tbuckley/cabot-search huggingface dataset:
Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6
Authors: Pengcheng Luo, Cong Qin, Lihua Zhu, Chun Fang, Yan Zhang, Hai Zhang, Fei Pei, Song Tian, Xue‐Yong Zhu, Jun Gong, Qing Mao, Chengcheng Xiao, Yang Su, Haizhou Zheng, Tao Xu, Jingxiao Lu, Jie Zhang
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin‐specific peptidase 10 (USP10), a member of the ubiquitin‐specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high‐fat diet (HFD)‐induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate‐induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte‐specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10‐regulated hepatic steatosis were further investigated in HFD‐treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate‐treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.
Abstract 16549: Single Cell Encapsulation Primes Explant-Derived Cardiac Stem Cells to Adopt an Invasive/Migratory Phenotype
Authors: Pushpinder Kanda, Duncan J Stewart, Darryl R Davis
Journal: Circulation (2016)

Background:  Single cell encapsulation of explant-derived cardiac stem cells (EDCs) boosts therapeutic regeneration by abrogating detachment induced cell death and vascular clearance of cocooned cells. Here, we test the hypothesis that encapsulation instructs cells to adopt an invasive/migratory phenotype favoring mobilization and increased myocardial function after transplantation into the injured heart.   Methods/Results:  Human EDCs were encapsulated within agarose cocoons of variable density (2 vs. 3.5% agarose) supplemented with extracellular matrix (fibrinogen and fibronectin). Multiplex analysis demonstrated that encapsulation alone promoted greater expression of matrix metalloproteinases (MMP1, MMP10 and EMMPRIN; p In vitro  kinetic profiling revealed that encapsulation within 3.5% agarose capsules delayed the half time of cell emergence from the capsule from 16±2 hours to 42±12 hours (p=0.02 vs. 2% agarose capsules; n=3). Once cells escaped the capsules, real time profiling demonstrated that increasing capsule density primed cells to migrate 3.8±0.3 fold faster across a porous membrane (p=0.0001 vs. 2% agarose capsules, n=4). Transplant of EDCs encapsulated in 2% agarose into the myocardium of immunodeficient mice 1 week after infarction increased the 4-week post infarct ejection fraction from 32.9±1.3% to 37.4±0.5% as compared to non-cocooned EDCs (p=0.008, n=6 per treatment group). Although encapsulation increased long term retention of transplanted cells by 6±2 fold (p=0.04 vs. suspended EDCs), increasing capsule density did not boost the long term cell retention (p=0.7 vs. 2% encapsulation) despite providing a marked increase in myocardial function (4-week post infarct ejection fraction: 47.6±1.5%, p=0.0001 vs 2% agarose, n=8).   Conclusion:  Encapsulation within dense cocoons enhances the migratory/invasive nature of EDCs to promote indirect repair of damaged myocardium.
Deviations of the immune cell lanscape between healthy liver and hepatocellular carcinoma
Authors: N. Rohr-Udilova, K. Tsuchiya, M. Herac, J. Stift, M. Salzmann, E. Jensen-Jarolim, R. Schulte-Hermann, T. Reiberger, G. Oberhuber, G. Timelthaler, R. Eferl, M. Pinter, M. Peck-Radosavljevic, M. Trauner
Journal: Journal of Hepatology (2018)
Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model
Authors: Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H. McDermott, Philip M. Murphy
Journal: Journal of Clinical Investigation (2018)

For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome - a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 - we performed competitive transplantation experiments using both lethally irradiated WT (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using BM cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only approximately 6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism after transplantation in unconditioned Cxcr4+/w recipient BM supported more than 70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days after transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning.
Epigenetic Aging in Major Depressive Disorder
Authors: Laura K.M. Han, Moji Aghajani, Shaunna L. Clark, Robin F. Chan, Mohammad W. Hattab, Andrey A. Shabalin, Min Zhao, Gaurav Kumar, Lin Ying Xie, Rick Jansen, Yuri Milaneschi, Brian Dean, Karolina A. Aberg, Edwin J.C.G. van den Oord, Brenda W.J.H. Penninx
Journal: American Journal of Psychiatry (2018)

Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue.DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain.Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes.As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.
The TIM3-Gal9 immune checkpoint axis is inter-linked with severity of Alcoholic Liver Disease
Authors: A. Riva, H. Adams, V. Patel, S. Azarian, G. Wright, S. Tarff, K. Katzarov, M. Simonova, T. Hadzhiolova, S. Pavlova, R. Williams, A. Evans, S. Chokshi
Journal: Journal of Hepatology (2018)
ELECTROMAGNETIC ASSISTED ENDOSCOPIC SUBMUCOSAL DISSECTION IS MORE EFFICIENT THAN WATER-JET ASSISTED AND CONVENTIONAL ESD IN EXPERIMENTAL MODEL
Authors: M Sánchez Alonso, E Rodríguez Sánchez, E de la Santa Belda, P Olivencia Palomar, R Salmoral Luque, J Olmedo Camacho, FJ Redondo Calvo, J Rodríguez Sánchez
Journal: Endoscopy (2018)

The adequate visualization of the dissection line, inside the submucosal layer, supposes the main challenging issue in endoscopic submucosal dissection (ESD). For this reason, several counter traction methods have been developed focused on overcoming this handicap. One of which, Magnetic anchor guided – ESD (MG-ESD) is an attractive alternative. However, the usefulness of this approach has been scarcely assessed and compared with other ESD strategies. Therefore, the aim of this study is to compare three different ESD alternatives in experimental faction.
Cost-Effectiveness Analyses of the 21-Gene Assay in Breast Cancer: Systematic Review and Critical Appraisal
Authors: Shi-Yi Wang, Weixiong Dang, Ilana Richman, Sarah S. Mougalian, Suzanne B. Evans, Cary P. Gross
Journal: Journal of Clinical Oncology (2018)

Purpose Prior studies examining cost effectiveness of the 21-gene assay (Oncotype DX [ODX]) for women with hormone receptor-positive, early-stage breast cancer have yielded disparate results. We aimed to explore why these analyses may have yielded different conclusions. Methods We conducted a systematic literature review of cost-effectiveness analyses (CEAs) of ODX. We examined the extent to which the structure of CEA modeling, the assumptions of the models, and the selection of input parameters influenced cost-effectiveness estimates. We also explored the prevalence of industry funding and whether industry funding was associated with study designs favoring ODX. Results We identified 27 analyses, 15 of which received industry funding. In 18 studies, the clinical characteristics (eg, tumor size and grade) commonly used to make chemotherapy decisions were not incorporated into simulation modeling; thus, these studies would favor ODX being cost effective and might not reflect clinical practice. Most studies ignored the heterogeneous effect of ODX on chemotherapy use; only five studies assumed that ODX would increase chemotherapy use for clinically low-risk patients but decrease chemotherapy use for clinically high-risk patients. No study used population-based joint distributions of ODX recurrence score and tumor characteristics, and 12 studies inappropriately assumed that chemotherapy would increase distant recurrence for the low recurrence score group; both approaches overestimated the benefits of ODX. Industry-funded studies tended to favor ODX; all five studies that reported ODX as being cost saving were industry funded. In contrast, two studies that reported an incremental cost-effectiveness ratio > $50,000 per quality-adjusted life-year were not funded by industry. Conclusion Although a majority of published analyses indicated that ODX is cost effective, they incorporated study designs that can increase the risk of bias.
Budesonide Suppositories Are Effective and Safe for Treating Acute Ulcerative Proctitis
Authors: Wolfgang Kruis, Viacheslav Neshta, Marina Pesegova, Olga Alekseeva, Pavel Andreev, Oleksii Datsenko, Olena Levchenko, Sayar Abdulkhakov, Yuriy Lozynskyy, Yuriy Mostovoy, Konstantin Soloviev, Andrey E. Dorofeyev, Michael Vieth, Michael Stiess, Roland Greinwald, Ralf Mohrbacher, Britta Siegmund
Journal: Clinical Gastroenterology and Hepatology (2018)

