tbuckley/cabot-search huggingface dataset:
Markers of progression of liver fibrotic changes in patients with chronic toxic drug-induced hepatitis
Authors: V.I. Didenko, O.M. Tatarchuk, O.P. Petishko, I.S. Konenko, S.L. Melanich
Journal: GASTROENTEROLOGY (2021)

Background. In recent years, as a result of the growing expansion of the pharmaceutical market, there has been a clear trend towards an increase in the incidence of chronic toxic drug-induced hepatitis of drug genesis (TDIH). The appearance of fibrosis is considered the most important histological change that determines the further course of the disease. Therefore, the search for non-invasive or minimally invasive markers for assessing fibrotic changes in the liver remains an urgent issue in clinical practice. The purpose was to determine the diagnostic value of immunological parameters for stratification of the severity of liver fibrosis in patients with TDIH. Materials and methods. The study included 41 patients with TDIH, who were divided into three groups: group I consisted of 12 people without liver fibrosis (F0), group II— 22 patients with moderate fibrosis (F1-F2), group III— 7 individuals with severe liver fibrosis (F3-F4). Shear wave elastography was performed using a Soneus P7 system (Ukraine-Switzerland). All patients underwent a biochemical blood test with the determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST). The subpopulation composition of lymphocytes, circulating immune complexes (CIC), the level of interleukins (IL-6, IL-10) and tumor necrosis factor α were assessed. Results.The progression of liver fibrosis is accompanied by an increase in cytolytic syndrome: patients with severe fibrosis have a 3.3-fold increase in the ALT (p&lt;0.05) compared to the controls and a 2.1-fold (p&lt;0.05) compared to that in patients with moderate fibrosis. The AST level is significantly higher— by 4.6 times (p=0.023) in patients with severe fibrosis than in those with moderate fibrosis. With the progression of liver fibrosis, there is a significant decrease in cellular immunity, an increase in the level of CIC and pro-inflammatory cytokines with a simultaneous decrease in the content of anti-inflammatory cytokines, which is confirmed by correlations between the liver stiffness index according to shear wave elastography data and the level of T-helpers (r=–0.466; p=0.03), IL-6 (r=0.364; p=0.01), IL-10 (r=–0.331; p=0.039) and CIC (r=0.381; p=0.017). Conclusions. Markers of the diagnosis of severe liver fibrosis in patients with TDIH are indicators such as the ratio of IL-6/IL-10 higher than 0.83 (sensitivity 81.8%, specificity 78.9%), CIC level more than 4.3 optical density units (sensitivity 77.3%, specificity 72.2%), the ratio of T-helpers/T-suppressors is less than or equal to 1.6 (sensitivity 72.7%, specificity 57.9%).
Abstract 115: Post-ischemic Estrogen Administration Protects the Myocardium Against Ischemia/Reperfusion Injury by Reducing Mitochondrial Protein Ubiquitination, Acetylation and Calpain10 Levels and Inhibition of the mPTP Opening via GPER1 Activation
Authors: Yansheng Feng, Ngonidzashe Benson Madungwe, Mohammad Enamul Kabir, Jean C. Bopassa
Journal: Circulation Research (2016)

Introduction: We recently found in isolated perfused hearts that acute pre-ischemic estrogen-induced cardioprotection against ischemia/reperfusion injury is mainly mediated via G protein-coupled estrogen receptor1 (GPER1) activation but not through classical estrogen receptors: alpha (ERα) and beta (ERβ). Hypothesis: We investigated whether acute post-ischemic estrogen (PI-E2) treatment can also induce cardioprotective effects via GPER1 activation in the intact animal subjected to ischemia/reperfusion injury. Methods: Male and ovariectomized female Sprague-Dawley rats were anesthetized with ketamine (80 mg/kg i.p.) and xylazine (8 mg/kg i.p.). Hearts were subjected to 35 min of the left anterior descending (LAD) artery occlusion, followed by 180 min reperfusion. An E2 bolus (50 mg/kg body weight) or PBS (same volume) was applied via the femoral vein 5 min before reperfusion and a GPER1 antagonist, G15, was given 10 min before E2. Area at risk (AAR) was identified using Evans Blue dye and myocardial infarct size assessed by TTC staining method. Mitochondria calcium retention capacity (CRC) required to induce mitochondrial permeability transition pore (mPTP) opening was assessed after 10 min reperfusion. Expression of ubiquitinated, acetylated, as well as calpains 1 and 10 proteins was measured by Western Blot in mitochondrial and cytosolic fractions. Results: We found that PI-E2 treatment reduced myocardial infarct size normalized to the AAR or the whole LV and improved mitochondrial CRC. PI-E2 treatment reduced mitochondrial protein acetylation, ubiquitination, and decreased calpain10 levels in mitochondrial but not in cytosolic fractions as compared to control, respectively. Interestingly, all these effects of E2 were abolished by addition of G15. Conclusion: Acute post-ischemic GPER1 activation by E2 induces cardioprotection against ischemia/reperfusion injury. PI-E2 effects through GPER1 involve the reduction of the levels of mitochondrial protein acetylation, ubiquitination, and calpain10. These PI-E2-GPER1 effects lead to inhibition of the mPTP opening.
P-164 MONEO: A phase II study of avelumab plus FLOT in the peri-operative treatment for patients with resectable gastric or gastroesophageal junction cancer
Authors: M. Alsina, M. Ponz-Sarvise, D. Lopez Garcia, M. Gonzalez, C. De Andrea, A. Gros, A. Vivancos, P. Jimenez Fonseca, M. Diez, V. Arrazubi, E. Sanz-García, E. Martinez de Castro, R. Guardeño Sanchez, M. Calvo Campos, C. Bugés Sánchez, F. Muñoz, J. Tabernero, G. Villacampa, S. Muñoz, I. Melero
Journal: Annals of Oncology (2021)
Hospital presentations for self-poisoning during COVID-19 in Sri Lanka: an interrupted time-series analysis
Authors: Duleeka Knipe, Tharuka Silva, Azra Aroos, Lalith Senarathna, Nirosha Madhuwanthi Hettiarachchi, Sampath R Galappaththi, Matthew J Spittal, David Gunnell, Chris Metcalfe, Thilini Rajapakse
Journal: The Lancet Psychiatry (2021)

