tbuckley/cabot-search huggingface dataset:
Considering the Links Between Nonalcoholic Fatty Liver Disease and Insulin Resistance: Revisiting the Role of Protein Kinase C ε
Authors: Varman T. Samuel, Max C. Petersen, Brandon M. Gassaway, Daniel F. Vatner, Jesse Rinehart, Gerald I. Shulman
Journal: Hepatology (2019)

Samuel, Varman T. M.D., Ph.D.; Petersen, Max C. M.D.; Gassaway, Brandon M. Ph.D.; Vatner, Daniel F. M.D., Ph.D.; Rinehart, Jesse Ph.D.; Shulman, Gerald I. M.D., Ph.D., F.A.C.P., M.A.C.E.Editor(s): Corey, Kathleen E.4; Malhi, Harmeet5 Author Information
CBP/p300 Drives the Differentiation of Regulatory T Cells through Transcriptional and Non-Transcriptional Mechanisms
Authors: Joseph Castillo, Esther Wu, Christopher Lowe, Shrividhya Srinivasan, Ron McCord, Marie-Claire Wagle, Sangeeta Jayakar, Melissa Gonzalez Edick, Jeffrey Eastham-Anderson, Bonnie Liu, Katherine E. Hutchinson, Wendell Jones, Matthew P. Stokes, Somayeh S. Tarighat, Thomas Holcomb, Andrew Glibicky, F. Anthony Romero, Steven Magnuson, Shih-Min A. Huang, Vicki Plaks, Jennifer M. Giltnane, Mark R. Lackner, Zineb Mounir
Journal: Cancer Research (2019)

Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of CBP/p300 loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering proinflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring CBP/p300 loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300, with potential clinical implications on alteration of the immune landscape. SIGNIFICANCE: This study provides insights into the dynamic role of CBP/p300 in the differentiation of Tregs, with potential clinical implications in the alteration of the immune landscape in follicular lymphoma.
PS1387 CARFILZOMIB IN RELAPSED AND REFRACTORY MULTIPLE MYELOMA (RRMM): FRAILTY SUBGROUP ANALYSIS FROM PHASE 3 ASPIRE AND ENDEAVOR
Authors: T. Facon, R. Niesvizky, K. Weisel, S. Bringhen, P.J. Ho, M. Obreja, Z. Yang, Z. Klippel, J. Blaedel, K. Mezzi, D. Siegel
Journal: HemaSphere (2019)

Background: Carfilzomib (K)‐based regimens improved progression‐free survival (PFS) and overall survival (OS) in relapsed and refractory multiple myeloma (RRMM) patients (pts) in ASPIRE (K [27 mg/m2]‐lenalidomide‐dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m2]‐dexamethasone [Kd56] vs bortezomib‐dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). Aims: We assessed post‐hoc pt outcomes by frailty status. Methods: PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history‐derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail. Results: Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K‐based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment‐emergent adverse events are summarized in the Table. Summary/Conclusion: Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit‐risk profile of KRd and Kd56 regardless of frailty score. image
PureCLIP: capturing target-specific protein–RNA interaction footprints from single-nucleotide CLIP-seq data
Authors: Sabrina Krakau, Hugues Richard, Annalisa Marsico
Journal: Genome biology (2017)

The iCLIP and eCLIP techniques facilitate the detection of protein–RNA interaction sites at high resolution, based on diagnostic events at crosslink sites. However, previous methods do not explicitly model the specifics of iCLIP and eCLIP truncation patterns and possible biases. We developed PureCLIP ( https://github.com/skrakau/PureCLIP ), a hidden Markov model based approach, which simultaneously performs peak-calling and individual crosslink site detection. It explicitly incorporates a non-specific background signal and, for the first time, non-specific sequence biases. On both simulated and real data, PureCLIP is more accurate in calling crosslink sites than other state-of-the-art methods and has a higher agreement across replicates.
Abstract 16074: Risk of Blood Transfusion(s) With New Oral Anticoagulants for Short-Term Thromboprophylaxis in Hip and Knee Surgery: Insights From a Meta-Analysis of Fifteen Randomized Trials Including 36,176 Patients
Authors: Parasuram Krishnamoorthy, Saurav Chatterjee, Jalaj Garg, Partha Sardar, Franz Messerli, Debabrata Mukherjee
Journal: Circulation (2014)

