mutation as an important newly \nrecognized cause of ALS, provide a more detailed characterization of the \nassociated clinical and pathological features and further demonstrate the \nclinical and molecular overlap between ALS and FTD.", "Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two \napparently distinct neurodegenerative diseases, the former characterized by \nselective loss of motor neurons in the brain and spinal cord and the latter \ncharacterized by selective atrophy of frontal and temporal lobes. Over the \nyears, however, growing evidence from clinical, pathological and genetic \nfindings has suggested that ALS and FTD belong to the same clinic-pathological \nspectrum disorder. This concept has been further supported by the identification \nof the most common genetic cause for both diseases, an aberrantly expanded \nhexanucleotide repeat GGGGCC/ CCCCGG sequence located in a non-coding region of \nthe gene C9orf72. Three hypotheses have been proposed to explain how this \nrepeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded \nrepeats interfere with transcription or translation of the gene, leading to \ndecreased expression of the C9orf72 protein; 2) RNA gain of function-RNA foci \nformed by sense and antisense transcripts of expanded repeats interact and \nsequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat \nassociated non-ATG initiated (RAN) translation of expanded sense GGGGCC and \nantisense CCCCGG repeats produces potential toxic dipeptide repeat protein \n(DPR). In this review, we assess current evidence supporting or arguing against \neach proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, \ncontroversial findings are also discussed. Lastly, we discuss the possibility \nthat the three pathogenic mechanisms are not mutually exclusive and all three \nmight be involved in disease.", "Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as \nthe most common pathogenic mutation in families with autosomal dominant \nfrontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. \nHerein we investigated frequency and penetrance of the C9ORF72 hexanucleotide \nrepeat pathological expansion in a large cohort of familial and sporadic FTLD \nand related disorders (FTLD and related disorders, n = 388; Controls, n = 201). \nMoreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking \ninto account the hexanucleotide repeat units number as a possible disease \nmodifier. In our cohort, the C9ORF72 pathological expansion: (i) showed a \nprevalence of 7.5%; (ii) showed a full penetrance by the age of 80; (iii) was \nrarely found in sporadic patients; (iv) was solely associated with FTLD; (v) was \nmainly associated with bvFTD clinical subtype; and (vi) was associated with \nearlier age of onset in the youngest generation compared with the previous \ngeneration within a pedigree. Interestingly, intermediate C9ORF72 expansion had \na risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units \nnumber influenced the disease phenotype in terms of age of onset and associated \nclinical subtype. Genome-wide studies in well characterized clinical cohorts \nwill be essential in order to decipher pathways of disease expression in \nC9ORF72-associated neurodegeneration.", "Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat \nin the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an \nunknown C9ORF72 protein, which was responsible for an unprecedented large \nproportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia \n(FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including \nthe brain. Emerging evidence has demonstrated that C9ORF72 mutations could \nreduce the level of C9ORF72 variant 1, which may influence protein expression \nand the formation of nuclear RNA foci. The spectrum of mutations is broad and \nprovides new insight into neurological diseases. Clinical manifestations of \ndiseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral \nsclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like \nsyndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review \nthe brief characterizations of the C9ORF72 gene, the expansion mutations, the \nrelated disorders, and their features, followed by a discussion of the \ndeficiency knowledge of C9ORF72 mutations. Based on the possible pathological \nmechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the \ntreatment of C9ORF72 mutation-related diseases. Future studies into the \nmechanisms, taking into consideration the discovery of those disorders, will \nsignificantly accelerate new discoveries in this field, including targeting \nidentification of new therapy.", "A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene was recently \nidentified as an important cause of familial amyotrophic lateral sclerosis (ALS) \nand frontotemporal dementia in Caucasian populations. The role of the C9ORF72 \nrepeat expansion in ALS in Chinese populations has received little attention. We \ntherefore performed mutation analyses in a Taiwanese cohort of 22 unrelated \nfamilial ALS (FALS) patients and 102 sporadic ALS patients of Han Chinese \ndescent. The C9ORF72 mutation was found in 4 FALS (18.2%; 4/22) and 2 sporadic \nALS patients (2.0%; 2/102). The C9ORF72 repeat numbers in the 300 healthy \ncontrols and the 118 ALS patients without the C9ORF72 mutation ranged from 3 to \n15. Needle biopsy in the left frontal cortex of 1 patient with \nFALS-frontotemporal dementia revealed numerous cytoplasmic TAR DNA-binding \nprotein 43 (TDP-43) inclusions and minimal neuritis, consistent with type B \nfrontotemporal lobar degeneration with TDP-43 (FTLD-TDP) pathology. This study \nclearly demonstrates the existence and importance of the C9ORF72 hexanucleotide \nrepeat expansion in a Taiwanese ALS cohort of Chinese origin, and supports the \nglobal presence of the C9ORF72 repeat expansion in ALS.", "Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss \nresulting in muscle weakness, spasticity and ultimately death. 5-10% are caused \nby inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS. Rarer \ngenetic causes of ALS include mutation of optineurin (mt OPTN). Furthermore, \noptineurin protein has been localized to the ubiquitylated aggregates in several \nneurodegenerative diseases, including ALS. This study: (i) investigated the \nfrequency of mt OPTN in ALS patients in England; (ii) characterized the clinical \nand neuropathological features of ALS associated with a mt OPTN; and (iii) \ninvestigated optineurin neuropathology in C9ORF72-related ALS (C9ORF72-ALS). We \nidentified a heterozygous p.E322K missense mutation in exon 10 of OPTN in one \nfamilial ALS patient who additionally had a C9ORF72 mutation. This patient had \nbulbar, limb and respiratory disease without cognitive problems. Neuropathology \nrevealed motor neurone loss, trans-activation response DNA protein 43 \n(TDP-43)-positive neuronal and glial cytoplasmic inclusions together with \nTDP-43-negative neuronal cytoplasmic inclusions in extra motor regions that are \ncharacteristic of C9ORF72-ALS. We have demonstrated that both TDP-43-positive \nand negative inclusion types had positive staining for optineurin by \nimmunohistochemistry. We went on to show that optineurin was present in \nTDP-43-negative cytoplasmic extra motor inclusions in C9ORF72-ALS cases that do \nnot carry mt OPTN. We conclude that: (i) OPTN mutations are associated with ALS; \n(ii) optineurin protein is present in a subset of the extramotor inclusions of \nC9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to \noccur in the same patient; and (iv) studies of optineurin are likely to provide \nuseful dataregarding the pathophysiology of ALS and neurodegeneration.", "BACKGROUND: Mutations in C9ORF72 are an important cause of frontotemporal \ndementia (FTD) and motor neuron disease. Accumulating evidence suggests that FTD \nassociated with C9ORF72 mutations (C9ORF72-FTD) is distinguished clinically by \nearly prominent neuropsychiatric features that might collectively reflect \nderanged body schema processing. However, the pathophysiology of C9ORF72-FTD has \nnot been elucidated.\nMETHODS: We undertook a detailed neurophysiological investigation of five \npatients with C9ORF72-FTD, in relation to patients with FTD occurring \nsporadically and on the basis of mutations in the microtubule-associated protein \ntau gene and healthy older individuals. We designed or adapted behavioural tasks \nsystematically to assess aspects of somatosensory body schema processing \n(tactile discrimination, proprioceptive and body part illusions and \nself/non-self differentiation).\nRESULTS: Patients with C9ORF72-FTD selectively exhibited deficits at these \nlevels of body schema processing in relation to healthy individuals and other \npatients with FTD.\nCONCLUSIONS: Altered body schema processing is a novel, generic \npathophysiological mechanism that may link the distributed cortico-subcortical \nnetwork previously implicated in C9ORF72-FTD with a wide range of \nneuropsychiatric and behavioural symptoms, and constitute a physiological marker \nof this neurodegenerative proteinopathy." ]	['https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D012162', 'http://www.disease-ontology.org/api/metadata/DOID:4448', 'http://www.disease-ontology.org/api/metadata/DOID:10871', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D057135', 'https://www.nlm.nih.gov/cgi/mesh/2017/MB_cgi?field=uid&exact=Find+Exact+Term&term=D008268', 'http://www.disease-ontology.org/api/metadata/DOID:14245', 'http://www.disease-ontology.org/api/metadata/DOID:8466']
550748a3bde8548216000001	[ 21062273, 21277190, 20493457, 24170257, 22709267, 24315539, 21967765, 21762454, 22787616, 22612257, 23409955, 22787626, 21770924, 22596016, 18469812, 20876469, 24189369, 23531706, 20845763, 20887364, 21204804, 24095819, 20887371, 21753172, 21364700, 19557857, 22722545 ]	train	Are mutations in the STXBP1 gene associated with epilepsy?	yesno	Yes,mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies.	yes	[ "Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. \nWe have recently identified that the de novo mutations of STXBP1 are important \ncauses for OS. Here we report a paternal somatic mosaicism of an STXBP1 \nmutation. The affected daughter had onset of spasms at 1 month of age, and \ninterictal electroencephalogram showed suppression-burst pattern, leading to the \ndiagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which \naffects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 \nsequences in the transcript. The mutant transcript had a premature stop codon, \nand was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived \nfrom the patient. High-resolution melting analysis of clinically unaffected \nparental DNAs suggested that the father was somatic mosaic for the mutation, \nwhich was also suggested by sequencing. Cloning of PCR products amplified with \nthe paternal DNA samples extracted from blood, saliva, buccal cells, and nails \nsuggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, \nrespectively. This is a first report of somatic mosaicism of an STXBP1 mutation, \nwhich has implications in genetic counseling of OS.", "Human epilepsy is a common and heterogeneous condition in which genetics play an \nimportant etiological role. We begin by reviewing the past history of epilepsy \ngenetics, a field that has traditionally included studies of pedigrees with \nepilepsy caused by defects in ion channels and neurotransmitters. We highlight \nimportant recent discoveries that have expanded the field beyond the realm of \nchannels and neurotransmitters and that have challenged the notion that single \ngenes produce single disorders. Finally, we project toward an exciting future \nfor epilepsy genetics as large-scale collaborative phenotyping studies come face \nto face with new technologies in genomic medicine.", "A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of \nfour individuals (group A) with early-onset West syndrome, severe \nhypomyelination, poor visual attention, and developmental delay. Although \nhaploinsufficiency of STXBP1 was involved in early infantile epileptic \nencephalopathy in a previous different cohort study (group B), no mutations of \nSTXBP1 were found in two of the remaining three subjects of group A (one was \nunavailable). We assumed that another gene within the deletion might contribute \nto the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is \nessential for proper myelination in zebrafish, turned out to be deleted. In two \nsubjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found \nat the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 \nwas further screened in six unrelated individuals with WS and hypomyelination, \nbut no mutations were found. Recombinant mutant (mut) and wild-type (WT) \nalpha-II spectrin could assemble heterodimers with beta-II spectrin, but \nalpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the \nalpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical \nneurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II \n(mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid \ncells from two subjects with in-frame mutations. Clustering of ankyrinG and \nvoltage-gated sodium channels at axon initial segment (AIS) was disturbed in \nrelation to the aggregates, together with an elevated action potential \nthreshold. These findings suggest that pathological aggregation of alpha/beta \nspectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations \nwere involved in pathogenesis of infantile epilepsy.", "Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been \nrecently described in Ohtahara syndrome, or early infantile epileptic \nencephalopathy with suppression-burst pattern, and in other early-onset \nepileptic encephalopathies. A 3-year-old boy affected by epileptic \nencephalopathy started at 8 months of age is described. Focal epilepsy was \ncharacterized by drug resistance seizures with multifocal interictal and ictal \nelectroencephalographic (EEG) features and variable EEG focus. Direct sequencing \nof the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a \np.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was \nattempted and patient became immediately seizure free for 4 months. The present \ncase further expands the clinical spectrum of \"STXBP1-related encephalopathy\" \nsuggesting molecular analysis of STXBP1 in early onset epileptic \nencephalopathies of unknown etiology (with onset within the first year of life). \nIn addition, the case provides valuable suggestions on seizures treatment in \nSTXBP1 mutated subjects.", "PURPOSE: Ohtahara syndrome (OS) is one of the most severe and earliest forms of \nepilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In \nthis study, we aimed to identify new genes involved in OS by copy number \nanalysis and whole exome sequencing.\nMETHODS: Copy number analysis and whole exome sequencing were performed in 34 \nand 12 patients with OS, respectively. Fluorescence in situ hybridization, \nquantitative polymerase chain reaction (PCR), and breakpoint-specific and \nreverse-transcriptase PCR analyses were performed to characterize a deletion. \nImmunoblotting using lymphoblastoid cells was done to examine expression of CASK \nprotein.\nKEY FINDINGS: Genomic microarray analysis revealed a 111-kb deletion involving \nexon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his \nmother, who was somatic mosaic for the deletion. Sequencing of the mutant \ntranscript expressed in lymphoblastoid cell lines derived from the patient \nconfirmed the deletion of exon 2 in the mutant transcript with a premature stop \ncodon. Whole exome sequencing identified another male patient who was harboring \na c.1A>G mutation in CASK, which occurred de novo. Both patients showed severe \ncerebellar hypoplasia along with other congenital anomalies such as \nmicrognathia, a high arched palate, and finger anomalies. No CASK protein was \ndetected by immunoblotting in lymphoblastoid cells derived from two patients.