Background & AimsAlthough proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis.MethodsWe performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency.ResultsThe mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%–85% of patients).ConclusionsIn a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41.
Association of malignant potential of BRAF mutant colorectal cancer with coexpression of PD-L1.
Authors: Eiji Shinozaki, Tsuyoshi Konishi, Seiji Sakata, Hiroki Osumi, Masashi Ueno, Kensei Yamaguchi, Kengo Takeuchi
Journal: Journal of Clinical Oncology (2018)

643 Background: PD-L1 is a member of the B7/CD28 family that regulates immune response, and also well known as targets for immune checkpoint inhibitor. On the other hand BRAF mutation (MT) is recognized as a strongly poor prognostic factor in colorectal cancer (CRC). Recently in addition to the RAS gene, a lot of new knowledge about some molecules playing an important role in the process of carcinogenesis or drug resistance, and emerging molecules as targets for new treatments have been reported. In this research, we aim to address the clinical significance of PD-L1 expression in colorectal carcinoma correlation between emerging molecules and differences through clinical stages in CRC using tissue array. Methods: Consecutive patients who underwent surgery in our hospital from June 2003 to March 2011 were enrolled in this study. Tissue array based profiling of emerging molecules was performed on archival samples using immunohistochemistry for BRAF, MLH1/MSH2/MSH6/PMS2, CDX2, HER2 and PD-L1. We analyzed PD-L1 expression and correlation with molecular profile, survival, clinicopathological findings and location of primary site. Results: A total of 1030 CRC from stage 0 to IV were analyzed. The expression rates of PD-L1 were 3.6% and increased significantly in BRAF MT, dMMR, lack of CDX-2, tumor grade3 (TG3), right sided colon of primary site (25%, 37.8%, 21.6%, 22.1%, 6.9%, respectively; P &lt; 0.001). In the univariate analysis, lack of CDX2, BRAF MT and TG3 were identified as prognostic factors in whole population of this cohort. Furthermore the survival of BRAF MT and lack of CDX2 with co-expression of PD-L1 were extremely poor (median OS in stage IV; 2.6 months in both). In Particular the co-expression rates of PD-L1 in BRAF MT were increasing as the clinical stage progress regardless of dMMR. Conclusions: Our study comprehensively summarized the significance of PD-L1 expression associated with the recent emerging molecules and suggested that malignant potential of BRAF mutant CRC may be explained in part due to escape from immunity by co-expression of PD-L1. Immune checkpoint inhibitor could be a candidate of target of BRAF mutant CRC with PD-L1expression irrespective of MSI status.
Early Weight Gain in Pregnancy and Infant Birth Weight
Authors: Vincent Rigalleau, Sophie Cambos, Laurence Blanco
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
210Genome-wide analysis reveals unique H3K27ac profile in acquired and inherited human myocardial remodelling
Authors: J Pei, M Harakalova, T Treibel, B Boukens, A Vink, J Moore, J Velden, M Mokry, C Cheng, F Asselbergs
Journal: Cardiovascular Research (2018)