Introduction: Blood transfusions have been associated with poor outcomes in cardiac patients. The objective of our study was to systematically examine the overall risk of blood transfusion with new oral anticoagulants (NOACs) and individually in thromboprophylaxis for hip and knee surgery. Hypothesis: Treatment with NOACs is safe for short-term thromboprophylaxis in patients undergoing hip and knee surgery compared with conventional therapy. Methods: PubMed, Cochrane CENTRAL, EMBASE, EBSCO, Web of Science and CINAHL databases were searched from January 01, 2001 through September 30, 2013. Systemic review of randomized controlled trials (RCTs) comparing the use of NOACs (apixaban, dabigatran and rivaroxaban) with conventional therapy was performed. Clinical and outcome data were extracted from individual studies by 2 independent authors. Primary endpoint of interest was transfusion events in the NOAC and comparator arms. Random effects model was used to pool event rates and results were expressed as risk ratios (RR) with 95% confidence intervals (CIs). Results: Fifteen randomized controlled trials (RCTs) including a total of 36,176 patients were included for analysis. Transfusion events were not higher with use of NOACs in comparison to all comparators in patients undergoing hip and knee surgery- RR 1.02 (95% CI 0.98-1.06), p=0.40. Statistical heterogeneity was negligible (I2=22%). Conclusions: Blood transfusion events with NOAC use were not significantly higher than that with conventional drugs in thromboprophylaxis for hip and knee surgery patients, as noted in evidence from contemporary RCTs.
Abstract P039: Longitudinal measures of serial plasma phospholipid de novo lipogenesis fatty acids and incident congestive heart failure in older adults: The Cardiovascular Health Study
Authors: Yujin Lee, Heidi T Lai, Marcia C de Oliveira Otto, Rozenn N Lemaitre, Xiaoling Song, David S Siscovick, Dariush Mozaffarian
Journal: Circulation (2018)

Introduction: De novo lipogenesis (DNL) is an endogenous pathway for converting excess carbohydrates and proteins into fatty acids (FAs). While elevated DNL is linked to several metabolic abnormalities, little is known about associations of longitudinal changes in DNL FAs with incident congestive heart failure (CHF), a growing condition in older adults. Methods: We investigated relations of longitudinal changes in DNL FAs, measured at year 0, year 6, and year 13, with incident CHF using serial measures of plasma phospholipid myristic acid (14:0), palmitic acid (16:0), 7-hexadecenoic acid (16:1n-9), palmitoleic acid (16:1n-7), stearic acid (18:0), oleic acid (18:1n-9), and cis-vaccenic acid (18:1n-7). Time-varying covariates were measured using standardized methods in 2,005 older adults with two or more FA measures and free of CHF at baseline. Incident CHF was centrally adjudicated using medical records. Risk was assessed by multivariable-adjusted Cox proportional hazards. Results: During 14,628 person-years, 553 CHF events occurred. After multivariate adjustment, serial changes in 16:0, 16:1n-9, and 18:1n-7 were positively associated with incident CHF, with HRs (95% CI) for each 30% change in levels of 2.84 (1.50, 5.37), 1.16 (1.00, 1.33), and 1.42 (1.15, 1.77), respectively ( Table ). Findings were similar in sensitivity analyses excluding individuals with prevalent coronary heart disease (not shown). In analyses evaluating absolute, rather than changes in, DNL FA levels, the associations of 16:0, 16:1n-9, and 18:1n-7 with incident CHF were no longer statistically significant although with consistent directions of association (not shown). Neither changes nor absolute levels of 14:0, 16:1n-7, 18:0, and 18:1n-9 were associated with CHF. Conclusion: Serial changes in plasma phospholipid 16:0, 16:1n-9, and 18:1n-7 were associated with an elevated risk of CHF in older adults. These results indicate that potential mechanisms of risk, especially related to DNL, deserve further investigation.
Adaptive Strategies of the Candidate Probiotic E. coli Nissle in the Mammalian Gut
Authors: Nathan Crook, Aura Ferreiro, Andrew J. Gasparrini, Mitchell W. Pesesky, Molly K. Gibson, Bin Wang, Xiaoqing Sun, Zevin Condiotte, Stephen Dobrowolski, Daniel Peterson, Gautam Dantas
Journal: Cell Host & Microbe (2019)
The Art of Caregiving
Authors: Michael Tran Duong
Journal: JAMA Neurology (2019)

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Beyond the SNP Threshold: Identifying Outbreak Clusters Using Inferred Transmissions
Authors: James Stimson, Jennifer Gardy, Barun Mathema, Valeriu Crudu, Ted Cohen, Caroline Colijn
Journal: Molecular Biology and Evolution (2018)

