tbuckley/cabot-search huggingface dataset:
Abstract 14862: miR-223 Regulates DNA Damage Signaling in Pulmonary Arterial Hypertension
Authors: Jolyane Meloche, Marie Le Guen, Francois Potus, Benoit Ranchoux, Fabrice Antigny, Eve Tremblay, Sandra Breuils-Bonnet, Frederic Perros, Steeve Provencher, Sebastien Bonnet
Journal: Circulation (2015)

Background: Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. We recently showed that the DNA damage activated PARP-1 was overexpressed in PAH and responsible for the proliferation/apoptosis imbalance in PAH-PASMCs. Nevertheless, the mechanism that regulates its overexpression in PAH remains elusive. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. Methods and Results: Using qRT-PCR, we demonstrated that miR-223 is significantly decreased in human lungs, distal pulmonary arteries (PAs) and isolated PASMCs of PAH patients compared to control donors (n=5-10, p&lt;0.01). PAH-PASMCs isolated from distal PAs exhibited a 2.5-fold decrease in miR-223 expression (n=5, p&lt;0.05). Furthermore, using a gain and loss of function approach, we showed that increased HIF-1α (using siRNA and adenoviruses) triggers miR-223 downregulation, subsequent overexpression of PARP-1 (n=5, p&lt;0.05) and alterations in DNA damage repair (γ-H2AX, n=4, p&lt;0.05). Using a bidirectionnal approach, we showed that decreased miR-223 triggers the proliferation/apoptosis imbalance observed in PAH-PASMC (Ki67 and AnnexinV, n=5, p&lt;0.05). Finally, we demonstrated that restoring the expression of miR-223, by nebulization of miR-223 mimics in lungs of rats with monocrotaline-induced PAH reversed established PAH as assessed by right heart catheterization (mean PA pressure, cardiac output) and provided beneficial effects on vascular remodeling (H&amp;E), pulmonary resistance, right ventricle hypertrophy and survival (n=8-10 per group, p&lt;0.05). Conclusion: We provide evidences that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH.
Earlier Phases of Bone Scintigraphy Can Better Delineate the Extent of Soft Tissue Involvement of Bone Metastasis
Authors: Derya Çayir, Mehmet Bozkurt, Salih Sinan Gültekin, Alper Özgür Karaçalioğlu
Journal: Clinical Nuclear Medicine (2018)

Three-phase bone scintigraphy is sometimes of great value in the detection of uncharacteristic metastases and assists the management of patients in terms of primary focus detection. While evaluating the skeletal system with whole-body bone scintigraphy, other system pathologies may also be detected incidentally. In this case, we present the extraordinary findings on the 3-phase MDP bone scintigraphy and F-FDG PET/CT imaging of the complicated bone metastases in a patient with thyroid carcinoma.
Sepsis induced hypotension: US consumer group asks regulator to stop trial, arguing flawed design
Authors: Susan Mayor
Journal: BMJ (2018)

The US consumer advocacy group Public Citizen has written to the Office for Human Research Protections, which oversees ethical and regulatory issues in biomedical research, asking it to immediately direct the National, Heart, Lung and Blood Institute (NHLBI) to stop enrolment of patients into a clinical trial of sepsis induced hypotension that it is funding and to launch an investigation into how the study was approved.1

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial is a phase III randomised, non-blinded trial of fluid treatment strategies in the first 24 hours for patients with sepsis induced hypotension.2 The trial plans to assign 2320 adult patients to a restrictive fluids strategy (vasopressors first, followed by rescue fluids) or a liberal fluid strategy (fluids …
Abstract P057: Clusters of Cardiovascular Risk Factors Predict Incidence of Type 2 Diabetes in Men and Women: A Swedish Population-based Study
Authors: Charlotte A Larsson, Bledar Daka, Margareta I Hellgren, Maria C Eriksson, Lennart Råstam, Ulf Lindblad
Journal: Circulation (2016)