BackgroundThere is widespread concern over the impact of public health measures, such as lockdowns, associated with COVID-19 on mental health, including suicide. High-quality evidence from low-income and middle-income countries, where the burden of suicide and self-harm is greatest, is scarce. We aimed to determine the effect of the pandemic on hospital presentations for self-poisoning.MethodsIn this interrupted time-series analysis, we established a new self-poisoning register at the tertiary care Teaching Hospital Peradeniya in Sri Lanka, a lower-middle-income country. Using a standard extraction sheet, data were gathered for all patients admitted to the Toxicology Unit with self-poisoning between Jan 1, 2019, and Aug 31, 2020. Only patients classified by the treating clinician as having intentionally self-poisoned were included. Data on date of admission, age or date of birth, sex, and poisoning method were collected. No data on ethnicity were available. We used interrupted time-series analysis to calculate weekly hospital admissions for self-poisoning before (Jan 1, 2019–March 19, 2020) and during (March 20–Aug 31, 2020) the pandemic, overall and by age (age <25 years vs ≥25 years) and sex. Individuals with missing date of admission were excluded from the main analysis.FindingsBetween Jan 1, 2019, and Aug 31, 2020, 1401 individuals (584 [41·7%] males, 761 [54·3%] females, and 56 [4·0%] of unknown sex) presented to the hospital with self-poisoning and had date of admission data. A 32% (95% CI 12–48) reduction in hospital presentations for self-poisoning in the pandemic period compared with pre-pandemic trends was observed (rate ratio 0·68, 95% CI 0·52–0·88; p=0·0032). We found no evidence that the impact of the pandemic differed by sex (rate ratio 0·64, 95% CI 0·44–0·94, for females vs 0·85, 0·57–1·26, for males; pinteraction=0·43) or age (0·64, 0·44–0·93, for patients aged <25 years vs 0·81, 0·57–1·16, for patients aged ≥25 years; pinteraction=0·077).InterpretationThis is the first study from a lower-middle-income country to estimate the impact of the pandemic on self-harm (non-fatal) accounting for underlying trends. If the fall in hospital presentations during the pandemic reflects a reduction in the medical treatment of people who have self-poisoned, rather than a true fall in incidence, then public health messages should emphasise the importance of seeking help early.FundingElizabeth Blackwell Institute University of Bristol, Wellcome Trust, and Centre for Pesticide Suicide Prevention.TranslationsFor the Sinhalese and Tamil translations of the abstract see Supplementary Materials section.
Adenine base editing reduces misfolded protein accumulation and toxicity in alpha-1 antitrypsin deficient patient iPSC-hepatocytes
Authors: Rhiannon B. Werder, Joseph E. Kaserman, Michael S. Packer, Jonathan Lindstrom-Vautrin, Carlos Villacorta-Martin, Lauren E. Young, Yvonne Aratyn-Schaus, Francine Gregoire, Andrew A. Wilson
Journal: Molecular Therapy (2021)

Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single-base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole-genome sequencing. These results reveal the feasibility and utility of base editing to correct the Z mutation in AATD patient cells.
Incidence and Outcome of Severe Thrombocytopenia Associated with Zika Virus Infection - Puerto Rico, 2016
Authors: Elizabeth A. Van Dyne, Paige Neaterour, Aidsa Rivera, Melissa Bello-Pagan, Laura Adams, Jorge Munoz-Jordan, Priscilla Baez-Merced, Myriam Garcia, Stephen H. Waterman, Nimia Reyes, Lisa C. Richardson, Tyler M. Sharp
Journal: Blood (2017)
A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion
Authors: Franziska Witte, Jorge Ruiz-Orera, Camilla Ciolli Mattioli, Susanne Blachut, Eleonora Adami, Jana Felicitas Schulz, Valentin Schneider-Lunitz, Oliver Hummel, Giannino Patone, Michael Benedikt Mücke, Jan Šilhavý, Matthias Heinig, Leonardo Bottolo, Daniel Sanchis, Martin Vingron, Marina Chekulaeva, Michal Pravenec, Norbert Hubner, Sebastiaan van Heesch
Journal: Genome biology (2021)

Abstract Background Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.
Abstract 57: Myofibrils From Pediatric IDC Patients Display Faster Relaxation Kinetics and Reduced Tension Generation
Authors: Mark Jeong, Kika Sucharov, Brian Stauffer, Amrut Ambardekar, Yin Lin, Jennifer Mahaffey, Shelley Miyamoto
Journal: Circulation Research (2016)

Objective: Pediatric patients with heart failure, compared to adults, respond differently to current armamentarium of heart failure (HF) therapeutics, indicating differences in the hearts of children and adults. We examined myofibril mechanics in children and adults with and without HF to determine: 1) baseline myofibril characteristics, 2) differences between children and adults, and 3) myofibril mechanics in the setting of HF. Methods: Myofibrils were obtained from pediatric and adult patients with IDC undergoing cardiac transplantation. Unused donor hearts were used as non-failing control (NF). Written informed consent was obtained. Myofibrils were stretched from slack length and set 5-10% above slack sarcomere length (SL), and Ca 2+ -activated and relaxed at 15°C. Mechanical and kinetic parameters: maximal tension (T max , mN/mm 2 ); rate constant of tension development ( k ACT , S -1 ); duration of slow relaxation phase ( t LIN , mSec), rate constant of fast phase relaxation ( k REL , S -1 ). Mechanical parameters ± SEM are shown. Results: Compared to NF adults, myofibrils from NF pediatric hearts had shorter SL (2.04±0.01 μm vs 2.11±0.01, p &lt; 0.0001), slower t LIN (202.7+9.0 msec vs 152.9+4.1, p &lt; 0.0001) and slower k REL (7.8+0.4 S -1 vs 15.7+0.8, p &lt; 0.0001). T max and k ACT were similar. In the adult cohort, myofibrils from adult IDC patients showed slower k ACT (0.45+0.02 S -1 vs 0.57+0.03, p &lt; 0.005) and slower k REL (11.9+0.7 S -1 vs 15.7+0.8, p &lt; 0.005). T max and t LIN were similar. In the pediatric cohort, myofibrils from IDC developed lower T max (35.3+2.5 mN/mm 2 vs 57.5+4.4, p &lt; 0.0001), and faster t LIN (136.6+3.2 msec vs 202.3+8.9, p &lt; 0.0001) and faster k REL (9.1+0.4 S -1 vs 7.8+0.4, p &lt; 0.05). k ACT was similar. Conclusion: NF myofibrils from children have shorter resting SL and slower relaxation kinetics than NF adults. While myofibrils from adults IDC result in slower activation and exponential relaxation kinetics, children with IDC display faster relaxation kinetic and reduced tension generation. These results show that myofibrils from children have fundamental differences in mechanical characteristics at baseline and in the setting of heart failure.
Non-Genotoxic Conditioning for Hematopoietic Stem Cell Transplant Using a Human Antibody Drug Conjugate Targeting C-KIT
Authors: Adam J. Hartigan, Bradley R. Pearse, Sean M. McDonough, Jennifer L. Proctor, Hillary L. Adams, Molly A. McShea, Megan D. Hoban, Rajiv Panwar, Sharon L. Hyzy, Kevin A. Goncalves, Rahul Palchaudhuri, Anthony E. Boitano, Michael P. Cooke
Journal: Blood (2017)
E-cigarette maker Juul pays $40m to North Carolina in landmark settlement
Authors: Owen Dyer
Journal: BMJ (2021)

Juul Labs, one of the world’s biggest e-cigarette manufacturers, will pay $40m (£28.9m; €33.7m) to North Carolina to settle a lawsuit that accused it of marketing to teenagers, in a case likely to set several precedents for the industry.

The deal allows the company to avoid a jury trial this summer, but lawsuits by 13 other US states and the District of Columbia are still to be resolved. There is also a consolidated suit filed against Juul in federal court by thousands of counties, cities, school districts, and other plaintiffs.