Whole-genome sequencing (WGS) is increasingly used to aid the understanding of pathogen transmission. A first step in analyzing WGS data is usually to define "transmission clusters," sets of cases that are potentially linked by direct transmission. This is often done by including two cases in the same cluster if they are separated by fewer single-nucleotide polymorphisms (SNPs) than a specified threshold. However, there is little agreement as to what an appropriate threshold should be. We propose a probabilistic alternative, suggesting that the key inferential target for transmission clusters is the number of transmissions separating cases. We characterize this by combining the number of SNP differences and the length of time over which those differences have accumulated, using information about case timing, molecular clock, and transmission processes. Our framework has the advantage of allowing for variable mutation rates across the genome and can incorporate other epidemiological data. We use two tuberculosis studies to illustrate the impact of our approach: with British Columbia data by using spatial divisions; with Republic of Moldova data by incorporating antibiotic resistance. Simulation results indicate that our transmission-based method is better in identifying direct transmissions than a SNP threshold, with dissimilarity between clusterings of on average 0.27 bits compared with 0.37 bits for the SNP-threshold method and 0.84 bits for randomly permuted data. These results show that it is likely to outperform the SNP-threshold method where clock rates are variable and sample collection times are spread out. We implement the method in the R package transcluster.
Abstract 1739: Fractalkine/CX3CR1 and MCP-1/CCR2 Act in a Complementary Way to Promote the Development of Atherosclerosis
Authors: Stephane Potteaux, Christophe Combadiere, Stephanie Riou, Tabassome Simon, Joffrey Zoll, Bruno Esposito, Cedric Lecureuil, Stephanie Lehoux, Alain Tedgui, Ziad Mallat
Journal: Circulation (2006)

Both Fractalkine/CX3CR1 and MCP-1/CCR2 pathways are known to be essential in leukocyte recruitment, which is the first step in the development of atherosclerosis. In vitro studies suggest that frac...
THU0501 MUSCULOSKELETAL DISORDERS IN TYPE 1 AND 2 DIABETIC PATIENTS: PREVALENCE AND ASSOCIATION WITH MICROVASCULAR COMPLICATIONS OF DIABETE
Authors: hamza toufik, Mohamed A Ghassem, Julien Djossou, Najlae EL Ouardi, Abderrahim Majjad, Abdellah EL Maghraoui
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Diabetes mellitus (DM), a worldwide high prevalence disease, is associated with a large variety of musculoskeletal (MS) disorders. They are poorly treated, as compared to microvascular complications. However, they are a common source of disability. <h3>Objectives:</h3> We designed this study to assess the prevalence of MS disorders among diabetic patients and their relation to microvascular complications of diabetes. <h3>Methods:</h3> A cross-sectional study enrolled consecutive subjects with diabetes seen in the Endocrinology department. We recorded age of patients, sex, body mass index, type and duration of diabetes, Long-term glycemic control assessed by hemoglobin A1c levels, and lipid profile. Musculoskeletal and microvascular disorders assessment was done by detailed history with clinical examinations and investigations if needed. <h3>Results:</h3> A total of 376 subjects were studied, (84.6% had type 2 diabetes). The mean age was 52.5±13.9 years, 41% had one or more microvascular complications, among which retinopathy was present in 28.2%, nephropathy in 16.1% and neuropathy in 12.8%. Moreover, 23.4% of the patients had one or more musculoskeletal disorders. Shoulder capsulitis was present in 12.5%; carpal tunnel syndrome in 8.8%; trigger finger in 5.9%; and 2.9% had diabetic cheiroarthropathy. Dupuytren's contracture and Charcot foot, were found in 0.5% and 0.3% of the cases respectively. Symptomatic osteoarthritis was found in 19.4%. Musculoskeletal disorders prevalence increased with age, diabetes duration, presence of dyslipidemia and various microvascular complications. Conclusion: this study shows a high prevalence of musculoskeletal disorders in diabetic's patients which were significantly associated with advanced age, longer duration of diabetes, presence of dyslipidemia and microvascular complications. <h3><b>Disclosure of Interests:</b>&nbsp;:</h3> None declared&nbsp;
THU0350 ANTI-INFLAMMATORY AND ANTI-FIBROTIC EFFECTS OF INTRAVENOUS ADIPOSE-DERIVED STEM CELL TRANSPLANTATION IN A MOUSE MODEL OF BLEOMYCIN-INDUCED SCLERODERMA
Authors: Takayasu Suzuka, Takuya Kotani, Shogo Matsuda, Masaaki Ii, Tohru Takeuchi, Shigeki Arawaka, Koji Nagai, Yumiko Wada
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microvascular damages and fibrosis. The main lesions of SSc are peripheral circulation insufficiency, sclerodermia, and interstitial pneumonia. Skin lesions are related to patient's ADL and QOL, however there is no effective treatment for normalizing the disease state. Adipose-derived stem cells (AdSCs) have recently been considered a useful treatment tool for autoimmune disease because of their anti-inflammatory and immunosuppressive effects (ref). <h3>Objectives:</h3> We investigated the therapeutic effect of intravenous mouse AdSCs (mAdSCs) transplantation in a SSc mouse model. <h3>Methods:</h3> SSc was induced by bleomycin (BLM) in Balb/c mice, and the mice were assigned in the following groups: 1. Control (BLM-SSc), 2. mAdSCs (1.0×10<sup>4</sup> cells), 3. mAdSCs (1.0×10<sup>5</sup> cells). After the administration of BLM, mAdSCs were injected via a tail vein on day 7. The mice were sacrificed at 14 days after mAdSCs injection, and the skins were harvested for histological analysis. <h3>Results:</h3> In mAdSCs (1.0×10<sup>5</sup> cells) group, thickening of skin, hydroxyproline content, infiltration of inflammatory cells, gene expression of inflammatory cytokines, and fibrotic factors were significantly reduced compared with control group (Figure). But in mAdSCs (1.0×10<sup>4</sup> cells) group, there were no reduction of them. mAdSCs did not accumulate in skin. The levels of MMP-2, MMP-9, and COL1A1 mRNA expression at 21 days after BLM administration were significantly lower in mAdSCs (1.0×10<sup>5</sup> cells) group compared with those in control group. <h3>Conclusion:</h3> Intravenous mAdSCs inhibited both skin inflammation and fibrosis of BLM-SSc mice in a dose-dependent manner. <h3>References:</h3> [1] Cell Transplant 2015.24: 2297-2305. [2] Journal of Autoimmunity, 2016. 70: 31-39. <h3>Acknowledgement:</h3> This study was supported by Grants-in-Aid for Scientific Research-KAKENHI- of Japan (Young Scientists B; 17K15761, 17K16216). <h3>Disclosure of Interests:</h3> None declared
Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications
Authors: Tathiane M Malta, Camila F de Souza, Thais S Sabedot, Tiago C Silva, Maritza S Mosella, Steven N Kalkanis, James Snyder, Ana Valeria B Castro, Houtan Noushmehr
Journal: Neuro-Oncology (2017)

Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.
PB2234 MUTATIONAL SIGNATURES AFFECT THE PHENOTYPIC PRESENTATION OF DISEASE SUBTYPES IN MPN PATIENTS FROM BOSNIA AND HERZEGOVINA
Authors: E. Islamagic, S. Kurtovic, H. Komic, A. Dizdarevic‐Rekic, A. Burekovic, A. Uzunovic, A. Kurtovic‐Kozaric
Journal: HemaSphere (2019)

Background: Philadelphia‐negative myeloproliferative neoplasms (MPNs), including PV, ET, PMF, and MPN‐U are a group of clonal myeloid disorders characterized by myeloproliferation without dysplasia. WHO 2016 revision lists the presence of driver mutations as one of several major criteria in the diagnosis of MPN patients. MPN subtypes have overlapping clinical symptoms and a common molecular basis. Aims: The aim of this study was to evaluate disease phenotypes and evolution in regards to the detected JAK2, CALR and MPL mutations in the population of MPN patients in Bosnia and Herzegovina. Also, we compared hematologic and clinical features of ET patients carrying either JAK2 or CALR mutations with JAK2 positive PV patients in order to determine the correlation of clinical features and disease evolution. Methods: A cohort of 138 patients diagnosed with MPN and treated at Clinical Center of the University of Sarajevo and Cantonal Hospital Zenica, in the period from January 2000 to June 2018 were included in this retrospective study. Analyzed patients were subcategorized according to BCR‐ABL negative MPN subtypes: ET (n = 41), PV (n = 56), PMF (n = 10), and MPN‐U (n = 31). Patients characteristics included full blood count, bone marrow characteristics, hepato/splenomegaly, overall survival as well as mutational status of JAK2 , CALR , and MPL genes. Comparisons of quantitative variables between groups of patients were carried out by one‐way ANOVA. Correlation between numerical variables was tested by the Spearman's coefficient. Survival probabilities were estimated with the Kaplan‐Meier method and compared using the log‐rank test. Data were analyzed using IBM SPSS v.21. Results: In the present work, we compared hematologic and clinical features of patients with JAK2 ‐mutated ET with those of patients with CALR ‐mutated ET and related the findings to features observed in patients with PV. Median follow‐up was 33 months (50, 45.5, 69 and 20 months for PV, ET, PMF and MPN‐U subtypes, respectively). We found that JAK2 V617F + patients had higher values for RBC, Hb and Hct compared to CALR + patients (p&lt;0.05). MPL + patients had higher values for Plt compared to JAK2 V617F + patients (p&lt;0.05). The mutant allele burden in JAK2 V617F + PV and ET patients was directly correlated with hematological parameters (ρ = 0.36, ρ = 0.14, and ρ = 0.21 for Hb, RBC, and Hct, respectively) and inversely correlated with Plt count (ρ = −0.12). JAK2 V617F + patients had worse survival compared to CALR + and MPL + patients, eventhough significant differences were not found (p &gt; 0.05). Summary/Conclusion: Mutant allele burden is a determinant of the clinical phenotypic features in JAK2 V617F MPN patients. Mutational profile define clinical course and outcomes in MPN subtypes.