\nSIGNIFICANCE: The detected mutations are highly likely to cause the loss of \nfunction of the CASK protein in male individuals. CASK mutations have been \nreported in patients with intellectual disability with microcephaly and \npontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome. \nOur data expand the clinical spectrum of CASK mutations to include OS with \ncerebellar hypoplasia and congenital anomalies at the most severe end.", "BACKGROUND: Ohtahara syndrome is a severe condition with early onset of \nrecurrent unprovoked seizures associated with abnormal electroencephalography \nand global developmental delay. Folinic acid-responsive seizures are treatable \ncauses of Ohtahara syndrome, which is thought to be due to recessive mutations \nin the ALDH7A1 gene, resulting in deficiency of antiquitin.\nMETHOD: Here we report a girl with Ohtahara syndrome who exhibited transient \nfolinic acid responsiveness but without evidence of antiquitin dysfunction.\nRESULTS: She was later found to have a known missense mutation (c.1439 C > T, \np.P480 L) in exon 16 of the STXBP1 gene.\nCONCLUSION: For infants presenting with Ohtahara syndrome with responsiveness to \nfolinic acid and negative antiquitin deficiency analyses, genetic testing for \nother possible causative genes such as STXBP1 mutation is recommended.", "Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with \nSuppression-Burst, is the most severe and the earliest developing age-related \nepileptic encephalopathy. Clinically, the syndrome is characterized by early \nonset tonic spasms associated with a severe and continuous pattern of burst \nactivity. It is a debilitating and early progressive neurological disorder, \nresulting in intractable seizures and severe mental retardation. Specific \nmutations in at least four genes (whose protein products are essential in lower \nbrain's neuronal and interneuronal functions, including mitochondrial \nrespiratory chains have been identified in unrelated individuals with EIEE and \ninclude: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 \nvariant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 \n(GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at \n9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship \nbetween early myoclonic encephalopathy (EME-ErbB4 mutations) versus the EIEE \nspectrum of disorders.", "PURPOSE: Dominant mutations in the STXBP1 gene are a recently identified cause \nof infantile epileptic encephalopathy without metabolic and structural brain \nanomalies. To date, 25 patients with heterozygous mutation or deletion of STXBP1 \nhave been reported. A diagnosis of early infantile epileptic encephalopathy with \nsuppression-burst (Ohtahara syndrome) was made in most of them, with infantile \nspasms and nonsyndromic infantile epileptic encephalopathy being the diagnosis \nin other patients. Although the phenotypic spectrum of STXBP1-related \nencephalopathy is emerging with evidence suggesting the relatively frequent \ninvolvement of this gene in infantile epileptic encephalopathies, accurate \nclinical descriptions of patients are still necessary to delineate this entity.\nMETHODS: The sequence of the STXPB1 gene was analyzed in 29 patients with early \nonset syndromic or nonsyndromic infantile epileptic encephalopathy without brain \nmagnetic resonance imaging (MRI) anomalies and with normal chromosomal and \nmetabolic checkup. Another patient with a complex phenotype was analyzed by \ncomparative genomic hybridization (CGH) array.\nKEY FINDINGS: From the studied series, 2 of 29 patients were found to carry a de \nnovo heterozygous mutation in STXBP1. One patient carried the recurrent \np.Arg406His mutation and the other an insertion of 10 bases leading to a \npremature termination codon. CGH array experiment detected a deletion of 3-3.5 \nMbp in the third patient with infantile epileptic encephalopathy and nail \nmalformations. All three had infantile spasms associated with partial seizures \nthat responded to antiepileptic drug therapy. Intellectual abilities were \nseverely impaired in all of them. Generalized tremor was the main neurologic \nstriking feature in the three patients, with one of them further displaying \nunilateral akinetic-hypertonic syndrome.\nSIGNIFICANCE: Mutations in STXBP1 are relatively frequent in patients with \ninfantile epileptic encephalopathies. STXBP1-related encephalopathy may present \nas drug-responsive infantile spasms with focal/lateralized discharges. \nGeneralized tremor appearing after the first year of life may be a clue to the \ndiagnosis in some patients.", "Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. \nBrain malformations or metabolic disorders are often associated with OS, but \nother cases remain etiologically unexplained. Here we show that de novo \nheterozygous mutations in the gene encoding STXBP1, also known as MUNC18-1, \nwhich is essential in synaptic vesicle release in multiple species, cause OS. A \nmicrodeletion involving STXBP1 and various point mutations, including missense, \nframeshift, nonsense, and splicing mutations, have been found in individuals \nwith OS. Transcripts associated with frameshift, nonsense, and splicing \nmutations are likely to be degraded by nonsense mediated mRNA decay. Moreover, \nSTXBP1 proteins harboring missense mutations were unstable compared with the \nwild-type, and were degraded in Neuroblastoma2A cells. Binding of a mutant \nprotein (p.C180Y) to syntaxin-1A was also significantly impaired. These findings \nstrongly suggest that haploinsufficiency of STXBP1 causes OS. Mutations of \nSTXBP1 also suggest that aberrations of genes involved in synaptic vesicle \nrelease might be associated with other types of infantile epilepsy.", "PURPOSE: Epilepsies have a highly heterogeneous background with a strong genetic \ncontribution. The variety of unspecific and overlapping syndromic and \nnonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents \nstraightforward genetic testing. Knowing the genetic basis of a patient's \nepilepsy can be valuable not only for diagnosis but also for guiding treatment \nand estimating recurrence risks.\nMETHODS: To overcome these diagnostic restrictions, we composed a panel of genes \nfor Next Generation Sequencing containing the most relevant epilepsy genes and \ncovering the most relevant epilepsy phenotypes known so far. With this method, \n265 genes were analyzed per patient in a single step. We evaluated this panel on \na pilot cohort of 33 index patients with concise epilepsy phenotypes or with a \nsevere but unspecific seizure disorder covering both sporadic and familial \ncases.\nKEY FINDINGS: We identified presumed disease-causing mutations in 16 of 33 \npatients comprising sequence alterations in frequently as well as in less \ncommonly affected genes. The detected aberrations encompassed known and unknown \npoint mutations (SCN1A p.R222X, p. E289V, p.379R, p.R393H; SCN2A p.V208E; STXBP1 \np.R122X; KCNJ10 p.L68P, p.I129V; KCTD7 p.L108M; KCNQ3 p.P574S; ARHGEF9 p.R290H; \nSMS p.F58L; TPP1 p.Q278R, p.Q422H; MFSD8 p.T294K), a putative splice site \nmutation (SCN1A c.693A> p.T/P231P) and small deletions (SCN1A p.F1330Lfs3X [1 \nbp]; MFSD8 p.A138Dfs10X [7 bp]). All mutations have been confirmed by \nconventional Sanger sequencing and, where possible, validated by parental \ntesting and segregation analysis. In three patients with either Dravet syndrome \nor myoclonic epilepsy, we detected SCN1A mutations (p.R222X, p.P231P, p.R393H), \neven though other laboratories had previously excluded aberrations of this gene \nby Sanger sequencing or high-resolution melting analysis.\nSIGNIFICANCE: We have developed a fast and cost-efficient diagnostic screening \nmethod to analyze the genetic basis of epilepsies. We were able to detect \nmutations in patients with clear and with unspecific epilepsy phenotypes, to \nuncover the genetic basis of many so far unresolved cases with epilepsy \nincluding mutation detection in cases in which previous conventional methods \nyielded falsely negative results. Our approach thus proved to be a powerful \ndiagnostic tool that may contribute to collecting information on both common and \nunknown epileptic disorders and in delineating associated phenotypes of less \nfrequently mutated genes.", "Mutations in STXBP1 have been identified in a subset of patients with early \nonset epileptic encephalopathy (EE), but the full phenotypic spectrum remains to \nbe delineated. Therefore, we screened a cohort of 160 patients with an \nunexplained EE, including patients with early myoclonic encephalopathy (EME), \nOhtahara syndrome, West syndrome, nonsyndromic EE with onset in the first year, \nand Lennox-Gastaut syndrome (LGS). We found six de novo mutations in six \npatients presenting as Ohtahara syndrome (2/6, 33%), West syndrome (1/65, 2%), \nand nonsyndromic early onset EE (3/64, 5%). No mutations were found in LGS or \nEME. Only two of four mutation carriers with neonatal seizures had Ohtahara \nsyndrome. Epileptic spasms were present in five of six patients. One patient \nwith normal magnetic resonance imaging (MRI) but focal seizures underwent \nepilepsy surgery and seizure frequency dropped drastically. Neuropathology \nshowed a focal cortical dysplasia type 1a. There is a need for additional \nneuropathologic studies to explore whether STXBP1 mutations can lead to \nstructural brain abnormalities.", "Infantile epileptic encephalopathies, such as Dravet syndrome, Ohtahara \nsyndrome, West syndrome, Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, \nand Landau-Kleffner syndrome, are devastating epilepsies. Cases are often \nsporadic or patients have only a limited family history of epilepsy. Although a \ncomplex inheritance has long been suspected in epilepsy, recent data indicate \nthat many sporadic rare epileptic disorders, such as Dravet syndrome, CDKL5/STK9 \nRett-like epileptic encephalopathy, ARX-related epilepsies, SRPX2-related \nrolandic epilepsy associated with oral and speech dyspraxia and mental \nretardation, and STXBP1-related West/Ohtahara syndromes, are due to a mutation \nin a unique gene. Dravet syndrome, for example, is mainly due to de novo \nmutations in SCN1A, the gene encoding the voltage-gated neuronal sodium channel \nalpha 1 subunit, which explains why most patients are isolated cases. All types \nof mutations are observed: missense mutations, premature termination codon and \nintragenic rearrangements. This large mutation spectrum contrasts with that of \ngeneralized epilepsy with febrile seizures plus (GEFS+), an autosomal dominant \ncondition also characterized by febrile and afebrile seizures but with a usually \nbenign outcome, in which only missense mutations are found. Recently, mutations \nin PCDH19, encoding protocadherin 19 on chromosome X, were identified in females \nwith an EFMR or Dravet-like phenotype. Heterozygous females are affected while \nhemizygous males are spared, this unusual inheritance probably being due to a \nmechanism called cellular interference. The genetic data accumulated for Dravet \nsyndrome and other related disorders have to be kept in mind when studying \nepileptic encephalopathies.", "PURPOSE: STXBP1 (MUNC18-1) mutations have been associated with various types of \nepilepsies, mostly beginning early in life. To refine the phenotype associated \nwith STXBP1 aberrations in early onset epileptic syndromes, we studied this gene \nin a cohort of patients with early onset epileptic encephalopathy.\nMETHODS: STXBP1 was screened in a multicenter cohort of 52 patients with early \nonset epilepsy (first seizure observed before the age of 3 months), no cortical \nmalformation on brain magnetic resonance imaging (MRI), and negative metabolic \nscreening. Three groups of patients could be distinguished in this cohort: (1) \nOhtahara syndromes (n = 38); (2) early myoclonic encephalopathies (n = 7); and \n(3) early onset epileptic encephalopathies that did not match any familiar \nsyndrome (n = 7). None of the patients displayed any cortical malformation on \nbrain MRI and all were screened through multiple video-electroencephalography \n(EEG) recordings for a time period spanning from birth to their sixth postnatal \nmonth. Subsequently, patients had standard EEG or video-EEG recordings.\nKEY FINDINGS: We found five novel STXBP1 mutations in patients for whom \nvideo-EEG recordings could be sampled from the beginning of the disease. All \npatients with a mutation displayed Ohtahara syndrome, since most early seizures \ncould be classified as epileptic spasms and since the silent EEG periods were on \naverage shorter than bursts. However, each patient in addition displayed a \nparticular clinical and EEG feature: In two patients, early seizures were \nclonic, with very early EEG studies exhibiting relatively low amplitude bursts \nof activity before progressing into a typical suppression-burst pattern, whereas \nthe three other patients displayed epileptic spasms associated with typical \nsuppression-burst patterns starting from the early recordings. Epilepsy \ndramatically improved after 6 months and finally disappeared before the end of \nthe first year of life for four patients; the remaining one patient had few \nseizures until 18 months of age. In parallel, EEG paroxysmal abnormalities \ndisappeared in three patients and decreased in two, giving place to continuous \nactivity with fast rhythms. Each patient displayed frequent nonepileptic \nmovement disorders that could easily be mistaken for epileptic seizures. These \nmovements could be observed as early as the neonatal period and, unlike \nseizures, persisted during all the follow-up period.\nSIGNIFICANCE: We confirm that STXBP1 is a major gene to screen in cases of \nOhtahara syndrome, since it is mutated in >10% of the Ohtahara patients within \nour cohort. This gene should particularly be tested in the case of a surprising \nevolution of the patient condition if epileptic seizures and EEG paroxysmal \nactivity disappear and are replaced by fast rhythms after the end of the first \npostnatal year.", "Mutations of the syntaxin binding protein 1 (STXBP1) have been associated with \nsevere infantile epileptic encephalopathies (Ohtahara syndrome and West \nsyndrome), but also with moderate to severe cognitive impairment and \nnonsyndromic epilepsy. We have studied a white infant who presented with focal \nseizures at age 2 weeks. Brain imaging was unremarkable. The \nelectroencephalograph (EEG) demonstrated normal background frequency content but \nwith multifocal sharp waves and no evidence of the typical patterns associated \nwith Ohtahara or West syndrome. Therapy with levetiracetam and oxcarbazepine \neffectively managed the seizure episodes. Investigation of genes associated with \ninfantile forms of epilepsy such as SCN1A, SCN1B, and ARX were negative, but we \nidentified a novel single-nucleotide duplication mutation, c.931dupT \n(p.S311FfsX3), in exon 11 of the STXBP1 gene. This previously unreported STXBP1 \nmutation in a subject with neonatal-onset focal seizures broadens the spectrum \nof clinically relevant human disorders caused by STXBP1 mutations.", "Early infantile epileptic encephalopathy with suppression-burst (EIEE), also \nknown as Ohtahara syndrome, is one of the most severe and earliest forms of \nepilepsy. Using array-based comparative genomic hybridization, we found a de \nnovo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation \nanalysis of candidate genes mapped to the deletion revealed that four unrelated \nindividuals with EIEE had heterozygous missense mutations in the gene encoding \nsyntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an \nevolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in \nsynaptic vesicle release in several species. Circular dichroism melting \nexperiments revealed that a mutant form of the protein was significantly \nthermolabile compared to wild type. Furthermore, binding of the mutant protein \nto syntaxin was impaired. These findings suggest that haploinsufficiency of \nSTXBP1 causes EIEE.", "OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding \nprotein 1, have recently been identified in Ohtahara syndrome, an epileptic \nencephalopathy with very early onset. In order to explore the phenotypic \nspectrum associated with STXBP1 mutations, we analyzed a cohort of patients with \nunexplained early-onset epileptic encephalopathies.