Introduction: Clusters of metabolic variables and their effects on incidence of type 2 diabetes have been studied previously; however, little is known about the effects on diabetes from risk factor clusters including lifestyle and self-rated health. Hypothesis: We assessed the hypothesis that clusters of common cardiovascular risk factors, including lifestyle and self-rated health, can predict development of type 2 diabetes in men and women, respectively. Methods: In 2002-2005, 2816 men and women, 30-74 years, were randomly selected from two municipalities in southwestern Sweden and assessed with regard to cardiovascular/metabolic risk factors within the Skaraborg Project (76% participation). Participants performed an OGTT, had blood samples drawn, had anthropometric measurements and blood pressure taken, and answered validated questionnaires about e.g. leisure-time physical activity (with four answer alternatives from intensive to sedentary) and self-rated health (with five alternatives from excellent to very poor). Using the same protocol, 1332 participants from the baseline survey where re-examined in 2011-2014. After excluding those with diabetes at baseline, 1268 participants were included in this prospective population-based study. Results: Factor analysis (using varimax rotation) identified significant loadings (≥0.40) on the following three identical factors in men and women: the metabolic factor , comprising HOMA-ir, WHR, systolic blood pressure, and apolipoprotein B-to-A1 ratio; the vitality factor , comprising physical activity and self-rated health; and the addiction factor , comprising smoking and alcohol consumption. After a mean follow-up of 9.7±1.4 years, 76 cases of diabetes were identified; 46 in men and 30 in women. In a logistic regression analysis adjusted for all principal components, age, and educational level, the metabolic factor significantly predicted type 2 diabetes in both men (OR: 3.3, CI: 2.3-5.0) and women (OR: 3.5, CI: 2.2-5.6). Furthermore, a predictive effect of the vitality factor was also seen in women (OR: 1.8, CI: 1.2-2.9), but not in men (OR: 1.1, CI: 0.8-1.6), whereas the addiction factor had no effect in either men or women. Conclusions: This is to our knowledge the first time principle components of cardiovascular risk factors, including both metabolic and lifestyle variables, have been used to predict incidence of type 2 diabetes. The gender difference observed with regard to the combined impact of self-rated health and physical activity are novel and indicates a mechanism beside the metabolic syndrome that warrants further gender-specific exploration in future studies.
GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting
Authors: Shoshana Revel-Vilk, Ela Shai, Ernest Turro, Nivin Jahshan, Esti Hi-Am, Galia Spectre, Hagit Daum, Yossef Kalish, Karina Althaus, Andreas Greinacher, Chaim Kaplinsky, Shai Izraeli, Rutendo Mapeta, Sri V. V. Deevi, Danuta Jarocha, Willem H. Ouwehand, Kate Downes, Mortimer Poncz, David Varon, Michele P. Lambert
Journal: Blood (2018)
Abstract 13235: Enhanced Receptor-independent Nucleoside Diphosphate Kinase Mediated Gs Protein Signaling Contributes to Arrhythmogenic Calcium Mishandling in Atrial Fibrillation
Authors: Marina Schaefer, Issam Abu-Taha, Patrice Naud, Xiao Yan Qi, Vanessa Gundlach, Markus Kamler, Thomas Wieland, Stanley Nattel, Dobromir Dobrev
Journal: Circulation (2016)

Background: Enhanced G-protein related cyclic AMP (cAMP) signaling and abnormal Ca2+ handling due to dysfunctional ryanodine receptor type-2 (RyR2) are implicated in atrial fibrillation (AF). Nucleoside diphosphate kinase (NDPK) forms complexes with Gs proteins, increasing cAMP signaling via receptor-independent G protein activation. Here, we studied the possible proarrhythmic role of NDPKs in clinical (chronic AF, cAF) and experimental AF. Methods: NDPK and G protein expression were assessed by immunoblotting in atria from sinus rhythm (Ctl) and cAF patients; dogs undergoing AF-mimicking tachycardia remodeling (ATR, 400 bpm, 7 days) or AF-promoting chronic atrial ischemia; and canine atrial cardiomyocytes (CMs) paced in vitro for 24-48 hrs at 1 (P1) or 3 Hz (P3). cAMP was measured by immunoassay. Immunostaining was used for protein visualization. Spontaneous sarcoplasmic reticulum (SR) Ca2+ release events (SCaEs) in CMs overexpressing NDPKs or EGFP-control (adenoviral gene-transfer) were recorded with ep...
Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer
Authors: Nagaraj S. Nagathihalli, Jason A. Castellanos, Purushottam Lamichhane, Fanuel Messaggio, Chanjuan Shi, Xizi Dai, Priyamvada Rai, Xi Chen, Michael N. VanSaun, Nipun B. Merchant
Journal: Cancer Research (2018)

