tbuckley/cabot-search huggingface dataset:
The Role of m6A/m-RNA Methylation in Stress Response Regulation
Authors: Mareen Engel, Carola Eggert, Paul M. Kaplick, Matthias Eder, Simone Röh, Lisa Tietze, Christian Namendorf, Janine Arloth, Peter Weber, Monika Rex-Haffner, Shay Geula, Mira Jakovcevski, Jacob H. Hanna, Dena Leshkowitz, Manfred Uhr, Carsten T. Wotjak, Mathias V. Schmidt, Jan M. Deussing, Elisabeth B. Binder, Alon Chen
Journal: Neuron (2018)

Highlights•m6A/m mRNA methylation in the adult mouse brain is regulated by stress•m6A/m mRNA regulation is brain region, time, and gene specific•Mettl3 and Fto cKO alter m6A/m, fear memory, expression, and synaptic plasticity•The m6A/m glucocorticoid response is impaired in major depressive disorder patientsSummaryN6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m6A/m-seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m6A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.Graphical abstract
Abstract 47: Atrial Fibrillation is Associated With Increased Risk of Incident Venous Thromboembolism: The Atherosclerosis Risk in Communities Study
Authors: Pamela L Lutsey, Faye L Norby, Alvaro Alonso, Mary Cushman, Lin Y Chen, Erin D Michos, Aaron R Folsom
Journal: Circulation (2017)

Background: It is well-established that atrial fibrillation (AF) is associated with thrombus formation in the left atrium, which can lead to ischemic stroke. Case reports, autopsies, and transesophageal echo data have indicated that clot formation also occurs in the right atrium (i.e. right-side intracardiac thrombosis) of AF patients, which could lead to pulmonary embolism (PE). However, it is unclear whether this occurrence is common. Objective: Test the hypotheses that individuals with incident AF are at elevated risk of developing venous thromboembolism (VTE), and that the association will be stronger for those presenting with PE alone versus PE and deep vein thrombosis (DVT) or DVT alone. Methods: A total of 15,205 Atherosclerosis Risk in Communities (ARIC) study participants, aged 45-64 years, were followed from baseline (1987-1989) to 2011 for incidence of AF and VTE (median follow-up 19.8 years). Incident AF and VTE events were identified via active surveillance and defined by relevant hospital discharge ICD codes. VTE events were validated by medical record review. Multivariable-adjusted Cox proportional hazards regression models were used, with AF modeled as a time-dependent covariate. We also evaluated separately risk of PE without evidence of DVT, DVT without PE, and events presenting with both PE and DVT. Results: At baseline participants were on average 54 years old, 55% female and 26% black. In the absence of AF there were 678 VTE events, for an incidence rate of 2.6 per 1000 person-years. After an AF diagnosis there were 77 events, with an incidence rate of 7.1 per 1000 person-years. In multivariable-adjusted models, having AF (versus no AF) was associated with a greater risk of incident VTE; the HR (95% CI) was 2.10 (1.65-2.68) after adjustment for demographics, 1.82 (1.42-2.32) additionally accounting for numerous AF and VTE risk factors, and 1.97 (1.53-2.53) after further adjusting for time-dependent anticoagulant use. When we restricted to PE events without evidence of DVT there were 188 events in total, of which 19 occurred following a diagnosis of AF. The HR for AF (versus no AF) was 1.53 (0.92-2.56) in fully adjusted models. For DVT alone there were 384 events in total, of which 48 occurred after AF diagnosis; the HR for AF was 2.43 (1.77-3.33). Among the 116 events presenting with both DVT and PE, 10 occurred after AF diagnosis, and the HR for AF was 1.36 (0.67-2.75). Conclusions: Diagnosis with AF was associated with a nearly 2-fold increased risk of incident VTE. The association was not stronger when isolated to those with PE without DVT, suggesting that higher risk of VTE among AF patients may be due to either the coagulation abnormalities that accompany AF, or shared risk factors that were not fully accounted for in this analysis.
PB2196 ANTIPLATELET THERAPY IN ESSENTIAL THROMBOCYTHEMIA: LABORATORY STUDY OF LOW‐DOSE ASPIRIN
Authors: R. Cacciola, V. Vecchio, E. Gentilini Cacciola, E. Cacciola
Journal: HemaSphere (2019)