\nMETHODS: We collected and clinically characterized 106 patients with early-onset \nepileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using \nsequence analysis of the exon and intron-exon boundaries and multiplex \namplification quantification to detect copy number variations.\nRESULTS: We identified 4 truncating mutations and 2 microdeletions partially \naffecting STXBP1 in 6 of the 106 patients. All mutations are predicted to \nabolish STXBP1 function and 5 mutations were proven to occur de novo. None of \nthe mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed \nwith West syndrome at disease onset, while the initial phenotype of 5 further \npatients did not fit into a specific recognized epilepsy syndrome. Three of \nthese patients later evolved to West syndrome. All patients had severe to \nprofound mental retardation, and ataxia or dyskinetic movements were present in \n5 patients.\nCONCLUSION: This study shows that mutations in STXBP1 are not limited to \npatients with Ohtahara syndrome, but are also present in 10% (5/49) of patients \nwith an early-onset epileptic encephalopathy that does not fit into either \nOhtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational \nanalysis should be considered in the diagnostic evaluation of this challenging \ngroup of patients.", "Author information:\n(1)Department of Neuropediatrics, Centre de Reference des Epilepsies Rares, \nHopital Necker Enfants Malades, Paris Descartes University, Paris, France; \nInserm U663, University Paris Descartes, PRES Sorbonne Paris Cité, Paris \nF-75005; CEA, Neurospin, 91190 Gif/Yvette, France.\n(2)Department of Genetics, Inserm U781, Hopital Necker Enfants Malades, Paris \nDescartes University, Paris, France.\n(3)APHM, CINAPSE, Pediatric Neurology Department, Timone Children Hospital, \nMarseille, France.\n(4)Department of Pediatric Neurology, Hôpital Erasme, Bruxelles, Belgium.\n(5)Department of Neuropediatrics, Centre de Reference des Epilepsies Rares, \nHopital Necker Enfants Malades, Paris Descartes University, Paris, France.\n(6)Department of Pediatric Radiology, Hopital Necker Enfants Malades, APHP, \nParis, Descartes University, Paris, France.\n(7)Department of Neuropediatrics, Centre de Reference des Epilepsies Rares, \nHopital Necker Enfants Malades, Paris Descartes University, Paris, France. \nElectronic address: rima.nabbout@nck.aphp.fr.", "Early-onset epileptic encephalopathies (EOEEs) are characterised by epileptic \nseizures beginning in the first months of life, abnormal background EEG \nactivity, and are associated with severe developmental delay and poor prognosis. \nMutations and deletions in the STXBP1 gene are associated with Ohtahara \nsyndrome, also known as \"early infantile epileptic encephalopathy\". We report an \ninfant affected by EOEE with a 9q34.11 deletion that encompassed the genes \nSTXBP1 and SPTAN1. The infant presented with neonatal encephalopathy without \nepileptic seizures and an EEG pattern varying from highly discontinuous to \nsuppression-burst. This was followed by West syndrome at 2 months with atypical \nhypsarrhythmia and spasms, easily controlled by therapy. Our findings suggest \nthat molecular analysis of STXBP1 should be considered for newborns affected by \nneonatal encephalopathy associated with a peculiar EEG pattern, even in the \nabsence of neonatal epileptic seizures.", "The ARX gene is involved in the development of GABAergic interneurons in the \nforebrain. Loss-of-function mutations, such as nonsense or frameshifts mutation, \nof ARX cause a group of brain malformations, such as hydranencephaly, \nlissencephaly, and agenesis of the corpus callosum, while expansion mutations of \nthe polyalanine tracts of ARX, supposed to be gain-of-function mutations, result \nin a non-malformation group, such as non-syndromic mental retardation, mental \nretardation with dystonia, West syndrome, and Ohtahara syndrome. A variety of \nphenotypes caused by pleiotropic mutations of the ARX gene are considered to \nshare a common pathological mechanism connected with the structural and \nfunctional disturbance of interneurons, designated as 'interneuronopathies'. We \nidentified the second gene responsible for Ohtahara syndrome, STXBP1, which is \nessential for synaptic vesicle release. Molecular studies of the diseases will \nreveal the relationships between the structure and function of the brain. It is \nindispensable to clarify the etiology of hereditary diseases and identify new \napproaches to treatment.", "PURPOSE: De novo STXBP1 mutations have been found in individuals with early \ninfantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our \naim was to delineate the clinical spectrum of subjects with STXBP1 mutations, \nand to examine their biologic aspects.\nMETHODS: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West \nsyndrome, respectively, as a second cohort. RNA splicing was analyzed in \nlymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. \nExpression of STXBP1 protein with missense mutations was examined in \nneuroblastoma2A cells.\nRESULTS: A total of seven novel STXBP1 mutations were found in nine EIEE cases, \nbut not in West syndrome. The mutations include two frameshift mutations, three \nnonsense mutations, a splicing mutation, and a recurrent missense mutation in \nthree unrelated cases. Including our previous data, 10 of 14 individuals (71%) \nwith STXBP1 aberrations had the onset of spasms after 1 month, suggesting \nrelatively later onset of epileptic spasms. Nonsense-mediated mRNA decay \nassociated with abnormal splicing was demonstrated. Transient expression \nrevealed that STXBP1 proteins with missense mutations resulted in degradation in \nneuroblastoma2A cells.\nDISCUSSION: Collectively, STXBP1 aberrations can account for about one-third \nindividuals with EIEE (14 of 43). These genetic and biologic data clearly showed \nthat haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.", "We performed STXBP1 mutation analyses in 86 patients with various types of \nepilepsies, including 10 patients with OS, 43 with West syndrome, 2 with \nLennox-Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with \nsymptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. \nIn all patients, the etiology was unknown, but ARX and CDKL5 mutations were \nnegative in all cases. All coding exons of STXBP1 were analyzed by \ndirect-sequencing. Two de novo nucleotide alterations of STXBP1 were identified \nin two patients with Ohtahara and West syndrome, respectively. No de novo or \ndeleterious mutations in STXBP1 were found in the remaining 84 patients with \nvarious types of symptomatic epilepsies. This is the first case report showing \nthat STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 \nanalysis should be considered as an etiology of symptomatic West syndrome \nwithout explainable cause.", "STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in \nOhtahara syndrome, a rare epileptic encephalopathy with suppression burst \npattern on EEG, in patients with infantile spasms and in a few patients with \nnonsyndromic mental retardation without epilepsy. We report a patient who \npresented late onset infantile spasms. Epilepsy was controlled but the patient \ndeveloped severe mental delay. A first diagnosis of mitochondrial disease was \nbased on clinical presentation and on a partial deficit of respiratory chain \ncomplex IV, but molecular screening for mitochondrial genes was negative. The \nsequencing of STXBP1 gene found a de novo nonsense mutation \n(c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to \nSTXBP1 mutations with the description of a patient with late onset infantile \nspasms. It raises the question of the value of epilepsy genes screening in \npatients with uncertain, partial or unconfirmed mitochondrial dysfunction.", "PURPOSE: Pyridoxine-dependent epilepsy (PDE) is characterized by \ntherapy-resistant seizures (TRS) responding to intravenous (IV) pyridoxine. PDE \ncan be identified by increased urinary alpha-aminoadipic semialdehyde (α-AASA) \nconcentrations and mutations in the ALDH7A1 (antiquitin) gene. Prompt \nrecognition of PDE is important for treatment and prognosis of seizures. We \naimed to determine whether immediate electroencephalography (EEG) alterations by \npyridoxine-IV can identify PDE in neonates with TRS.\nMETHODS: In 10 neonates with TRS, we compared online EEG alterations by \npyridoxine-IV between PDE (n = 6) and non-PDE (n = 4). EEG segments were \nvisually and digitally analyzed for average background amplitude and total power \nand relative power (background activity magnitude per frequency band and \ncontribution of the frequency band to the spectrum).\nRESULTS: In 3 of 10 neonates with TRS (2 of 6 PDE and 1 of 4 non-PDE neonates), \npyridoxine-IV caused flattening of the EEG amplitude and attenuation of \nepileptic activity. Quantitative EEG alterations by pyridoxine-IV consisted of \n(1) decreased central amplitude, p < 0.05 [PDE: median -30% (range -78% to -3%); \nnon-PDE: -20% (range -45% to -12%)]; (2) unaltered relative power; (3) decreased \ntotal power, p < 0.05 [PDE: -31% (-77% to -1%); -27% (-73% to -13%); -35% (-56% \nto -8%) and non-PDE: -16% (-43% to -5%); -28% (-29% to -17%); -26% (-54% to \n-8%), in delta-, theta- and beta-frequency bands, respectively]; and (4) similar \nEEG responses in PDE and non-PDE.\nDISCUSSION: In neonates with TRS, pyridoxine-IV induces nonspecific EEG \nresponses that neither identify nor exclude PDE. These data suggest that \nneonates with TRS should receive pyridoxine until PDE is fully excluded by \nmetabolic and/or DNA analysis.", "OBJECTIVE: To determine the genetic etiology of the severe early infantile onset \nsyndrome of malignant migrating partial seizures of infancy (MPSI).\nMETHODS: Fifteen unrelated children with MPSI were screened for mutations in \ngenes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, \nSTXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy \nnumber variations.\nRESULTS: One patient had a de novo SCN1A missense mutation p.R862G that affects \nthe voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb \ndeletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included \nSCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 \nfemales), and the 3 common European mutations of POLG (11/15) was negative. \nPathogenic copy number variations were not detected in 11/12 cases.\nCONCLUSION: Epilepsies associated with SCN1A mutations range in severity from \nfebrile seizures to severe epileptic encephalopathies including Dravet syndrome \nand severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A \nphenotype described to date. While not a common cause of MPSI, SCN1A screening \nshould now be considered in patients with this devastating epileptic \nencephalopathy.", "STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of \nsecretory vesicles to the presynaptic membrane for the release of \nneurotransmitters. De novo missense mutations in STXBP1 were recently reported \nin patients with Ohtahara syndrome, a form of encephalopathy with severe \nearly-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in \n95 patients with non-syndromic intellectual disability (NSID) revealed de novo \ntruncating mutations in two patients who also showed severe non-specific \nepilepsy, suggesting that STXBP1 disruption has the potential of causing a wide \nspectrum of epileptic disorders in association with intellectual disability. \nHere, we report on the mutational screening of STXBP1 in a different series of \n50 patients with NSID and the identification of a novel de novo truncating \nmutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no \nhistory of epilepsy. This is the first report of a patient with a truncating \nmutation in STXBP1 that does not show epilepsy, thus, expanding the clinical \nspectrum associated with STXBP1 disruption.", "We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, \nSNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are \nessential for neurotransmission, in 95 patients with idiopathic mental \nretardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; \nsplicing, c.169+1G>A) in two patients with severe mental retardation and \nnonsyndromic epilepsy. Reverse transcriptase polymerase chain reaction and \nsequencing showed that the splicing mutation creates a stop codon downstream of \nexon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control \nsubjects, or in 142 autistic patients. These results suggest that STXBP1 \ndisruption is associated with autosomal dominant mental retardation and \nnonsyndromic epilepsy.", "PURPOSE: A number of genes in the 9q34.11 region may be haploinsufficient. \nHowever, studies analyzing genotype-phenotype correlations of deletions \nencompassing multiple dosage-sensitive genes in the region are lacking.\nMETHODS: We mapped breakpoints of 10 patients with 9q34.11 deletions using \nhigh-resolution 9q34-specific array comparative genomic hybridization (CGH) to \ndetermine deletion size and gene content.\nRESULTS: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients \nexhibit intellectual disability and share a common deleted region including \nSTXBP1; four manifest variable epilepsy. In five subjects, deletions include \nSPTAN1, previously associated with early infantile epileptic encephalopathy, \ninfantile spasms, intellectual disability, and hypomyelination. In four \npatients, the deletion includes endoglin (ENG), causative of hereditary \nhemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, \nof which molecular defects lead to early-onset primary dystonia. Ninety-four \nother RefSeq genes also map to the genomic intervals investigated.\nCONCLUSION: STXBP1 haploinsufficiency results in progressive encephalopathy \ncharacterized by intellectual disability and may be accompanied by epilepsy, \nmovement disorders, and autism. We propose that 9q34.11 genomic deletions \ninvolving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic \nvascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual \ndisability, therefore revealing cis-genetic effects leading to complex \nphenotypes." ]	['http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009154', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004829', 'http://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&exact=Find+Exact+Term&term=D059645', 'http://www.disease-ontology.org/api/metadata/DOID:1826', 'http://www.uniprot.org/uniprot/STXB1_PONAB']