Abstract Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+; LSL-KrasG12D/+; and Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i–treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSCs. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR–dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC. Significance: This report describes an inverse correlation between MEK and STAT3 signaling as key mechanisms of resistance in PDAC and shows that combined inhibition of MEK and STAT3 overcomes this resistance and provides an improved therapeutic strategy to target the RAS pathway in PDAC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg. Cancer Res; 78(21); 6235–46. ©2018 AACR.
Abstract 13855: Electrophysiological Substrate and Risk of Mortality in Incident Hemodialysis Patients: Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) Study
Authors: Larisa G Tereshchenko, Andrew Oehler, Lucy Meoni, Elyar Ghafoori, Esther Kim, Tejal Rami, Maggie Maly, Muammar Kabir, Lauren Hawkins, Joao Lima, Bernard Jaar, Stephen Sozio, Michelle Estrella, Rulan Parekh
Journal: Circulation (2015)

Introduction: Mortality in end-stage renal disease (ESRD) patients on dialysis is high; sudden cardiac death is the leading cause. Hypothesis: Left ventricular hypertrophy (LVH), late potentials on signal averaged ECG (SAECG) and wide spatial QRS-T angle are independently associated with mortality in incident hemodialysis patients. Methods: SAECGs were recorded at baseline (within 3-6 months of start of dialysis) in 360 participants [mean age 57.2±13.4 y; 59% male; 73% black; mean left ventricular (LV) ejection fraction (EF) 65.5±12.1%] from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease study, a prospective cohort of incident hemodialysis participants. Spatial mean QRS-T angle was measured on an averaged beat. ECG-LVH was defined as sex-adjusted Cornell product &gt;2440 mm*ms. Echo-LVH was defined as LV mass index &gt;131 g/m2 (M); &gt;113 g/m2 (F). Late potentials were detected on SAECG. All-cause mortality is the primary outcome. Results: During 2.4±1.3 years of follow-up, 75 patients died. Cumulative unadjusted mortality was higher in participants with QRS-T angle ≥ 75° (Figure). In Cox regression analyses, stratified by presence of bundle branch block, QRS-T angle ≥ 75° was associated with a greater than two-fold increase in risk for mortality after adjustment for age, sex, race, and BMI [HR 2.62(1.53-4.48); P&lt;0.001]. The association remained significant after the addition to the model: 1) diabetes and prevalent cardiovascular disease [2.47(1.44-4.23); P=0.001], 2) LVEF, QRS duration, and LVH [2.64(1.53-4.55); P&lt;0.0001], and 3) averaged 90-day serum albumin and creatinine [HR 2.29(1.28-4.10); P=0.005]. Abnormal SAECG, ECG-LVH and Echo-LVH were not associated with mortality. Conclusions: Spatial QRS-T angle, but not late potentials on SAECG or LVH, is independently associated with mortality after adjustment for both traditional and dialysis-related cardiovascular risk factors in incident hemodialysis.
Recombinant BCG Overexpressing phoP-phoR Confers Enhanced Protection against Tuberculosis
Authors: Sang Kyun Ahn, Vanessa Tran, Andrea Leung, Mark Ng, Ming Li, Jun Liu
Journal: Molecular Therapy (2018)