Background: The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombosis. The daily low‐dose aspirin (ASA) is a cornerstone in the prevention of the thrombotic events. In the ET an accelerated platelet turnover translates in a renewal of the drug target shortening the duration of cyclooxygenase (COX‐1) inhibition and may dictate new dosing strategies particularly in ASA “low‐responders” patients. Aims: Therefore, we evaluated platelet count, β‐thromboglobulin (β‐TG) and platelet factor 4 (PF4), as markers of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot firmness. Methods We studied 60 patients (20 men, 40 women; mean age 51 years, range 32‐70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β‐TG and PF4 were determined by ELISA. ASA platelet sensitivity and CT, CFT and MCF were measured by Platelet Function Analyzer (PFA‐100) and by ROTEM delta, respectively. Results: The mean platelet count was 455 ± 200 × 109/L. All patients had normal β‐TG and PF4 (12 ± 5 IU/ml and 4 ± 1 IU/ml), prolonged C/EPI closure time (T, unit: s, n.v. 84‐160 s) (249 ± 40 s), normal CT (CT, unit: s. n.v. 100‐240 s) (110 ± 20 s), normal CFT (CFT, unit: s, n.v. 30‐110 s) (45 ± 5 s) and normal MCF (MCF, unit: mm, n.v. 50‐72 mm) (61 ± 2 mm). Summary/Conclusion: These findings suggest that in ET patients the daily low‐dose ASA represents an optimal dosing strategy.
Abstract 14367: Mitochondrial Protein Acetylation in Skeletal Muscle Was Associated With Exercise Intolerance in Heart Failure After Myocardial Infarction in Mice
Authors: Masaya Tsuda, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takashi Yokota, Wataru Mizushima, Takaaki Furihata, Junichi Matsumoto, Takashi Katayama, Takayuki Nakajima, Satoshi Maekawa, Hideo Nambu, Ryosuke Shirakawa, Naoya Kakutani, Koichi Okita, Hiroyuki Tsutsui
Journal: Circulation (2016)

Background: Exercise intolerance is a major clinical manifestation and an independent predictor of poor prognosis in heart failure (HF) patients, due largely to skeletal muscle abnormalities. Prote...
NFATc1 protein expression and its relationship with clinical characteristics in breast cancer.
Authors: Xinmei Kang, Shuhuai Wang, Ying Song
Journal: Journal of Clinical Oncology (2012)

e11095 Background: The nuclear factors of activated T cells (NFATs) have been previously studied in the immune system as transcription factors during the activation of T lymphocyte. In the recent years, emerging evidences have showed that they may play an important role in the development and progression of human cancer. In this study we investigate NFATc1 protein expression and its relationship with clinical characteristics in breast cancer. Methods: NFATc1 protein expression was determined by immunohistochemical analysis in 86 surgically resected breast cancer samples between Jul 2004 and Jun 2006. The relationship between NFATc1 expression and clinical characteristics of breast cancer was analyzed by multivariate logistic regression and survival analyses. Results: NFATc1 protein was significantly overexpressed in breast cancer tumor cells compared with the matched normal tissues. High expression of NFATc1 proteins was associated with high tumor grade, lymph nodes involved and shorter disease free survival (P&lt;0.05), but there was no correlation between NFATc1 protein expression and tumor size, hormone receptor status or overall survival (P&gt;0.05). Conclusions: This study suggested that high NFATc1 expression was present in breast cancer and it might be involved in the process of cancer development and related to poor prognosis of breast cancer.
Fitness Effects of Cis-Regulatory Variants in the Saccharomyces cerevisiae TDH3 Promoter
Authors: Fabien Duveau, William Toubiana, Patricia J. Wittkopp
Journal: Molecular Biology and Evolution (2017)