5a87efa961bb38fb2400000e	[ 19475561, 17581973 ]	train	Are mutations in the nf1 gene associated with memory?	yesno	Yes, distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation.	yes	[ "Neurofibromatosis 1 (NF1) is a common single-gene disorder that causes learning \nimpairments in patients. Neurofibromin encoded by the NF1 causal gene regulates \nRas/MAPK and cAMP signaling pathways. These signaling pathways play critical \nroles in controlling gene transcription during synaptic plasticity and memory \nformation. We hypothesized that NF1 mutations disturb the expression of genes \nimportant for memory formation. To test this hypothesis, we performed DNA \nmicroarray analysis on the hippocampus of NF1(+/-) mice, the mouse model for NF1 \nlearning disabilities. Our results indicated that genes involved in a wide \nspectrum of biological processes are dysregulated in the NF1(+/-) hippocampus. \nMany of the NF1-affected genes play critical roles in synaptic plasticity, such \nas Rabs, synaptotagmins, NMDAR1, CaMKII, and CREB1. Because NF1-associated \nlearning disabilities can be reversed by lovastatin, we also determined the \neffect of lovastatin treatment on genome-wide expression patterns of the \nNF1(+/-) hippocampus. We found that lovastatin altered the expression of a large \nnumber of genes, including those disturbed by NF1 mutations. Our results reveal \na genome-wide overview of the molecular abnormalities in the NF1(+/-) \nhippocampus and should be useful for further identifying the novel molecular \npathways that cause NF1 learning deficits.", "Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors \nof the peripheral nervous system. In addition, >40% of afflicted children have \nlearning difficulties. The NF1 protein contains a highly conserved \nGTPase-activating protein domain that inhibits Ras activity, and the C-terminal \nregion regulates cAMP levels via G-protein-dependent activation of adenylyl \ncyclase. Behavioral analysis indicates that learning is disrupted in both \nDrosophila and mouse NF1 models. Our previous work has shown that defective cAMP \nsignaling leads to the learning phenotype in Drosophila Nf1 mutants. In the \npresent report, our experiments showed that in addition to learning, long-term \nmemory was also abolished in Nf1 mutants. However, altered NF1-regulated Ras \nactivity is responsible for this defect rather than altered cAMP levels. \nFurthermore, by expressing clinically relevant human NF1 mutations and deletions \nin Drosophila Nf1-null mutants, we demonstrated that the GAP-related domain of \nNF1 was necessary and sufficient for long-term memory, whereas the C-terminal \ndomain of NF1 was essential for immediate memory. Thus, we show that two \nseparate functional domains of the same protein can participate independently in \nthe formation of two distinct memory components." ]	nan
5a8866958cb19eca6b000003	[ 28643105, 28154140, 27725662, 27664583 ]	train	Are neurexins localized at pre-synapses?	yesno	Yes, neurexins are localized at pre-synapses.	yes	[ "Perisomatic GABAergic synapses onto hippocampal pyramidal cells arise from two \npopulations of basket cells with different neurochemical and functional \nproperties. The presence of the dystrophin-glycoprotein complex in their \npostsynaptic density (PSD) distinguishes perisomatic synapses from GABAergic \nsynapses on dendrites and the axon-initial segment. Targeted deletion of \nneuroligin 2 (NL2), a transmembrane protein interacting with presynaptic \nneurexin, has been reported to disrupt postsynaptic clustering of GABAA \nreceptors (GABAAR) and their anchoring protein, gephyrin, at perisomatic \nsynapses. In contrast, targeted deletion of Gabra2 disrupts perisomatic \nclustering of gephyrin, but not of α1-GABAAR, NL2, or dystrophin/dystroglycan. \nUnexpectedly, conditional deletion of Dag1, encoding dystroglycan, selectively \nprevents the formation of perisomatic GABAergic synapses from basket cells \nexpressing cholecystokinin. Collectively, these observations suggest that \nmultiple mechanisms regulate formation and molecular composition of the \nGABAergic PSD at perisomatic synapses. Here, we further explored this issue by \ninvestigating the effect of targeted deletion of Gabra1 and NL2 on the \ndystrophin-glycoprotein complex and on perisomatic synapse formation, using \nimmunofluorescence analysis with a battery of GABAergic pre- and postsynaptic \nmarkers. We show that the absence of α1-GABAAR increases GABAergic synapses \ncontaining the α2 subunit, without affecting the clustering of dystrophin and \nNL2; in contrast, the absence of NL2 produces highly variable effects \npostsynaptically, not restricted to perisomatic synapses and being more severe \nfor the GABAAR subunits and gephyrin than dystrophin. Altogether, the results \nconfirm the importance of NL2 as organizer of the GABAergic PSD and unravel \ndistinct roles for α1- and α2-GABAARs in the formation of GABAergic circuits in \nclose interaction with the dystrophin-glycoprotein complex.", "Establishment, specification, and validation of synaptic connections are thought \nto be mediated by interactions between pre- and postsynaptic cell-adhesion \nmolecules. Arguably, the best-characterized transsynaptic interactions are \nformed by presynaptic neurexins, which bind to diverse postsynaptic ligands. In \na proteomic screen of neurexin-1 (Nrxn1) complexes immunoisolated from mouse \nbrain, we identified carbonic anhydrase-related proteins CA10 and CA11, two \nhomologous, secreted glycoproteins of unknown function that are predominantly \nexpressed in brain. We found that CA10 directly binds in a cis configuration to \na conserved membrane-proximal, extracellular sequence of α- and β-neurexins. The \nCA10-neurexin complex is stable and stoichiometric, and results in formation of \nintermolecular disulfide bonds between conserved cysteine residues in neurexins \nand CA10. CA10 promotes surface expression of α- and β-neurexins, suggesting \nthat CA10 may form a complex with neurexins in the secretory pathway that \nfacilitates surface transport of neurexins. Moreover, we observed that the Nrxn1 \ngene expresses from an internal 3' promoter a third isoform, Nrxn1γ, that lacks \nall Nrxn1 extracellular domains except for the membrane-proximal sequences and \nthat also tightly binds to CA10. Our data expand the understanding of \nneurexin-based transsynaptic interaction networks by providing further insight \ninto the interactions nucleated by neurexins at the synapse.", "Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic \nneurexins. Mutations in neuroligin-3 predispose to autism, but how such \nmutations affect synaptic function remains incompletely understood. Here we \nsystematically examined the effect of three autism-associated mutations, the \nneuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic \ntransmission in the calyx of Held, a central synapse ideally suited for \nhigh-resolution analyses of synaptic transmission. Surprisingly, germline \nknockout of neuroligin-3 did not alter synaptic transmission, whereas the \nneuroligin-3 R451C and R704C knockins decreased and increased, respectively, \nsynaptic transmission. These puzzling results prompted us to ask whether \nneuroligin-3 mutant phenotypes may be reshaped by developmental plasticity. \nIndeed, conditional knockout of neuroligin-3 during late development produced a \nmarked synaptic phenotype, whereas conditional knockout of neuroligin-3 during \nearly development caused no detectable effect, mimicking the germline knockout. \nIn canvassing potentially redundant candidate genes, we identified \ndevelopmentally early expression of another synaptic neurexin ligand, \ncerebellin-1. Strikingly, developmentally early conditional knockout of \ncerebellin-1 only modestly impaired synaptic transmission, whereas in contrast \nto the individual single knockouts, developmentally early conditional double \nknockout of both cerebellin-1 and neuroligin-3 severely decreased synaptic \ntransmission. Our data suggest an unanticipated mechanism of developmental \ncompensation whereby cerebellin-1 and neuroligin-3 functionally occlude each \nother during development of calyx synapses. Thus, although acute manipulations \nmore likely reveal basic gene functions, developmental plasticity can be a major \nfactor in shaping the overall phenotypes of genetic neuropsychiatric disorders.", "Neurexins and neuroligins are two distinct families of single-pass transmembrane \nproteins localized at pre- and postsynapses, respectively. They \ntrans-synaptically interact with each other and induce synapse formation and \nmaturation. Common variants and rare mutations, including copy number \nvariations, short deletions, and single or small nucleotide changes in neurexin \nand neuroligin genes have been linked to the neurodevelopmental disorders, such \nas autism spectrum disorders (ASDs). In this review, we summarize the structure \nand basic synaptic function of neurexins and neuroligins, followed by behaviors \nand synaptic phenotypes of knock-in and knock-out mouse of these family genes. \nFrom the studies of these mice, it turns out that the effects of neurexins and \nneuroligins are amazingly neural circuit dependent, even within the same brain \nregion. In addition, neurexins and neuroligins are commonly involved in the \nendocannabinoid signaling. These finding may provide not only insight into \nunderstanding the pathophysiology, but also the concept for strategy of \ntherapeutic intervention for ASDs." ]	nan
513596225274a5fb0700000d	[ 20351051, 1587867, 21148149, 19463783 ]	train	Are nucleosomes positioned at DNA replication origins?	yesno	No, origins of replication occur in nucleosome-free regions in both budding yeast and Drosophila. Open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication.	no	[ "The origin recognition complex (ORC) specifies replication origin location. The \nSaccharomyces cerevisiae ORC recognizes the ARS (autonomously replicating \nsequence) consensus sequence (ACS), but only a subset of potential genomic sites \nare bound, suggesting other chromosomal features influence ORC binding. Using \nhigh-throughput sequencing to map ORC binding and nucleosome positioning, we \nshow that yeast origins are characterized by an asymmetric pattern of positioned \nnucleosomes flanking the ACS. The origin sequences are sufficient to maintain a \nnucleosome-free origin; however, ORC is required for the precise positioning of \nnucleosomes flanking the origin. These findings identify local nucleosomes as an \nimportant determinant for origin selection and function.", "Circular duplex DNA containing the SV40 replication origin was assembled into \nchromosomes in vitro with core histones and nucleosome assembly factor from HeLa \ncells. Their ability to serve as a template for replication was examined by \nincubating them with SV40 T antigen and HeLa cell extract. Nucleosome assembly \nof the template prevented DNA replication. Replication of chromosomes was \nseverely inhibited at more than two-thirds of physiological nucleosome density. \nWhen the DNA was preincubated with T antigen and then assembled into \nchromosomes, however, inhibition of DNA replication was greatly reduced. These \nresults suggest that nucleosome assembly of the template inhibits initiation of \nSV40 DNA replication and that the inhibition can be overcome by formation of an \ninitiation complex before nucleosome assembly.", "Genome-scale mapping of pre-replication complex proteins has not been reported \nin mammalian cells. Poor enrichment of these proteins at specific sites may be \ndue to dispersed binding, poor epitope availability or cell cycle stage-specific \nbinding. Here, we have mapped sites of biotin-tagged ORC and MCM protein binding \nin G1-synchronized populations of Chinese hamster cells harboring amplified \ncopies of the dihydrofolate reductase (DHFR) locus, using avidin-affinity \npurification of biotinylated chromatin followed by high-density microarray \nanalysis across the DHFR locus. We have identified several sites of significant \nenrichment for both complexes distributed throughout the previously identified \ninitiation zone. Analysis of the frequency of initiations across stretched DNA \nfibers from the DHFR locus confirmed a broad zone of de-localized initiation \nactivity surrounding the sites of ORC and MCM enrichment. Mapping positions of \nmononucleosomal DNA empirically and computing nucleosome-positioning information \nin silico revealed that ORC and MCM map to regions of low measured and predicted \nnucleosome occupancy. Our results demonstrate that specific sites of ORC and MCM \nenrichment can be detected within a mammalian initiation zone, and suggest that \ninitiation zones may be regions of generally low nucleosome occupancy where \nflexible nucleosome positioning permits flexible pre-RC assembly sites.", "The distribution of DNA replication origins (ORIs) on eukaryotic chromosomes is \nnonrandom, but the reasons behind this are not well understood. Previous studies \nhave suggested a prominent role of transcriptional activity in determining the \nORI organization. Here, we identify nucleosome occupancy as a likely candidate \nto set up ORI distribution. Combining genome-wide data on nucleosome positioning \nand ORI organization in yeast and humans, we demonstrate that open chromatin \ndomains, characterized by nucleosome depletion, are preferentially permissive \nfor replication. However, contrary to priori claims, the impact of \ntranscriptional activity is considerably weaker than previously proposed and \ncould partly be explained by our nucleosome exclusion model. We propose that the \nORI organization imposed by nucleosome positioning is phylogenetically \nwidespread in eukaryotes." ]	['http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D018741', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D009707', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D051738', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004261', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D042522', 'http://www.nlm.nih.gov/cgi/mesh/2012/MB_cgi?field=uid&exact=Find+Exact+Term&term=D051716']
56e0797451531f7e3300000f	[ 23340416, 19581573, 24965021, 25012388, 25678887, 24005292, 25451697, 24491965, 23637949, 23406911, 24590406, 22698957, 22890709, 23143518, 24573293, 25710834, 25303540, 23871610, 25108607 ]	train	Are optogenetics tools used in the study and treatment of epilepsy?	yesno	Using optogenetics tools it is possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies.	yes	[ "Temporal lobe epilepsy is the most common type of epilepsy in adults, is often \nmedically refractory, and due to broad actions and long-time scales, current \nsystemic treatments have major negative side-effects. However, temporal lobe \nseizures tend to arise from discrete regions before overt clinical behaviour, \nmaking temporally and spatially specific treatment theoretically possible. Here \nwe report the arrest of spontaneous seizures using a real-time, closed-loop, \nresponse system and in vivo optogenetics in a mouse model of temporal lobe \nepilepsy. Either optogenetic inhibition of excitatory principal cells, or \nactivation of a subpopulation of GABAergic cells representing <5% of hippocampal \nneurons, stops seizures rapidly upon light application. These results \ndemonstrate that spontaneous temporal lobe seizures can be detected and \nterminated by modulating specific cell populations in a spatially restricted \nmanner. A clinical approach built on these principles may overcome many of the \nside-effects of currently available treatment options.", "The optogenetic approach to gain control over neuronal excitability both in \nvitro and in vivo has emerged as a fascinating scientific tool to explore \nneuronal networks, but it also opens possibilities for developing novel \ntreatment strategies for neurologic conditions. We have explored whether such an \noptogenetic approach using the light-driven halorhodopsin chloride pump from \nNatronomonas pharaonis (NpHR), modified for mammalian CNS expression to \nhyperpolarize central neurons, may inhibit excessive hyperexcitability and \nepileptiform activity. We show that a lentiviral vector containing the NpHR gene \nunder the calcium/calmodulin-dependent protein kinase IIalpha promoter \ntransduces principal cells of the hippocampus and cortex and hyperpolarizes \nthese cells, preventing generation of action potentials and epileptiform \nactivity during optical stimulation. This study proves a principle, that \nselective hyperpolarization of principal cortical neurons by NpHR is sufficient \nto curtail paroxysmal activity in transduced neurons and can inhibit stimulation \ntrain-induced bursting in hippocampal organotypic slice cultures, which \nrepresents a model tissue of pharmacoresistant epilepsy. This study demonstrates \nthat the optogenetic approach may prove useful for controlling epileptiform \nactivity and opens a future perspective to develop it into a strategy to treat \nepilepsy.", "New genetic investigation techniques, including next-generation sequencing, \nepigenetic profiling, cell lineage mapping, targeted