In addition to paying $40m over six years to fund addiction treatment and research in North Carolina, Juul undertook to sell its store bought products only from behind the counter and to use third party age verification systems for online sales. …
Abstract 15279: Understanding a Paradox in Patients with Myocardial Ischemia with Increased Diastolic Wall Stress. A Dobutamine Stress MR study
Authors: Jesus G Mirelis, Cosima Jahnke, Ingo Paetsch, Rolf Gebker
Journal: Circulation (2012)

BACKGROUND DSMR is a valuable tool to diagnosis ischemia in a wide spectrum of patients. The population with concentric geometry (either hypertrophy or remodeling) have unexpected lower sensitiviti...
Stopping <i>versus</i> continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study)
Authors: Wendy C. Moore, Oliver Kornmann, Marc Humbert, Claude Poirier, Elisabeth H. Bel, Norihiro Kaneko, Steven G. Smith, Neil Martin, Martyn J. Gilson, Robert G. Price, Eric S. Bradford, Mark C. Liu
Journal: European Respiratory Journal (2021)

Background The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use. Methods COMET ( NCT02555371 ) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA ( NCT01691859 ) or COSMEX ( NCT02135692 ) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed. Results Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17–2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13–2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL −1 ; ratio (stopping versus continuing) 6.19, 95% CI 4.89–7.83; p&lt;0.001). Differences in efficacy outcomes between groups were observed when assessed from week 12 (16 weeks after last mepolizumab dose). Exacerbations requiring hospitalisation/emergency department visit were rare. Adverse events in patients continuing mepolizumab were consistent with previous studies. For patients who stopped mepolizumab, the safety profile was consistent with other eosinophilic asthma populations. Conclusion Patients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.
Effect of Sotagliflozin on Total Hospitalizations in Patients With Type 2 Diabetes and Worsening Heart Failure
Authors: Michael Szarek, Deepak L. Bhatt, Ph. Gabriel Steg, Christopher P. Cannon, Lawrence A. Leiter, Darren K. McGuire, Julia B. Lewis, Matthew C. Riddle, Adriaan A. Voors, Marco Metra, Lars H. Lund, Michel Komajda, Jeffrey M. Testani, Christopher S. Wilcox, Piotr Ponikowski, Renato D. Lopes, Phillip Banks, Eshetu Tesfaye, Justin A. Ezekowitz, Subodh Verma, Bertram Pitt
Journal: Annals of Internal Medicine (2021)

In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%.To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial.Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934).306 sites in 32 countries.1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure.200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo.The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models.Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days).Other than heart failure, the primary reason for each hospitalization was unspecified.Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life.Sanofi at initiation and Lexicon Pharmaceuticals at completion.
Abstract 262: A Rat Model of Heart Failure With Preserved Ejection Fraction Induced by Pressure Overload
Authors: Shu-Yu Sun, Barry Campbell, Valdeci Da Cunha, Xuening Hong, Chin-hu Huang, Richard Kennan, Xiaoli Ping, Xiaolan Shen, Kersten Small, Liming Yang, Huawei Zhao, Shuqin Zheng, Jeffrey B Madwed
Journal: Circulation Research (2016)

The absence of animal models displaying clinical phenotypes of HFpEF represents a challenge to the pharmaceutical industry in the hope of identifying novel treatments that would benefit patients with this syndrome. We, at Merck, examined the supracoronary aortic banding (SAB) in rats as a potential model and set out to characterize its phenotypes. Juvenile Sprague-Dawley rats were used; a hemostatic clip with an opening of 0.7 mm was placed around the ascending aorta to elicit a pressure overload to the LV. Echocardiography was performed every 3 weeks and invasive hemodynamics was measured at week 9 to evaluate cardiac structural and functional effects; heart and lungs were harvested at the end for morphological and histological analysis. Nine weeks after SAB, LV hypertrophy and dysfunction were apparent, as manifested by increases in LVEDP, left atrial pressure, plasma BNP, LV and lung weights; LV relaxation time constant (Tau) and mitral early to late inflow ratio (E/A) were also increased; while EF and FS were preserved (see table, mean ± SEM). In addition, SAB rats had elevated mean pulmonary pressure (sham 14 ± 1.7 vs. SAB 37 ± 4.4 mm Hg, p&lt;0.05) with an abnormal transpulmonary gradient (sham 12 ± 2.5 vs. SAB 23 ± 0.1 mm Hg, p&lt;0.05), indicating comorbidity of pulmonary hypertension. Finally, piloerection, dyspnea and loss of muscle mass were evident and exercise tolerance measured by treadmill test was decreased in SAB rats. In summary, rats undergoing SAB exhibit many of the clinical phenotypes of HFpEF. Further work includes examining the effects of novel therapies in SAB rats on improving these clinical phenotypes of HFpEF and expanding the model to study morbidity and mortality.