Variation in gene expression is widespread within and between species, but fitness consequences of this variation are generally unknown. Here, we use mutations in the Saccharomyces cerevisiae TDH3 promoter to assess how changes in TDH3 expression affect cell growth. From these data, we predict the fitness consequences of de novo mutations and natural polymorphisms in the TDH3 promoter. Nearly all mutations and polymorphisms in the TDH3 promoter were found to have no significant effect on fitness in the environment assayed, suggesting that the wild-type allele of this promoter is robust to the effects of most new cis-regulatory mutations.
F-box and WD repeat domain-containing 7 (FBXW7) mRNA and outcome in biliary tract cancer.
Authors: Gerardo F. Arroyo, Diego Kaen, Alejandro Salvatierra, Sandra Viviana Rojo, Ruben Dario Kowalyszyn, Marcos Ortiz, Marcela Carballido, Luis Alberto Kaen, Juan Jose Zarba, Enrique Luis Roca, Carlota Costa, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Clara Mayo, Ana Gimenez Capitan, Jose Javier Sanchez, Susana Benlloch, Antoinette Lemoine, Miquel Taron, Rafael Rosell
Journal: Journal of Clinical Oncology (2012)

e14521 Background: Thestandard treatment for biliary tract cancer is gemcitabine plus platinum, but median progression-free survival (PFS) is only 5-8 months (m) (Valle et al, NEJM 2010). Gene expression or somatic mutations may influence the clinical phenotype, which will affect decisions on individualized treatment. Methods: We retrospectively analyzed tissue blocks from 54 advanced or metastatic cholangiocarcinoma, gallbladder or ampulllary cancer patients (p) treated with single-agent gemcitabine or gemcitabine plus carboplatin or cisplatin. Using RT-PCR, we analyzed the mRNA expression levels of oncogenes, tumor suppressors and DNA repair genes (BRCA1, RRM1, AEG-1, RAP80, SPINK1 and FBXW7) and correlated results with PFS, overall survival (OS) and response. In addition, FBXW7 hotspot mutations were assessed. Results: p characteristics: 72% females; median age, 60 (40-87). Only FBXW7 expression correlated with PFS and OS. When FBXW7 levels were dichotomized at the median value, PFS was 4.2 m for p with low levels vs 12.6 m for p with high levels (p=0.02). When FBXW7 expression was divided by terciles, PFS was 4.9 m for p in the lowest tercile, 7.6 for p in the intermediate tercile, and 26.9 m for p in the highest tercile (p=0.08). OS was 6.2 m for p in the lowest tercile, 8 m for p in the intermediate tercile, and not reached for p in the highest tercile. No other significant correlation was observed between expression levels of the other genes examined and PFS or OS. Only AEG-1 expression correlated with response (p=0.05). No FBXW7 hotspot mutations were detected. Conclusions: Although we did not find the FBXW7 hotspot mutations previously described in biliary tract cancer, FBXW7 mRNA expression significantly influenced PFS and OS. A separate cohort of p is being analyzed to validate the prognostic role of FBXW7.
Decreased endothelin receptor A autoantibody levels are associated with early ischaemic events in patients with giant-cell arteritis
Authors: Sebastian Klapa, Antje Müller, Andreas Koch, Harald Heidecke, Wataru Kähler, Juliane Junker, Susanne Schinke, Gabriela Riemekasten, Peter Lamprecht
Journal: Annals of the Rheumatic Diseases (2019)

Endothelin 1 (ET-1) is a potent vasoactive peptide hormone produced by endothelial cells, macrophages and vascular smooth muscle cells (VSMCs). Elevated ET-1 plasma levels have been reported in patients with ischaemic complications in giant-cell arteritis (GCA), a systemic vasculitis predominantly affecting large vessels and their branches.1 In temporal artery biopsy specimens, increased expression of ET-1 and the G protein-coupled vasoconstrictive endothelin receptor A (ETAR) has been found.2 ETAR activation induces focal adhesion kinase-mediated morphological changes and increased motility of VSMC potentially contributing to intimal hyperplasia and vascular occlusion in GCA.3 VSMC migration can be blocked by specific ETAR antagonists.3 Notably, disease-specific anti-G protein-coupled receptor autoantibody (aab) signatures have been found in different autoimmune diseases.4 5 Anti-ETAR aabs are increased and associated with pulmonary arteriolar occlusion and hypertension in systemic sclerosis.5 6 Anti-ETAR aabss induce vascular adhesion molecules, interleukin (IL)-8 and chemokine ligand CCL-18 productions and exhibit chemotactic activity by mediating neutrophil and T cell migration.5 6