genetic manipulation of \nspecific neuronal cell types, stem cell reprogramming, and optogenetic \nmanipulations within epileptic networks are progressively unraveling the \nmysteries of epileptogenesis and ictogenesis. These techniques have opened new \navenues to discover the molecular basis of epileptogenesis and to study the \nphysiologic effects of mutations in epilepsy-associated genes on a multilayer \nlevel, from cells to circuits. This manuscript reviews recently published \napplications of these new genetic technologies in the study of epilepsy, as well \nas work presented by the authors at the genetic session of the XII Workshop on \nthe Neurobiology of Epilepsy (WONOEP 2013) in Quebec, Canada. Next-generation \nsequencing is providing investigators with an unbiased means to assess the \nmolecular causes of sporadic forms of epilepsy and has revealed the complexity \nand genetic heterogeneity of sporadic epilepsy disorders. To assess the \nfunctional impact of mutations in these newly identified genes on specific \nneuronal cell types during brain development, new modeling strategies in \nanimals, including conditional genetics in mice and in utero knock-down \napproaches, are enabling functional validation with exquisite cell-type and \ntemporal specificity. In addition, optogenetics, using cell-type-specific Cre \nrecombinase driver lines, is enabling investigators to dissect networks involved \nin epilepsy. In addition, genetically encoded cell-type labeling is providing \nnew means to assess the role of the nonneuronal components of epileptic networks \nsuch as glial cells. Furthermore, beyond its role in revealing coding variants \ninvolved in epileptogenesis, next-generation sequencing can be used to assess \nthe epigenetic modifications that lead to sustained network hyperexcitability in \nepilepsy, including methylation changes in gene promoters and noncoding \nribonucleic acid (RNA) involved in modifying gene expression following seizures. \nIn addition, genetically based bioluminescent reporters are providing new \nopportunities to assess neuronal activity and neurotransmitter levels both in \nvitro and in vivo in the context of epilepsy. Finally, genetically rederived \nneurons generated from patient induced pluripotent stem cells and genetically \nmodified zebrafish have become high-throughput means to investigate disease \nmechanisms and potential new therapies. Genetics has changed the field of \nepilepsy research considerably, and is paving the way for better diagnosis and \ntherapies for patients with epilepsy.", "Recent technological advances open exciting avenues for improving the \nunderstanding of mechanisms in a broad range of epilepsies. This chapter focuses \non the development of optogenetics and on-demand technologies for the study of \nepilepsy and the control of seizures. Optogenetics is a technique which, through \ncell-type selective expression of light-sensitive proteins called opsins, allows \ntemporally precise control via light delivery of specific populations of \nneurons. Therefore, it is now possible not only to record interictal and ictal \nneuronal activity, but also to test causality and identify potential new \ntherapeutic approaches. We first discuss the benefits and caveats to using \noptogenetic approaches and recent advances in optogenetics related tools. We \nthen turn to the use of optogenetics, including on-demand optogenetics in the \nstudy of epilepsies, which highlights the powerful potential of optogenetics for \nepilepsy research.", "The holy grail of epilepsy research is to understand the mechanisms underlying \nseizures so that patients with epilepsy can receive effective treatment or be \ncured, ideally with no significant side effects. Recent advances in neuroscience \ngive such hope. Optogenetics is a modern neuroscience research tool that allows \nprecise spatiotemporal control of defined cells and circuits and, thus, \ndissection of critical players and targeting them for responsive treatments. \nHere we review the state of the art of these approaches and their applications \nand implications in epilepsy research.", "Axonal sprouting of excitatory neurons is frequently observed in temporal lobe \nepilepsy, but the extent to which inhibitory interneurons undergo similar axonal \nreorganization remains unclear. The goal of this study was to determine whether \nsomatostatin (SOM)-expressing neurons in stratum (s.) oriens of the hippocampus \nexhibit axonal sprouting beyond their normal territory and innervate granule \ncells of the dentate gyrus in a pilocarpine model of epilepsy. To obtain \nselective labeling of SOM-expressing neurons in s. oriens, a Cre \nrecombinase-dependent construct for channelrhodopsin2 fused to enhanced yellow \nfluorescent protein (ChR2-eYFP) was virally delivered to this region in SOM-Cre \nmice. In control mice, labeled axons were restricted primarily to s. \nlacunosum-moleculare. However, in pilocarpine-treated animals, a rich plexus of \nChR2-eYFP-labeled fibers and boutons extended into the dentate molecular layer. \nElectron microscopy with immunogold labeling demonstrated labeled axon terminals \nthat formed symmetric synapses on dendritic profiles in this region, consistent \nwith innervation of granule cells. Patterned illumination of ChR2-labeled fibers \nin s. lacunosum-moleculare of CA1 and the dentate molecular layer elicited \nGABAergic inhibitory responses in dentate granule cells in pilocarpine-treated \nmice but not in controls. Similar optical stimulation in the dentate hilus \nevoked no significant responses in granule cells of either group of mice. These \nfindings indicate that under pathological conditions, SOM/GABAergic neurons can \nundergo substantial axonal reorganization beyond their normal territory and \nestablish aberrant synaptic connections. Such reorganized circuitry could \ncontribute to functional deficits in inhibition in epilepsy, despite the \npresence of numerous GABAergic terminals in the region.", "Epilepsy is a neurological disorder that affects around 1% of the population \nworldwide. The two main therapies, pharmacology and the electrical stimulation, \nboth have some shortcomings. For instance, pharmacological therapy is frequently \naccompanied by side effects, and current anticonvulsive drugs fail to be \neffective to around a third of patients. These patients could suffer \nastrocyte-related epilepsy, as increasing evidence indicates that dysfunctions \nof astrocytes can result in epilepsy. However, epilepsy drugs that affect \nastrocytes are not available currently. Although electrical stimulation has \nbenefited many patients, the electrode stimulates unselective neurons or \ncircuits. All these need to develop new strategies for improving the life of the \npatients. As channelrhodopsins (ChRs) were discovered, a novel method referred \nto as \"optogenetics\" was developed. It has advantages over electrical \nstimulation of being less-invasiveness and allowing spatiotemporally \nstimulation. Recently, a number of experiments have explored the treatments for \nepilepsy with optogenetic control of neurons. Here, we discuss the possibility \nthat an optogenetic approach could be used to control the release of \ngliotransmitters and improve astrocyte function such as glutamate and K(+) \nuptake, and thereby offer a potential strategy to investigate and treat \nastrocyte-related epilepsy.", "Synchronized activity is common during various physiological operations but can \nculminate in seizures and consequently in epilepsy in pathological \nhyperexcitable conditions in the brain. Many types of seizures are not possible \nto control and impose significant disability for patients with epilepsy. Such \nintractable epilepsy cases are often associated with degeneration of inhibitory \ninterneurons in the cortical areas resulting in impaired inhibitory drive onto \nthe principal neurons. Recently emerging optogenetic technique has been proposed \nas an alternative approach to control such seizures but whether it may be \neffective in situations where inhibitory processes in the brain are compromised \nhas not been addressed. Here we used pharmacological and optogenetic techniques \nto block inhibitory neurotransmission and induce epileptiform activity in vitro \nand in vivo. We demonstrate that NpHR-based optogenetic hyperpolarization and \nthereby inactivation of a principal neuronal population in the hippocampus is \neffectively attenuating seizure activity caused by disconnected network \ninhibition both in vitro and in vivo. Our data suggest that epileptiform \nactivity in the hippocampus caused by impaired inhibition may be controlled by \noptogenetic silencing of principal neurons and potentially can be developed as \nan alternative treatment for epilepsy.", "Epilepsy is a devastating disease, currently treated with medications, surgery \nor electrical stimulation. None of these approaches is totally effective and our \nability to control seizures remains limited and complicated by frequent side \neffects. The emerging revolutionary technique of optogenetics enables \nmanipulation of the activity of specific neuronal populations in vivo with \nexquisite spatiotemporal resolution using light. We used optogenetic approaches \nto test the role of hippocampal excitatory neurons in the lithium-pilocarpine \nmodel of acute elicited seizures in awake behaving rats. Hippocampal pyramidal \nneurons were transduced in vivo with a virus carrying an enhanced halorhodopsin \n(eNpHR), a yellow light activated chloride pump, and acute seizure progression \nwas then monitored behaviorally and electrophysiologically in the presence and \nabsence of illumination delivered via an optical fiber. Inhibition of those \nneurons with illumination prior to seizure onset significantly delayed \nelectrographic and behavioral initiation of status epilepticus, and altered the \ndynamics of ictal activity development. These results reveal an essential role \nof hippocampal excitatory neurons in this model of ictogenesis and illustrate \nthe power of optogenetic approaches for elucidation of seizure mechanisms. This \nearly success in controlling seizures also suggests future therapeutic avenues.", "PURPOSE OF REVIEW: Tremendous advances have occurred in recent years in \nelucidating basic mechanisms of epilepsy at the level of ion channels and \nneurotransmitters. Epilepsy, however, is ultimately a disease of functionally \nand/or structurally aberrant connections between neurons and groups of neurons \nat the systems level. Recent advances in neuroimaging and electrophysiology now \nmake it possible to investigate structural and functional connectivity of the \nentire brain, and these techniques are currently being used to investigate \ndiseases that manifest as global disturbances of brain function. Epilepsy is \nsuch a disease, and our understanding of the mechanisms underlying the \ndevelopment of epilepsy and the generation of epileptic seizures will \nundoubtedly benefit from research utilizing these connectomic approaches.\nRECENT FINDINGS: MRI using diffusion tensor imaging provides structural \ninformation, whereas functional MRI and electroencephalography provide \nfunctional information about connectivity at the whole brain level. \nOptogenetics, tracers, electrophysiological approaches, and calcium imaging \nprovide connectivity information at the level of local circuits. These \napproaches are revealing important neuronal network disturbances underlying \nepileptic abnormalities.\nSUMMARY: An understanding of the fundamental mechanisms underlying the \ndevelopment of epilepsy and the generation of epileptic seizures will require \ndelineation of the aberrant functional and structural connections of the whole \nbrain. The field of connectomics now provides approaches to accomplish this.", "We have reviewed some of the important studies published within the last 18 \nmonths that have advanced our understanding of the epilepsies, their aetiology \nand treatment. Clinical studies have revealed new insights into old themes \nincluding seizure prediction, mortality in epilepsy, febrile seizures and the \npathophysiology of focal cortical dysplasias. The rapid advances in genetics and \nparticularly whole exome sequencing have had an impact on our understanding of \nepileptic encephalopathies, and the aetiology of hippocampal sclerosis. \nExperimental research techniques such as viral vector gene delivery, \noptogenetics and cell based transplantation techniques have set the framework \nfor novel approaches to the treatment of pharmacoresistant epilepsy. These few \nexamples are indicative of the great strides that have recently been made in \nepilepsy research.", "Optogenetic tools comprise a variety of different light-sensitive proteins from \nsingle-cell organisms that can be expressed in mammalian neurons and effectively \ncontrol their excitability. Two main classes of optogenetic tools allow to \neither depolarize or hyperpolarize, and respectively generate or inhibit action \npotentials in selective populations of neurons. This opens unprecedented \npossibilities for delineating the role of certain neuronal populations in brain \nprocessing and diseases. Moreover, optogenetics may be considered for developing \npotential treatment strategies for brain diseases, particularly for excitability \ndisorders such as epilepsy. Expression of the inhibitory halorhodopsin NpHR in \nhippocampal principal cells has been recently used as a tool to effectively \ncontrol chemically and electrically induced epileptiform activity in slice \npreparations, and to reduce in vivo spiking induced by tetanus toxin injection \nin the motor cortex. In this review we give a comprehensive summary of what has \nbeen achieved so far in the field of epilepsy using optogenetics, and discuss \nsome of the possible strategies that could be envisaged in the future. We also \npoint out some of the challenges and pitfalls in relation to possible outcomes \nof using optogenetics for controlling network excitability, and associated brain \ndiseases. This article is part of the Special Issue entitled 'New Targets and \nApproaches to the Treatment of Epilepsy'.", "Epilepsy is characterised by the propensity of the brain to generate spontaneous \nrecurrent bursts of excessive neuronal activity, seizures. GABA-mediated \ninhibition is critical for restraining neuronal excitation in the brain, and \ntherefore potentiation of GABAergic neurotransmission is commonly used to \nprevent seizures. However, data obtained in animal models of epilepsy and from \nhuman epileptic tissue suggest that GABA-mediated signalling contributes to \ninterictal and ictal activity. Prolonged activation of GABA(A) receptors during \nepileptiform bursts may even initiate a shift in GABAergic neurotransmission \nfrom inhibitory to excitatory and so have a proconvulsant action. Direct \ntargeting of the membrane mechanisms that reduce spiking in glutamatergic \nneurons may better control neuronal excitability in epileptic tissue. \nManipulation of brain pH may be a promising approach and recent advances in gene \ntherapy and optogenetics seem likely to provide further routes to effective \ntherapeutic intervention.", "Cerebrocortical injuries such as stroke are a major source of disability. \nMaladaptive consequences can result from post-injury local reorganization of \ncortical circuits. For example, epilepsy is a common sequela of cortical stroke, \nbut the mechanisms responsible for seizures following cortical injuries remain \nunknown. In addition to local reorganization, long-range, extra-cortical \nconnections might be critical for seizure maintenance. In rats, we found that \nthe thalamus, a structure that is remote from, but connected to, the injured \ncortex, was required to maintain cortical seizures. Thalamocortical neurons \nconnected to the injured epileptic cortex underwent changes in HCN channel \nexpression and became hyperexcitable. Targeting these