The live tuberculosis vaccine Mycobacterium bovis BCG (Bacille Calmette-Guérin) comprises a number of genetically distinct substrains. In BCG-Prague, phoP of the PhoP-PhoR two-component system is a pseudogene due to a single insertion mutation. We hypothesized that this mutation partially accounts for the low immunogenicity of BCG-Prague observed in the 1970s. In this study, we showed that complementation with the M. bovis allele of phoP restored BCG-Prague's immunogenicity. Furthermore, we showed that overexpression of the M. bovis allele of phoP-phoR in BCG-Japan, a strain already containing a copy of phoP-phoR, further enhanced immunogenicity and protective efficacy. Vaccination of C57BL/6 mice with the recombinant strain rBCG-Japan/PhoPR induced higher levels of interferon-γ (IFN-γ) production by CD4+ T cells than that with the parental BCG. Guinea pigs vaccinated with rBCG-Japan/PhoPR were better protected against challenge with Mycobacterium tuberculosis than those immunized with the parental BCG, showing significantly longer survival time, reduced bacterial burdens, and less severe pathology. Taken together, our study has identified a genetic modification that could be generally applied to generate new recombinant BCG vaccines.
Opportunities to Prevent Overdose Deaths Involving Prescription and Illicit Opioids, 11 States, July 2016–June 2017
Authors: Christine L. Mattson, Julie O’Donnell, Mbabazi Kariisa, Puja Seth, Lawrence Scholl, R. Matthew Gladden
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In 2016, 63,632 drug overdose deaths occurred in the United States, 42,249 (66.4%) of which involved opioids (1). The development of prevention programs are hampered by a lack of timely data on specific substances contributing to and circumstances associated with fatal overdoses. This report describes opioid overdose deaths (referred to as opioid deaths) for decedents testing positive for prescription opioids (e.g., oxycodone and hydrocodone), illicit opioids (e.g., heroin, illicitly manufactured fentanyl, and fentanyl analogs), or both prescription and illicit opioids, and describes circumstances surrounding the overdoses, in 11 states participating in CDC's Enhanced State Opioid Overdose Surveillance (ESOOS) program.* During July 2016-June 2017, among 11,884 opioid overdose deaths, 17.4% of decedents tested positive for prescription opioids only, 58.7% for illicit opioids only, and 18.5% for both prescription and illicit opioids (type of opioid could not be classified in 649 [5.5%] deaths). Approximately one in 10 decedents had been released from an institutional setting in the month preceding the fatal overdose. Bystanders were reportedly present in approximately 40% of deaths; however, naloxone was rarely administered by a layperson. Enhanced surveillance data from 11 states provided more complete information on the substances involved in and circumstances surrounding opioid overdose deaths. Consistent with other emerging evidence and recommendations,† these data suggest prevention efforts should prioritize naloxone distribution to persons misusing opioids or using high dosage prescription opioids and to their family members and friends. In addition, these data suggest a need to expand treatment and support for persons who have experienced a nonfatal overdose and to expand treatment in detention facilities and upon release.
Removal of a migrated fully covered metal biliary stent by cholangioscope-assisted inversion technique
Authors: Erik Rahimi, Samreen Khuwaja, Nirav Thosani
Journal: Endoscopy (2018)

Proximal biliary stent migration is a rare and unwanted complication. Various endoscopic methods have been used to remove migrated biliary stents, including the use of direct cholangioscopy for plastic biliary stent migration [1] [2] [3] [4]. Here, we describe a case of cholangioscopy-assisted removal of a proximally migrated fully covered metal biliary stent by inversion technique.
<i>Notes from the Field:</i> Fatal <i>Vibrio anguillarum</i> Infection in an Immunocompromised Patient — Maine, 2017
Authors: Jennifer A. Sinatra, Kate Colby
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In July 2017, an immunocompromised woman aged 65 years admitted to a emergency department in Maine was found to have Vibrio anguillarum and developed septic shock and multiorgan failure, dying 2 days after admission.
Pan-Costochondritis Caused by Aspergillus Diagnosed by 18F-FDG PET/CT
Authors: Patricia Oliván-Sasot, Begoña Martínez-Sanchis, Raquel Sánchez-Vañó, Ana María Yepes-Agudelo, Pilar Bello-Arques
Journal: Clinical Nuclear Medicine (2018)