To address …
Identification of Novel Oncogenes and Tumor Suppressor Genes in Newly Diagnosed Multiple Myeloma
Authors: Brian A Walker, Christopher P. Wardell, Konstantimos Mavrommatis, Cody Cody Ashby, Michael Bauer, Mehmet Kemal Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Matthew Trotter, Anjan Thakurta, Nikhil Munshi, Gareth J. Morgan
Journal: Blood (2017)
Abstract 16812: Aortic Size in National Football League Scouting Combine Participants
Authors: Andrew Lincoln, Robert Vogel, Andrew Tucker, Reginald Dunn, Lon Castle, Richard Kovacs
Journal: Circulation (2013)

Aortic rupture is an uncommon but feared cause of sudden death in athletes. Identification of athletes at risk is a goal of pre-participation screening programs, and some athletes may be excluded f...
Satisfaction with hospital care falls as pressure mounts on NHS, finds CQC
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Satisfaction among hospital patients in England has stalled or fallen across many key indicators, show the results of a survey by the Care Quality Commission.

The healthcare sector regulator’s annual survey of hospital inpatients found that in July 2018 most people had confidence in the doctors and nurses treating them and thought that staff answered their questions clearly.1 However, in comparison with the 2017 results, more people reported lengthy delays, greater dissatisfaction with the amount of information provided when leaving hospital, and a lack of involvement in their care.

The CQCs’ survey included 144 acute care NHS trusts across England and more than 75 000 adults who had stayed …
Single-Cell Analysis of CAR-T Cell Activation Reveals A Mixed T<b>H</b>1/T<b>H</b>2 Response Independent of Differentiation
Authors: Iva Xhangolli, Burak Dura, GeeHee Lee, Dongjoo Kim, Yang Xiao, Rong Fan
Journal: Genomics Proteomics & Bioinformatics (2019)