neurons with a closed-loop \noptogenetic strategy revealed that reducing their activity in real-time was \nsufficient to immediately interrupt electrographic and behavioral seizures. This \napproach is of therapeutic interest for intractable epilepsy, as it spares \ncortical function between seizures, in contrast with existing treatments, such \nas surgical lesioning or drugs.", "Optogenetic techniques provide powerful tools for bidirectional control of \nneuronal activity and investigating alterations occurring in excitability \ndisorders, such as epilepsy. In particular, the possibility to specifically \nactivate by light-determined interneuron populations expressing \nchannelrhodopsin-2 provides an unprecedented opportunity of exploring their \ncontribution to physiological and pathological network activity. There are \nseveral subclasses of interneurons in cortical areas with different functional \nconnectivity to the principal neurons (e.g., targeting their perisomatic or \ndendritic compartments). Therefore, one could optogenetically activate specific \nor a mixed population of interneurons and dissect their selective or concerted \ninhibitory action on principal cells. We chose to explore a conceptually novel \nstrategy involving simultaneous activation of mixed populations of interneurons \nby optogenetics and study their impact on ongoing epileptiform activity in mouse \nacute hippocampal slices. Here we demonstrate that such approach results in a \nbrief initial action potential discharge in CA3 pyramidal neurons, followed by \nprolonged suppression of ongoing epileptiform activity during light exposure. \nSuch sequence of events was caused by massive light-induced release of GABA from \nChR2-expressing interneurons. The inhibition of epileptiform activity was less \npronounced if only parvalbumin- or somatostatin-expressing interneurons were \nactivated by light. Our data suggest that global optogenetic activation of mixed \ninterneuron populations is a more effective approach for development of novel \ntherapeutic strategies for epilepsy, but the initial action potential generation \nin principal neurons needs to be taken in consideration.", "Current treatment options for epilepsy are inadequate, as too many patients \nsuffer from uncontrolled seizures and from negative side effects of treatment. \nIn addition to these clinical challenges, our scientific understanding of \nepilepsy is incomplete. Optogenetic and designer receptor technologies provide \nunprecedented and much needed specificity, allowing for spatial, temporal and \ncell type-selective modulation of neuronal circuits. Using such tools, it is now \npossible to begin to address some of the fundamental unanswered questions in \nepilepsy, to dissect epileptic neuronal circuits and to develop new intervention \nstrategies. Such specificity of intervention also has the potential for direct \ntherapeutic benefits, allowing healthy tissue and network functions to continue \nunaffected. In this Perspective, we discuss promising uses of these technologies \nfor the study of seizures and epilepsy, as well as potential use of these \nstrategies for clinical therapies.", "Optogenetics is a novel technology that combines optics and genetics by optical \ncontrol of microbial opsins, targeted to living cell membranes. The versatility \nand the electrophysiologic characteristics of the light-sensitive ion-channels \nchannelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton \npump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in \ncontrolling neuronal firing in models of epilepsy and in providing insights into \nthe physiology and pathology of neuronal network organization and \nsynchronization. Opsins allow selective activation of excitatory neurons and \ninhibitory interneurons, or subclasses of interneurons, to study their activity \npatterns in distinct brain-states in vivo and to dissect their role in \ngeneration of synchrony and seizures. The influence of gliotransmission on \nepileptic network function is another topic of great interest that can be \nfurther explored by using light-activated Gq protein-coupled opsins for \nselective activation of astrocytes. The ever-growing optogenetic toolbox can \nalso be combined with emerging techniques that have greatly expanded our ability \nto record specific subtypes of cortical and hippocampal neurons in awake \nbehaving animals such as juxtacellular recording and two-photon guided \nwhole-cell recording, to identify the specific subtypes of neurons that are \naltered in epileptic networks. Finally, optogenetic tools allow rapid and \nreversible suppression of epileptic electroencephalography (EEG) activity upon \nphotoactivation. This review outlines the most recent advances achieved with \noptogenetic techniques in the field of epilepsy by summarizing the presentations \ncontributed to the 13th ILAE WONOEP meeting held in the Laurentian Mountains, \nQuebec, in June 2013.", "The complexity of the brain, in which different neuronal cell types are \ninterspersed and complexly interconnected, has posed a major obstacle in \nidentifying pathophysiological mechanisms underlying prevalent neurological \ndisorders. This is largely based in the inability of classical experimental \napproaches to target defined neural populations at sufficient temporal and \nspatial resolution. As a consequence, effective clinical therapies for prevalent \nneurological disorders are largely lacking. Recently developed optogenetic \nprobes are genetically expressed photosensitive ion channels and pumps that in \nprincipal overcome these limitations. Optogenetic probes allow millisecond \nresolution functional control over selected optogenetically transduced neuronal \npopulations targeted based on promoter activity. This optical cell control \nscheme has already been applied to answer fundamental questions pertaining to \nneurological disorders by allowing researchers to experimentally intercept, or \ninduce, pathophysiological neuronal signaling activity in a highly controlled \nmanner. Offering high temporal resolution control over neural activity at high \ncellular specificity, optogenetic tools constitute a game changer in research \naiming at understanding pathophysiological signaling mechanisms in neurological \ndisorders and in developing therapeutic strategies to correct these. In this \nregard, recent experimental work has provided new insights in underlying \nmechanisms, as well as preliminary proof-of-principle for optogenetic therapies, \nof several neurological disorders, including Parkinson's disease, epilepsy and \nprogressive blindness. This review synthesizes experimental work where \noptogenetic tools have been applied to explore pathologic neural network \nactivity in models of neurological disorders.", "BACKGROUND: Electrical high frequency stimulation (HFS) has been shown to \nsuppress seizures. However, the mechanisms of seizure suppression remain unclear \nand techniques for blocking specific neuronal populations are required.\nOBJECTIVE: The goal is to study the optical HFS protocol on seizures as well as \nthe underlying mechanisms relevant to the HFS-mediated seizure suppression by \nusing optogenetic methodology.\nMETHODS: Thy1-ChR2 transgenic mice were used in both vivo and in vitro \nexperiments. Optical stimulation with pulse trains at 20 and 50 Hz was applied \non the focus to determine its effects on in vivo seizure activity induced by \n4-AP and recorded in the bilateral and ipsilateral-temporal hippocampal CA3 \nregions. In vitro methodology was then used to study the mechanisms of the in \nvivo suppression.\nRESULTS: Optical HFS was able to generate 82.4% seizure suppression at 50 Hz \nwith light power of 6.1 mW and 80.2% seizure suppression at 20 Hz with light \npower of 2.0 mW. The suppression percentage increased by increasing the light \npower and saturated when the power reached above-mentioned values. In vitro \nexperimental results indicate that seizure suppression was mediated by \nactivation of GABA receptors. Seizure suppression effect decreased with \ncontinued application but the suppression effect could be restored by \nintermittent stimulation.\nCONCLUSIONS: This study shows that optical stimulation at high frequency \ntargeting an excitatory opsin has potential therapeutic application for fast \ncontrol of an epileptic focus. Furthermore, electrophysiological observations of \nextracellular and intracellular signals revealed that GABAergic \nneurotransmission activated by optical stimulation was responsible for the \nsuppression." ]	['http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D004827', 'http://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?field=uid&exact=Find+Exact+Term&term=D062308']
5a679be1b750ff4455000005	[ 24669633 ]	train	Are organisms in the genus Morexella associated with sepsis?	yesno	Moraxella species may cause neonatal sepsis	yes	[ "BACKGROUND: Neonatal sepsis is characterised by bacteraemia and clinical \nsymptoms caused by microorganisms and their toxic products. Gram negative \nbacteria are the commonest causes of neonatal Sepsis. The resistance to the \ncommonly used antibiotics is alarmingly high. The major reason for emerging \nresistance against antibiotics is that doctors often do not take blood cultures \nbefore starting antibiotics. We have carried out this study to find out various \nbacteria causing neonatal sepsis and their susceptibility to antibiotics for \nbetter management of neonatal sepsis.\nMETHODS: A total of 130 neonates with sepsis who were found to be blood culture \npositive were taken in this study. Culture/sensitivity was done, isolated \norganisms identified and their sensitivity/resistance was noted against \ndifferent antibiotics. Data were arranged in terms of frequencies and \npercentage.\nRESULTS: Out of 130 culture proven cases of neonatal sepsis, gram negative \nbacteria were found in 71 (54.6%) cases and gram positive bacteria in 59 (45.4%) \ncases. Staphylococcus aureus was the most common bacteria found in 35 (26.9%) \ncases followed by Escherichia coli in 30 (23.1%) cases. Acinetobacter species, \nStaphylococcus epidermidis, Klebseila, Streptococci, Enterobacter cloacae and \nMorexella species were found in 17 (13.1%), 17 (13.1%), 13 (10%), 7 (5.4%), 6 \n(4.6%), and 5 (3.8%) cases respectively. In most of the cases causative \norganisms were found to be resistant to commonly used antibiotics like \nampicillin, amoxicillin, cefotaxime, and ceftriaxone (77.7%, 81.5%, 63.1%, and \n66.9% respectively). There was comparatively less (56.9%) resistance to \nceftazidime. Gentamicin had resistance in 55.1% cases, while amikacin and \ntobramycin had relatively less resistance (17.4% and 34.8% cases respectively). \nQuinolones and imipenem had relatively less resistance. Vancomycin was found to \nbe effective in 100% cases of Staphylococcus group.\nCONCLUSION: Staphylococcus aureus are the most common gram positive bacteria and \nEscherichia coli are the most common gram negative bacteria causing neonatal \nsepsis. Resistance to commonly used antibiotics is alarmingly increasing. \nContinued surveillance is mandatory to assess the resistance pattern at a \ncertain level." ]	['https://meshb.nlm.nih.gov/record/ui?ui=D000071074', 'https://meshb.nlm.nih.gov/record/ui?ui=D018805']
5a6e21b4b750ff445500003a	[ 28667373, 20482863, 16860306, 27634932, 20621981, 18493055 ]	train	Are paralog genes co-regulated?	yesno	Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression.	yes	[ "MicroRNAs (miRNAs) are small non-coding RNA chains that can each interact with \nthe 3'-untranslated region of multiple target transcripts in various organisms, \nhumans included. MiRNAs tune entire biological pathways, spanning stress \nreactions, by regulating the stability and/or translation of their targets. \nMiRNA genes are often subject to co-evolutionary changes together with their \ntarget transcripts, which may be reflected by differences between paralog mouse \nand primate miRNA/mRNA pairs. However, whether such evolution occurred in \nstress-related miRNAs remained largely unknown. Here, we report that the \nstress-induced evolutionarily conserved miR-132-3p, its target transcripts and \nits regulated pathways provide an intriguing example to exceptionally robust \nconservation. Mice and human miR-132-3p share six experimentally validated \ntargets and 18 predicted targets with a common miRNA response element. \nEnrichment analysis and mining in-house and web-available experimental data \nidentified co-regulation by miR-132 in mice and humans of stress-related, \ninflammatory, metabolic, and neuronal growth pathways. Our findings demonstrate \npan-mammalian preservation of miR-132's neuronal roles, and call for further \nexploring the corresponding stress-related implications.", "BACKGROUND: Genome amplification through duplication or proliferation of \ntransposable elements has its counterpart in genome reduction, by elimination of \nDNA or by gene inactivation. Whether loss is primarily due to excision of random \nlength DNA fragments or the inactivation of one gene at a time is controversial. \nReduction after whole genome duplication (WGD) represents an inexorable collapse \nin gene complement.\nRESULTS: We compare fifteen genomes descending from six eukaryotic WGD events \n20-450 Mya. We characterize the collapse over time through the distribution of \nruns of reduced paralog pairs in duplicated segments. Descendant genomes of the \nsame WGD event behave as replicates. Choice of paralog pairs to be reduced is \nrandom except for some resistant regions of contiguous pairs. For those paralog \npairs that are reduced, conserved copies tend to concentrate on one chromosome.