Introduction:The changing landscape of chromatin activity is a crucial factor in transcriptional gene regulation.It is an important hallmark of diseases, however it has not yet been investigated systematically in human remodelled myocardium.Purpose: To address this gap of knowledge, we aim to reveal genome-wide chromatin activity based on myocardial samples from patients either with acquired myocardial remodelling due to severe aortic stenosis (AS) or inherited myocardial remodelling in patients with hypertrophic cardiomyopathy (HCM) due to mutated MYBPC3 gene; and donors without myocardial remodelling.Methods: Myocardial samples from 20 AS patients, 14 HCM patients and 5 healthy controls were included.We performed chromatin immunoprecipitation followed by sequencing using H3K27ac histon mark to identify differentially acetylated regions among three groups on a genome-wide scale.Comprehensive in silico analyses were performed, including (1) gene and pathway annotation of the whole dataset, (2) identification of transcription factor binding motifs and interacting genes, (3) identification of acquired-and inherited-specific H3K27ac signatures in remodelled myocardium.Results: In total, 5,634 regions with more activity (hyperacetylated) and 5,724 regions with less activity (hypoacetylated) were detected in acquired myocardial remodelling group compared to controls (FDR<0.05); while 7,216 hyperacetylated regions and 7,214 hypoacetylated regions were detected in inherited myocardial remodelling group compared to controls.Pathway annotation showed that genes in the vicinity of differentially acetylated regions were most enriched for fibrosis formation and decreased cell metabolism.Conclusions: This study presents for the first time a genome wide overview of H3K27ac profile using human cardiac tissue to study chromatin regulatory regions in both acquired and inherited myocardial remodelling.It demonstrates that chromatin regulatory signatures can provide valuable new information and aid in discovery of key pathways and transcription mechanisms in disease aetiology. 211High glucose exposure promotes epigenetic activation of pro-inflammatory RELA/p65 gene in cord blood-derived CD341 stem cells
B-Type Natriuretic Peptide Assessment in Patients Undergoing Revascularization for Left Main Coronary Artery Disease
Authors: Björn Redfors, Shmuel Chen, Aaron Crowley, Ori Ben-Yehuda, Bernard J. Gersh, Nicholas J. Lembo, W. Morris Brown, Adrian P. Banning, David P. Taggart, Patrick W. Serruys, Arie Pieter Kappetein, Joseph F. Sabik, Gregg W. Stone
Journal: Circulation (2018)

Background: Elevated B-type natriuretic peptide (BNP) is reflective of impaired cardiac function and is associated with worse prognosis among patients with coronary artery disease (CAD). We sought to assess the association between baseline BNP, adverse outcomes, and the relative efficacy of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in patients with left main CAD. Methods: The EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized patients with left main CAD and low or intermediate SYNTAX scores (Synergy Between PCI With TAXUS and Cardiac Surgery) to PCI with everolimus-eluting stents versus CABG. The primary end point was the composite of all-cause death, myocardial infarction, or stroke. We used multivariable Cox proportional hazards regression to assess the associations between normal versus elevated BNP (≥100 pg/mL), randomized treatment, and the 3-year risk of adverse events. Results: BNP at baseline was elevated in 410 of 1037 (39.5%) patients enrolled in EXCEL. Patients with elevated BNP levels were older and more frequently had additional cardiovascular risk factors and lower left ventricular ejection fraction than those with normal BNP, but had similar SYNTAX scores. Patients with elevated BNP had significantly higher 3-year rates of the primary end point (18.6% versus 11.7%; adjusted hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.16–2.28; P =0.005) and higher mortality (11.5% versus 3.9%; adjusted HR, 2.49; 95% CI, 1.48–4.19; P =0.0006), both from cardiovascular and noncardiovascular causes. In contrast, there were no significant differences in the risks of myocardial infarction, stroke, ischemia-driven revascularization, stent thrombosis, graft occlusion, or major bleeding. A significant interaction ( P interaction =0.03) was present between elevated versus normal BNP and treatment with PCI versus CABG for the adjusted risk of the primary composite end point at 3 years among patients with elevated BNP (adjusted HR for PCI versus CABG, 1.54; 95% CI, 0.96–2.47) versus normal BNP (adjusted HR, 0.74; 95% CI, 0.46–1.20). This interaction was stronger when log(BNP) was modeled as a continuous variable ( P interaction =0.002). Conclusions: In the EXCEL trial, elevated baseline BNP levels in patients with left main CAD undergoing revascularization were independently associated with long-term mortality but not nonfatal adverse ischemic or bleeding events. The relative long-term outcomes after PCI versus CABG for revascularization of left main CAD may be conditioned by the baseline BNP level. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01205776.
Appropriateness of inclusion criteria according to transaminases ALT in studies assessing performances of non-invasive tests in type-2 diabetes patients (T2D)
Authors: T. Poynard, F. Charlotte, V. Paradis, Y. Ngo, M. Munteanu, V. Peta, R. Pais, V. Ratziu, C. Laouenan, P. Stanislas, C. Boitard, D. Valla
Journal: Journal of Hepatology (2018)