The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor, but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cytokine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4+ helper T (TH) cells and CD8+ cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of TH1 and TH2 signature cytokines, e.g., interferon γ, tumor necrotic factor α, interleukin 5 (IL5), and IL13, as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However, rather than conforming to stringent TH1 or TH2 subtypes, single-cell analysis reveals that the predominant response is a highly mixed TH1/TH2 function in the same cell. The regulatory T cell activity, although observed in a small fraction of activated cells, emerges from this hybrid TH1/TH2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced from the majority of cells regardless of the polarization states, further contrasting CAR-T to classic T cells. Surprisingly, the cytokine response is minimally associated with differentiation status, although all major differentiation subsets such as naïve, central memory, effector memory, and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canonical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF, supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.
AB0697D CARDIOVASCULAR RISK FACTORS ARE HIGHER IN MALNOURISHED PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: Anna Wojteczek, Marcin Ziętkiewicz, Zbigniew Zdrojewski, Sylwia Małgorzewicz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Cardiovascular disease (CVD) is a well known complication in rheumatoid arthritis and systemic lupus erythematosus. Atherosclerosis (ATS) and its impact on CVD in patients with systemic sclerosis (SSc) still remains unclear. Most of studies are suggesting higher frequency of CVD in SSc in comparison to healthy controls. CVD is a leading cause of death in most developed countries, whereas in SSc population it ranges from 20 to 30%. The etiology of aTS in SSc is unknown. Traditional risk factors, endothelial dysfunction and inflammation can contribute to aTS in SSc population. However, there is lack of data about the impact of the nutritional status on CVD factors in SSc patients. <h3>Objectives:</h3> The aim of the study was to determine CVD factors among SSc patients depending on the nutritional status. <h3>Methods:</h3> In 55 patients with SSc (72,7% well-nourished, 18,1% malnourished, 9,1% pre-cachexia) and 49 healthy controls we measured markers of endothelial dysfunction (asymmetric dimethylarginine - aDMA), inflammation (C-reactive protein - CRP, high sensitivity C-reactive protein - hsCRP, interleukin 6 - IL-6) and dyslipoproteinemia (oxidized low-density lipoprotein - ox-LDL, high-density lipoprotein- HDL, low-density lipoprotein – LDL and total cholesterol). Nutritional status was determined with subjective global assessment (SGA), body mass index (BMI), bioelectrical impedance analysis (BIA) and anthropometric measurements. <h3>Results:</h3> Well-nourished SSc patients had significantly higher level of IL-6 (6,4±10,1 vs. 2,8±3,6 pg/ml; p=0,002) and lower HDL cholesterol (49,9±11,6 vs. 57±13,6 mg/dl; p=0,011) in comparison to healthy control. In malnourished SSc patients there was higher concentration of aDMA (1,68±0,53 vs. 1,24±0,34 µmol/l; p=0.003), CRP (18±28,8 vs. 2,4±2,5 mg/l; p=0.04), IL-6 (21,6±34,9 vs. 2,8±3,6 pg/ml; p=0.004) and lower HDL cholesterol (42,5±18,3 vs. 57±13,6 mg/dl; p=0.01) in comparison to healthy control. Pre-cachexia SSc group had significantly lower total cholesterol (166,8±28,5 vs. 219,3±40,9 mg/dl; p=0.008) and LDL cholesterol (96,8±21,6 vs. 139,6±36 mg/dl; p=0.007). There were no differences in concentration of oxLDL and hsCRP in those groups. <h3>Conclusion:</h3> Nutritional status may play role in risk of CVD in SSc patients. Although its contribution to morbidity and mortality rates in CVD in SSc is yet to be established. <h3>Disclosure of interests:</h3> None declared
AB0217 ASSOCIATION OF EUROPEAN SCLERODERMA STUDY GROUP ACTIVITY INDEX (ESCSG-AI) WITH PROGRESSION PULMONARY ALTERATIONS BY HRCT IN PATIENTSWITH SYSTEMIC SCLEROSIS OVER A FIVE YEAR PERIOD
Authors: Olga Ovsyannikova, Lidia P. Ananyeva, Olga Koneva, Liudmila Garzanova, Oxana Desinova, Mayya Starovoytova
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. Patients with early active SSc are at great risk for progressive ILD. <h3>Objectives</h3> To assess the EScSG-AI in patients with systemic sclerosis (SSc) and interstitial lung disease over a five year period. <h3>Methods</h3> It was a longitudinal study involving 77 pts with SSc-ILD (mean age was 46,2±13,4; 69% have limited subset of the disease; 93% were female). The mean duration of follow up was 58,9±11,4 months. Pts. were investigated with HRCT twice (at first visit and at the end of the study) and according the CT-changes were divided into 3 groups: the 1st group (16 pts) with improvement; 2nd group (39 pts) without any changes and 3rd group (22 pts) with worsening of fibrosis. Disease activity was assessed by the 2001 European Scleroderma Study Group Activity Index (EScSG- AI). <h3>Results</h3> There were no significant differences between groups related to sex, frequency of diffuse form and duration disease. Mean dates of EScSG-AI score of all pts and in the each groups in first visit and the end of follow up are present in table 1. After 5 years of follow up mean values of EScSG-AI score increased significantly in group 3 and was more than 3, this actually means the activity of the disease. The mean values of EScSG-AI score in group 3 was significantly higher than in groups 1,2 (p &lt; 0,01 and p &lt; 0,04 accordingly) at the end of the study. <h3>Conclusion</h3> Mean values of EScSG-AI score associated with and were accompanied by progression pulmonary alterations in pts SSc so EScSG-AI score can be used as valuable tool for long-term follow-up studies. <h3>Disclosure of Interests</h3> None declared
Abstract 13825: Neuronal Nitric Oxide Synthase Modulates Cardiac Metabolism and Contractile Function in LV Myocytes from Hypertensive Rats
Authors: Chun Zi Jin, Ji Hyun Jang, Hae Jin Kim, Eun Yeong Seo, Sung Joon Kim, Yin Hua Zhang
Journal: Circulation (2012)

Background: Accumulating evidence has shown that fatty acid (FA)-dependent cardiac metabolism is impaired in hypertension. Whether such a modulation attenuates myocardial contractility remains elus...