\nCONCLUSIONS: Both the contiguous regions of reduction-resistant pairs and the \nconcentration of runs of single copy genes on a single chromosome are evidence \nof transcriptional co-regulation, dosage sensitivity or other functional \ninteraction constraining the reduction process. These constraints and their \nevolution over time show a consistent pattern across evolutionary domains and a \nhighly reproducible pattern, as replicates, for the several descendants of a \nsingle WGD.", "The expression of zebrafish hoxb3a and hoxb4a has been found to be mediated \nthrough five transcripts, hoxb3a transcripts I-III and hoxb4a transcripts I-II, \ndriven by four promoters. A \"master\" promoter, located about 2 kb downstream of \nhoxb5a, controls transcription of a pre-mRNA comprising exon sequences of both \ngenes. This unique gene structure is proposed to provide a novel mechanism to \nensure overlapping, tissue-specific expression of both genes in the posterior \nhindbrain and spinal cord. Transgenic approaches were used to analyze the \nfunctions of zebrafish hoxb3a/hoxb4a promoters and enhancer sequences containing \nregions of homology that were previously identified by comparative genomics. Two \nneural enhancers were shown to establish specific anterior expression borders \nwithin the hindbrain and mediate expression in defined neuronal populations \nderived from hindbrain rhombomeres (r) 5 to 8, suggesting a late role of the \ngenes in neuronal cell lineage specification. Species comparison showed that the \nzebrafish hoxb3a r5 and r6 enhancer corresponded to a sequence within the mouse \nHoxA cluster controlling activity of Hoxa3 in r5 and r6, whereas a homologous \nregion within the HoxB cluster activated Hoxb3 expression but limited to r5. We \nconclude that the similarity of hoxb3a/Hoxa3 regulatory mechanisms reflect the \nshared descent of both genes from a single ancestral paralog group 3 gene.", "Paralog genes arise from gene duplication events during evolution, which often \nlead to similar proteins that cooperate in common pathways and in protein \ncomplexes. Consequently, paralogs show correlation in gene expression whereby \nthe mechanisms of co-regulation remain unclear. In eukaryotes, genes are \nregulated in part by distal enhancer elements through looping interactions with \ngene promoters. These looping interactions can be measured by genome-wide \nchromatin conformation capture (Hi-C) experiments, which revealed \nself-interacting regions called topologically associating domains (TADs). We \nhypothesize that paralogs share common regulatory mechanisms to enable \ncoordinated expression according to TADs. To test this hypothesis, we integrated \nparalogy annotations with human gene expression data in diverse tissues, \ngenome-wide enhancer-promoter associations and Hi-C experiments in human, mouse \nand dog genomes. We show that paralog gene pairs are enriched for \nco-localization in the same TAD, share more often common enhancer elements than \nexpected and have increased contact frequencies over large genomic distances. \nCombined, our results indicate that paralogs share common regulatory mechanisms \nand cluster not only in the linear genome but also in the three-dimensional \nchromatin architecture. This enables concerted expression of paralogs over \ndiverse cell-types and indicate evolutionary constraints in functional genome \norganization.", "Cancer is among the major causes of human death and its mechanism(s) are not \nfully understood. We applied a novel meta-analysis approach to multiple sets of \nmerged serial analysis of gene expression and microarray cancer data in order to \nanalyze transcriptome alterations in human cancer. Our methodology, which we \ndenote 'COgnate Gene Expression patterNing in tumours' (COGENT), unmasked \nnumerous genes that were differentially expressed in multiple cancers. COGENT \ndetected well-known tumor-associated (TA) genes such as TP53, EGFR and VEGF, as \nwell as many multi-cancer, but not-yet-tumor-associated genes. In addition, we \nidentified 81 co-regulated regions on the human genome (RIDGEs) by using \nexpression data from all cancers. Some RIDGEs (28%) consist of paralog genes \nwhile another subset (30%) are specifically dysregulated in tumors but not in \nnormal tissues. Furthermore, a significant number of RIDGEs are associated with \nGC-rich regions on the genome. All assembled data is freely available online \n(www.oncoreveal.org) as a tool implementing COGENT analysis of multi-cancer \ngenes and RIDGEs. These findings engender a deeper understanding of cancer \nbiology by demonstrating the existence of a pool of under-studied multi-cancer \ngenes and by highlighting the cancer-specificity of some TA-RIDGEs.", "Gene duplications have been broadly implicated in the generation of \ntestis-specific genes. To perform a comprehensive analysis of paralogous \ntestis-biased genes, we characterized the testes transcriptome of Drosophila \nmelanogaster by comparing gene expression in testes vs. ovaries, heads, and \ngonadectomized males. A number of the identified 399 testis-biased genes code \nfor the known components of mature sperm. Among the detected 69 genes \ndownregulated in testes, a large fraction is required for viability. By \nanalyzing paralogs of testis-biased genes, we identified \"co-regulated\" \nparalogous pairs in which both genes are testis biased, \"anti-regulated\" pairs \nin which one paralog is testis biased and the other downregulated in testes, and \n\"neutral\" pairs in which one paralog is testis biased and the other \nconstitutively expressed. The numbers of identified co-regulated and \nanti-regulated pairs were higher than expected by chance. Testis-biased genes \nincluded in these pairs show decreased frequency of lethal mutations, suggesting \ntheir specific role in male reproduction. These genes also show exceptionally \nhigh interspecific variability of expression in comparison between D. \nmelanogaster and the closely related D. simulans. Further, interspecific changes \nin testis bias of expression are generally correlated within the co-regulated \npairs and are anti-correlated within the anti-regulated pairs, suggesting \ncoordinated regulation within both types of paralogous gene pairs." ]	nan
5a6f87c5b750ff4455000056	[ 24153350, 21842694, 17408137, 22208651, 17992593, 19745687, 1608349, 27336863, 28779180, 10414252, 529328, 17119030, 24159176, 22497865, 12064854, 23845207, 26998372, 12886135, 21805176, 21172862 ]	train	Are patients with Sjogren syndrome at increased risk for lymphoma?	yesno	Yes, the heightened risk of non-Hodgkin lymphoma (NHL) development in primary Sjogren syndrome is well established. Five per cent of patients with primary Sjogren's syndrome develop malignant non-Hodgkin's lymphoma, usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands. The incidence of lymphoma is higher in patients with Sjögren's syndrome than in the general population.	yes	[ "Sjogren's syndrome (SS) is a chronic autoimmune disorder with the highest risk \nfor lymphoma development among all autoimmune diseases. In order to evaluate \nwhether the presence of the recently described MYD88 L265P mutation in patients \nwith Waldenström's macroglobulinemia (WM) is contributory to SS-associated \nlymphomagenesis, a quantitative allele-specific PCR method was performed in \nperipheral blood derived from 90 SS patients as well as in minor salivary gland \ntissues derived from 12 primary SS patients with or without lymphoma. MYD88 \nL265P was not detected in either of the samples tested. Although the absence of \nthe MyD88 L265P somatic mutation in our SS cohort does not exclude a common \ngermline susceptibility gene in SS, it might suggest a distinct operating \npathogenetic mechanism in SS-related lymphoma compared with WM and other \nhematological malignancies.", "A 62-year-old woman with Sjogren syndrome was admitted for computed tomographic \n(CT) evaluation of a thickened trachea and parotid tumor. She had been given a \ndiagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma 6 years \npreviously, and had undergone surgical resection of the parotid tumor. \nEndoscopic examination revealed an annular tumor that had formed a stricture in \nthe mid-trachea. Pathologic specimens were obtained by surgical resection of the \nparotid tumor and bronchoscopic biopsy of the tracheal tumor. Both histological \nexaminations revealed MALT-type marginal zone B-cell lymphoma. Because CD20 \nimmunostaining was positive, the patient received 6 cycles of rituximab plus \ncyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) without any \nsigns of major toxicity. All lesions disappeared after treatment, and this \npatient remained disease-free for 40 months.", "Sjögren syndrome is one of the most prevalent autoimmune diseases in which the \nbody's immune system mistakenly attacks its own moisture producing glands. \nAlthough Sjögren syndrome occurs in all age groups in both women and men, women \nin their fourties are the most affected. Sjögren's syndrome can occur alone or \nin the presence of another connective tissue disease, respectively called \nprimary and secundary Sjögren syndrome. When two of the three clinical \nhallmarks: keratoconjunctivitis sicca, xerostomia or connective tissue disease \nare present, Sjögren 's syndrome should be considered. To confirm the diagnosis \nof Sjögren's syndrome several tests are required. e.g. blood tests, \nophthalmologic tests and oral tests. Rheumatologists have the primary \nresponsibility for managing Sjögren's syndrome. Other specialists can treat the \nrelated symptoms. The incidence of lymphoma is higher in patients with Sjögren's \nsyndrome than in the general population. Therefore patients must be monitored \ncarefully for the development of related autoimmune diseases, lymphoma and other \ncomplications. Sjögren's syndrome is serious but generally not fatal if \ncomplications are diagnosed and treated early.", "It has long been demonstrated that a subset of patients with Sjogren's syndrome \n(SS) develop ectopic lymphoid structures (ELS) in the salivary glands (SG). \nThese structures are characterised by periductal clusters of T and B \nlymphocytes, development of high endothelial venules and differentiation of \nfollicular dendritic cells (FDC) networks. Evidence in patients with and animal \nmodels of SS demonstrated that the formation and maintenance of ELS in the SG is \ncritically dependent on the ectopic expression of lymphotoxins (LT) and lymphoid \nchemokines CXCL13, CCL19, CCL21 and CXCL12. Several cell types, including \nresident epithelial, stromal and endothelial cells as well as different subsets \nof infiltrating immune cells, have been shown to be capable of producing some of \nthese factors during chronic inflammation in SS. In this review we focus on the \ncellular and molecular mechanisms regulating the formation of ELS in SS SG, with \nparticular emphasis on the role of lymphoid chemokines. In addition, we \nsummarise accumulating data in support of the notion that ELS in SS represent \nfunctional niches whereby autoreactive B cells undergo affinity maturation, \nclonal selection and differentiation into autoantibody producing cells, thus \ncontributing to autoimmunity over and above secondary lymphoid organs. \nFurthermore, we review the emerging role of ELS and lymphoid chemokines in \ndriving extranodal B cell lymphomagenesis in SS and we focus on recent evidence \nsuggesting that ELS identify subsets of SS patients at increased risk of \ndeveloping systemic manifestations and lymphoma.", "Among autoimmune diseases, Sjogren's syndrome (SS) displays the highest \nincidence of non-Hodgkin lymphoma (NHL) development with the salivary extranodal \nmarginal zone B cell lymphomas being the most common type. The majority of \nSS-associated NHLs are characterized by localized stage, indolent clinical \ncourse, and recurrence in other extranodal sites. Although the transition from a \nchronic inflammatory condition to malignant lymphoma is a multistep process yet \npoorly understood, there is increasing evidence that chronic antigenic \nstimulation by an exoantigen or autoantigens plays an essential role in the \ndevelopment of SS associated lymphoproliferation. Additional molecular oncogenic \nevents such as microsatellite instability, loss of the B cell cycle control, and \nthe forced overproduction of specific B cell biologic stimulators seem to \ncontribute to the emergence and progression of the malignant overgrowth. Among \nthe clinical and serological parameters that have been associated with lymphoma \ndevelopment in SS patients, the presence of palpable purpura, low C4, and mixed \nmonoclonal cryoglobulinemia constitute the main predictive markers, and patients \ndisplaying these risk factors should be monitored closely.", "The diverse hematologic manifestations of primary Sjögren syndrome (pSS) have \nnot been systematically investigated, and their prognostic relevance remains \nunclear. We conducted a retrospective study of 536 consecutive patients followed \nin our institution to assess the prevalence of hematologic abnormalities and \ntheir associations with various disease manifestations in pSS. We also aimed to \nidentify risk factors for the development of non-Hodgkin lymphoma (NHL) overall \nand by subtype. Anemia of chronic disease and hypergammaglobulinemia were the \nmost prevalent hematologic manifestations encountered at diagnosis and during \nthe course of pSS. Univariate analysis between cytopenias and glandular \nmanifestations revealed a statistically significant correlation between \nlymphocytopenia and parotid gland enlargement (p = 0.002), as well as between \nneutropenia and xerostomia (p = 0.019). Anemia, lymphocytopenia, \nthrombocytopenia, hypergammaglobulinemia, the presence of monoclonal serum \nproteins, and cryoglobulinemia correlated significantly with the presence of \nextraglandular symptoms such as palpable purpura, lymphadenopathy, and \nsplenomegaly. Lymphoma was diagnosed in 7.5% (95% confidence interval [CI], \n5.4%-10%) of patients. Marginal zone B-cell lymphomas (MZBCLs) were the \npredominant histologic type (65%; 95% CI, 48.3%-79.4%), while diffuse large \nB-cell lymphomas (DLBCLs) accounted for 17.5% (95% CI, 7.3%-32.8%) of all cases. \nThe development of NHL in patients with pSS could be predicted by the presence \nof simple clinical and laboratory factors at diagnosis: neutropenia (p = 0.041), \ncryoglobulinemia (p = 0.008), splenomegaly (p = 0.006), lymphadenopathy (p = \n0.021), and low C4 levels (p = 0.009). Patients carrying any of these factors \nhad a more than 5-fold increased risk of NHL compared to patients with no risk \nfactors at all. The above set of disease characteristics could predict \nsubsequent development of MZBCL; the presence of lymphocytopenia (p = 0.044) at \ndiagnosis served as a risk factor for the development of a non-MZBCL, most \ncommonly DLBCL. Anemia of chronic disease and hypergammaglobulinemia are common \nhematologic manifestations at diagnosis and during the course of pSS. \nNeutropenia and cryoglobulinemia at diagnosis are significantly associated with \nan increased risk of lymphoma development.", "Sjogren's syndrome is an autoimmune disease with a known predisposition for \nlymphoma development. Eight of 120 patients with primary Sjogren's syndrome \nfollowed at the University of Ioannina over the past 7 years developed \nnon-Hodgkin's lymphoma diagnosed according to the Kiel classification. The \nlymphomas differed by location and grading. Six were called low grade \n(immunocytoma) and two intermediate grade non-Hodgkin's lymphomas. Five of the \nimmunocytomas involved the minor salivary or lacrimal glands. Immunoperoxidase \nstaining for light chains revealed monoclonal populations. Two patients showed \nspontaneous regression not previously reported in Sjogren's syndrome. Thus, in \nSjogren's syndrome, low grade non-Hodgkin's lymphomas and especially \nimmunocytomas are the most common lymphomas. These lymphomas tend to evolve very \nslowly and may regress spontaneously. Given these facts, a conservative approach \nto treatment is indicated in those patients with only localized disease.", "The heightened risk of non-Hodgkin lymphoma (NHL) development in primary Sjogren \nsyndrome (SS) is well established. Several adverse clinical and laboratory \npredictors have been described. In the current work, we aimed to formulate a \npredictive score for NHL development, based on clinical, serological, and \nhistopathological findings at the time of SS diagnosis. In the present \ncase-control study of 381 primary SS patients and 92 primary SS patients with \nconcomitant NHL, clinical, serological, and histopathological variables at the \ntime of SS diagnosis were retrospectively recorded. For the identification of \npredictors for NHL development univariate and multivariate models were \nconstructed. Salivary gland enlargement (SGE), lymphadenopathy, Raynaud \nphenomenon, anti-Ro/SSA or/and anti-La/SSB autoantibodies, rheumatoid factor \n(RF) positivity, monoclonal gammopathy, and C4 hypocomplementemia were shown to \nbe independent predictors for NHL development. On the basis of the number of \nindependent risk factors identified, a predictive risk score for NHL development \nwas formulated. Thus, patients presenting with ≤2 risk factors had a 3.8% \nprobability of NHL development, those with 3 to 6 risk factors 39.9% (OR \n(95%CI): 16.6 [6.5-42.5], P < 0.05), while in the presence of all 7 risk factors \nthe corresponding probability reached 100% (OR [95%CI]: 210.0 [10.0-4412.9], \nP < 0.0001). In conclusion, an easy to use diagnostic scoring tool for NHL \ndevelopment in the context of SS is presented. This model is highly significant \nfor the design of early therapeutic interventions in high risk SS patients for \nNHL development.", "Author information:\n(1)Department of Physiology, School of Medicine, National and Kapodistrian \nUniversity of Athens, Athens, Greece.\n(2)Institute of Biology, Medicinal Chemistry and Biotechnology, National \nHellenic Research Foundation, Athens, Greece.\n(3)Department of Pathology, School of Medicine, National and Kapodistrian \nUniversity of Athens, Athens, Greece.\n(4)Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of \nPharmacy, School of Health Sciences, National and Kapodistrian University of \nAthens, Athens, Greece.\n(5)Department of Pathophysiology, School of Medicine, National and Kapodistrian \nUniversity of Athens, Athens, Greece.\n(6)Joint Academic Rheumatology Program, National and Kapodistrian University of \nAthens, School of Medicine, Athens, Greece.\n(7)First Department of Propaedeutic Internal Medicine, National and Kapodistrian \nUniversity of Athens School of Medicine, Athens, Greece.\n(8)Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, Weill \nMedical College of Cornell University, New York, NY, USA.\n(9)Department of Physiology, School of Medicine, National and Kapodistrian \nUniversity of Athens, Athens, Greece. kmauragan@med.uoa.gr.\n(10)Department of Pathophysiology, School of Medicine, National and Kapodistrian \nUniversity of Athens, Athens, Greece. kmauragan@med.uoa.gr.\n(11)Joint Academic Rheumatology Program, National and Kapodistrian University of \nAthens, School of Medicine, Athens, Greece. kmauragan@med.uoa.gr.", "LYMPHOMA RISK: Lymphoma is a very severe complication of primary Sjögren's \nsyndrome: 5 to 10% of patients followed for more than 10 years will develop a \nlymphoma. Predictive factors include serum monoclonal immunoglobulins or \ncryoglobulins and a B clone population in accessory salivary glands. TYPICAL \nCLINICAL AND HISTOLOGICAL PRESENTATION: Mucosal involvement (parotid as well as \ngastric or pulmonary localizations) is frequent. According to the recent \nclassification of lymphomas, most lymphomas developing in patients with \nSjögren's syndrome are B lymphomas of the marginal zone: MALT lymphomas or \nlow-grade nodal monocytoid lymphomas which are sometimes not identified until \ntransformation to the giant cell stage. SIMILARITIES WITH HEPATITIS C LYMPHOMAS: \nThe pathophysiology of lymphoma in Sjögrën's syndrome remains unknown. To date, \nthere is no argument favoring a viral infection or a deregulation of a unique \noncogene or anti-oncogene. Certain similarities between lymphomas in Sjögren's \nsyndrome and lymphomas associated with hepatitic C virus would suggest a common \npathogenisis: possibly a permanent stimulation of auto-reactive B cells carrying \na surface immunoglobulin with rheumatoid factor activity in the target organs of \nthe autoimmune disease. These B lymphocytes would then proliferate secondarily.", "A case of pulmonary pseudolymphoma and Sjogren syndrome is presented. Unusually, \nthe lung involvement preceded the salivary disease by more than two years. The \ninitial gammopathy and abnormal serologies are more consistent with \nuncomplicated Sjogren syndrome, but were present when the pseudolymphoma was \nsolely apparent.", "Certain autoimmune and chronic inflammatory conditions, such as Sjögren's \nsyndrome and rheumatoid arthritis (RA), have consistently been associated with \nan increased risk of malignant lymphomas, but it is unclear whether elevated \nlymphoma risk is a phenomenon that accompanies inflammatory conditions in \ngeneral. Likewise, it is debated whether the increased risk identified in \nassociation with some disorders pertains equally to all individuals or whether \nit varies among groups of patients with different phenotypic or \ntreatment-related characteristics. It is similarly unclear to what extent the \nincreased lymphoma occurrence is mediated through specific lymphoma subtypes. \nThis update reviews the many findings on risks, risk levels, and lymphoma \ncharacteristics that have been presented recently in relation to a broad range \nof chronic inflammatory, including autoimmune, conditions. Recent results \nclearly indicate an association between severity of chronic inflammation and \nlymphoma risk in RA and Sjögren's syndrome. Thus, the average risk of lymphoma \nin RA may be composed of a markedly increased risk in those with most severe \ndisease and little or no increase in those with mild or moderate disease. The \nroles of immunosuppressive therapy and EBV infection seem to be limited. \nFurthermore, RA, Sjögren's syndrome, systemic lupus erythematosus, and possibly \nceliac disease may share an association with risk of diffuse large B-cell \nlymphoma, in addition to well-established links of Sjögren's syndrome with risk \nof mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of \nsmall intestinal lymphoma. However, there is also obvious heterogeneity in risk \nand risk mediators among different inflammatory diseases.", "Several autoimmune diseases, including primary Sjögren's syndrome (pSS), are \nassociated with an increased risk for lymphoma. Polymorphisms of TNFAIP3, which \nencodes the A20 protein that plays a key role in controlling nuclear factor κB \nactivation, have been associated with several autoimmune diseases. Somatic \nmutations of TNFAIP3 have been observed in the mucosa-associated lymphoid tissue \nlymphoma subtype frequently associated with pSS. We studied germline and somatic \nabnormalities of TNFAIP3 in 574 patients with pSS, including 25 with lymphoma. \nNineteen additional patients with pSS and lymphoma were available for exome \nsequence analysis. Functional abnormalities of A20 were assessed by gene \nreporter assays. The rs2230926 exonic variant was associated with an increased \nrisk for pSS complicated by lymphoma (odds ratio, 3.36 [95% confidence interval, \n1.34-8.42], and odds ratio, 3.26 [95% confidence interval, 1.31-8.12], vs \ncontrols and pSS patients without lymphoma, respectively; P = .011). Twelve \n(60%) of the 20 patients with paired germline and lymphoma TNFAIP3 sequence data \nhad functional abnormalities of A20: 6 in germline DNA, 5 in lymphoma DNA, and 1 \nin both. The frequency was even higher (77%) among pSS patients with \nmucosa-associated lymphoid tissue lymphoma. Some of these variants showed \nimpaired control of nuclear factor κB activation. These results support a key \nrole for germline and somatic variations of A20 in the transformation between \nautoimmunity and lymphoma.", "Oral Diseases (2012) doi:10.1111/j.1601-0825.2012.01932.x Biologic therapy has a \npotential to benefit patients with orofacial manifestations of Sjogren syndrome \n(SS). The most appropriate use of biologics would appear to be in patients with \nsevere or multisystem features of SS, but their use early in the pathogenesis \nhas the potential to prevent disease progression. Tumour necrosis factor-alpha \nblockade has not proven effective in SS. B-cell depletion using rituximab has \nbeen of benefit, mainly in relation to extraglandular features, and to some \nextent in relation to hyposalivation where there is still residual salivary \nfunction. Rituximab is also effective in the treatment of SS-associated \n(extrasalivary) lymphomas, although the therapeutic response in salivary \nlymphoma is poorer. Rituximab is given as a single or periodic intravenous \ninfusion. Potential adverse effects exist, notably infusion reactions and \ninfection, and so a full risk/benefit analysis is indicated for prospective \npatients. This and clinical use is best performed and monitored in conjunction \nwith rheumatologists with appropriate training and experience in biologic \ntherapies. Further studies of rituximab in SS are ongoing, and newer agents \nunder trial include belimumab.", "We describe a patient with primary biliary cirrhosis (PBC) and secondary \nSjogren's syndrome (SS) with pulmonary involvement who developed a cutaneous T \ncell lymphoma. The clinical course of secondary SS in PBC is thought to be less \ncomplicated than in progressive systemic scleroderma and SS. In contrast to \nsecondary SS, the risk for developing non-Hodgkin's lymphoma is highly increased \nin patients with primary SS. Moreover, these lymphomas are usually of B cell \norigin. There are few reports of T cell lymphoma in primary SS. The occurrence \nof a T cell lymphoma in a patient with PBC and secondary SS indicates the \nnecessity to investigate lymphoma in patients with secondary SS.", "Primary Sjogren's syndrome (pSS) is complicated by B-cell lymphoma in 5-10% of \npatients. Several clinical and serological features are proposed as adverse \npredictors for such complication and define a high risk pSS phenotype. We aimed \nto explore whether previously described polymorphisms of the B-cell activating \nfactor (BAFF) could be related to pSS-related lymphomagenesis. Five single \nnucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, \nrs9514828, rs1041569 and the rs9514827) were evaluated in 111 low risk pSS \npatients (type II), 82 high risk/lymphoma patients (type I) and 137 healthy \ncontrols (HC) by PCR-based assays. The classification of pSS patients into types \nI and II was based on the presence or absence of risk factors or lymphoma \ndevelopment, respectively. Genotype and haplotype analysis was performed for all \nvariants in the pSS groups. Since the rs1041569 SNP was not in Hardy-Weinberg \nequilibrium in the HC group (p < 0.001), haplotype analysis was performed in the \nremaining four out of the five SNPs tested when comparisons with HC individuals \nwere performed. The high risk pSS group was characterized by higher frequency of \nthe minor T allele of the rs9514828 BAFF polymorphism compared to HC. Compared \nto the low risk pSS patients but not the HC, the high risk pSS group exhibited \nlower frequencies of the AA genotype of the rs12583006 polymorphism as well as \nthe TACAC and TACC haplotypes and higher frequency of the TTTC haplotype. The \nlow risk pSS group exhibited higher frequency of the minor A allele and AA \ngenotype of the rs12583006 variant compared to HC. Both pSS groups were \ncharacterized by increased frequency of the haplotype TATT and GTTC and \ndecreased frequency of the TTCT when compared to HC. Taken together, these \nfindings suggest the implication of the host's genetic background in pSS-related \nlymphomagenesis. The interaction of pSS-related BAFF gene haplotypes together \nwith distinct BAFF genetic variants appears to contribute to this complication.", "Sjögren's syndrome (SS) has the highest incidence of malignant \nlymphoproliferative disorders transformation among autoimmune diseases. We \npresent a case of extranodal high grade lymphoma of the liver in a 52-year-old \npatient with long history of SS. Lymphoma manifested with sharp significant pain \nin the right hypochondrium, weakness, and profuse night sweats. \nContrast-enhanced computed tomography scan (CT-scan) of the abdomen revealed \nmultiple low density foci with homogeneous structure and clear contours in both \nlobes of the liver. Histologically, proliferation of medium sized lymphoma cells \nwith round-oval and slightly irregular nuclei with fine chromatin was shown. \nImmunohistochemical and molecular features of the tumors allowed diagnosis of \ndiffuse large B-cell lymphoma (DLBCL). To exclude secondary liver lesion by \nnon-Hodgkin lymphoma, chest and small pelvis CT-scan, endoscopy of upper and \nlower gastrointestinal tract and study of bone marrow were performed. After 8 \ncycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, \nvincristine, and prednisone), the complete remission was achieved, which \npersists after 45 months of follow-up. Primary hepatic lymphomas are extremely \nrare, and previously only low-grade hepatic lymphomas have been described in SS. \nTo our knowledge, the patient described here represents the first reported case \nof DLBCL with primary liver involvement in SS.", "OBJECTIVE: To describe and correlate the clinical and imaging findings of \nlymphomas in patients with Sjögren syndrome.\nMETHODS: The authors reviewed the medical and imaging records of 27 cases of \nlymphoma from among a total of 463 patients with Sjögren syndrome. The estimated \nprevalence of lymphoma in patients with Sjögren syndrome was 5.8%. There were 22 \nwomen and 5 men. Histopathologically, 26 of the 27 neoplasms were non-Hodgkin \nlymphoma, including 6 mucosa-associated lymphoid tissue lymphomas, and the other \nneoplasm was Hodgkin lymphoma. The clinical and imaging findings of lymphomas \nwere analyzed.\nRESULTS: No obvious correlations were present between the duration or severity \nof Sjögren syndrome and the lymphoma development. At the initial diagnosis, \nextranodal involvement was observed in 14 (52%) of the 27 patients, including \nthe salivary gland (n = 9), lacrimal gland (n = 2), lung (n = 2), and thyroid \ngland (n = 1), mostly in the neck organs. On the other hand, nodal involvement \nwas observed in 21 (78%) of the 27 patients. Of these 21 patients, 19 had at \nleast cervical lymph node involvement.\nCONCLUSION: Patients with Sjögren syndrome are at increased risk of lymphoma \ndevelopment. Because most lymphomas initially involve the neck organs, including \nthe lymph nodes, meticulous imaging studies mainly focused on the cervical \nregions are recommended in the follow-up of patients with Sjögren syndrome.", "Five per cent of patients with primary Sjogren's syndrome (pSS) develop \nmalignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated \nlymphoid tissue (MALT) and most frequently located in the major salivary glands. \nRituximab (RTX), a chimeric monoclonal antibody against the CD20 molecule \nexpressed on the surface of mature B cells that has been approved for the \ntreatment of NHL, has been used to treat pSS-associated lymphoma. We have \ndescribed two cases: one with MALT lymphoma in the parotid glands and the other \nwith a rare thymus lymphoma accompanied by the rare complication of a bullous \npneumopathy. Both were treated with RTX at haematological doses, which was \nunsuccessful in the patient with a salivary lymphoma; in the case of the patient \nwith a thymus lymphoma, the mediastinum mass disappeared and did not relapse. \nBoth patients experienced an improvement in the subjective symptoms of dryness, \nand their Schirmer's test and scialoscintigraphy results stabilised. The \npulmonary bullae remained unchanged.", "BACKGROUND: The prevalence of peripheral neuropathy in patients with Sjögren \nsyndrome remains unclear owing to conflicting results in the published series, \nwith numbers ranging from 2% to over 60% of Sjögren syndrome patients. Whether \nperipheral neuropathy is a feature of the systemic or glandular disease or \nwhether it is related to a circulating antineuronal antibody remains also \nuncertain.\nMETHODS: The authors reviewed the records of patients with primary Sjögren \nsyndrome (pSS), fulfilling the Revised European-American Classification \nCriteria, seen in their department from 1992 to 2009. The patients with \npreviously recorded neuropathic features were re-examined clinically and \nelectrophysiologically. Other causes of polyneuropathy were excluded. The \nauthors also searched for circulating antineural antibodies using \nimmunofluorescence and western blot and for antibodies against muscarinic and \nnicotinic acetylcholine receptors as potential biomarkers.\nRESULTS: 509 cases met the diagnostic criteria for pSS. Among these, 44 patients \nwere recorded as having neuropathic symptoms. After completing the evaluation, \nhowever, only nine (1.8%) had polyneuropathy with objective clinical signs and \nabnormal electrophysiological findings. The neuropathy was axonal in all, in \nfive pure sensory and in four sensorimotor. The patients with peripheral \nneuropathy had extraglandular manifestations such as palpable purpura and \nvasculitis. No evidence of antineural autoimmunity was found, and no candidate \nbiomarkers were identified.\nCONCLUSION: Polyneuropathy is a rare manifestation of pSS occurring in 1.8% of \npatients. In the majority of patients, it is a late event and frequently \nassociated with systemic disease or risk factors for lymphoma development." ]	['https://meshb.nlm.nih.gov/record/ui?ui=D012859', 'https://meshb.nlm.nih.gov/record/ui?ui=D008223', 'https://meshb.nlm.nih.gov/record/ui?ui=D012306', 'http://www.disease-ontology.org/api/metadata/DOID:12894']

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