Thoracic pain is an entity that can be difficult to diagnose etiologically. Once the cardiac origin has been ruled out, the rheumatologic, neoplastic, and infectious causes have to be taken into account. We present the case of a patient with atypical chest pain after triple-bypass surgery in whom F-FDG PET/CT scan showed an important uptake of the radiopharmaceutical in costal cartilages, in relation to pan-costochondritis due to Aspergillus.
Abstract 15493: Renal Sympathetic Denervation Reduces Ventricular Arrhythmias Inducibility in Dogs With Healed Myocardial Infarction
Authors: Bing Huang, Lilei Yu, Zhibing Lu, Bo He, Zhuo Wang, Liping Zhou, Hong Jiang
Journal: Circulation (2015)

Introduction: Previous studies have suggested that renal sympathetic denervation (RSD) could suppress acute myocardial ischemia-induced ventricular arrhythmias (VAs), but the long-term effects of RSD in a post-infarction canine model is not fully established. Methods: Thirty dogs underwent embolization of the left anterior descending artery. After a 14-days of recovery period, all the dogs were equally randomized to the RSD, medicine (MED; carvedilol 12.5mg PO BID), or control (CTRL; no therapy) group. Animals were monitored for 3 months after interventions. The serum norepinephrine (NE), echocardiographic indices, heart rate variability (HRV), and VAs inducibility were measured at the end of 90-day follow-up. Tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) expressions in the peri-infarcted zone were also determined immunohistochemically. The protein levels of metrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor of matalloproteinases (TIMP-1) were also determined. Results: When compared with CTRL group, RSD significantly (1) decreased heart rate, serum NE, sympathetic nerve indices of HRV, and the density of both TH- and GAP43-positive nerves in the peri-infarcted zone; (2) increased left ventricular ejection fraction and reduced left ventricular dilatation; (3) decreased the protein levels of MMP-2, MMP-9 and TIMP-1 in left ventricular tissues; (4) decreased the inducibility of ventricular tachyarrhythmias. Beta-receptor blockade by carvedilol showed comparable effects. Conclusions: RSD could reduce VAs inducibility in a canine model of healed myocardial infarction. Inhibition of autonomic and structural remodeling by RSD may be responsible for this salutary result.
Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis
Authors: Kasper Iversen, Nikolaj Ihlemann, Sabine U. Gill, Trine Madsen, Hanne Elming, Kaare T. Jensen, Niels E. Bruun, Dan E. Høfsten, Kurt Fursted, Jens J. Christensen, Martin Schultz, Christine F. Klein, Emil L. Fosbøll, Flemming Rosenvinge, Henrik C. Schønheyder, Lars Køber, Christian Torp-Pedersen, Jannik Helweg-Larsen, Niels Tønder, Claus Moser, Henning Bundgaard
Journal: New England Journal of Medicine (2018)

Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intravenous to oral antibiotics once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown.
Relationship between age and likelihood of lymph node metastases in patients with intermediate thickness melanoma (1.01-4.00 mm): A National Cancer Database study
Authors: Andrew N. Hanna, Andrew J. Sinnamon, Robert E. Roses, Rachel R. Kelz, David E. Elder, Xiaowei Xu, Barbara A. Pockaj, Jonathan S. Zager, Douglas L. Fraker, Giorgos C. Karakousis
Journal: Journal of the American Academy of Dermatology (2018)
Pharyngeal electrical stimulation for early decannulation in tracheotomised patients with neurogenic dysphagia after stroke (PHAST-TRAC): a prospective, single-blinded, randomised trial
Authors: Rainer Dziewas, Rebecca Stellato, Ingeborg van der Tweel, Ernst Walther, Cornelius J Werner, Tobias Braun, Giuseppe Citerio, Mitja Jandl, Michael Friedrichs, Katja Nötzel, Milan R Vosko, Satish Mistry, Shaheen Hamdy, Susan McGowan, Tobias Warnecke, Paul Zwittag, Philip M Bath, Tobias Braun, Rainer Dziewas, Michael Friedrichs, Mitja Jandl, Katja Nötzel, Ernst Walther, Cornelius J. Werner, Giuseppe Citerio, Milan Vosko, Ilia Aroyo, Christof Bucka, Thomas Kerz, Markus Köstenberger, Nicole Marschner-Preuth, Wolf-Dirk Niesen, Bettina Pfausler
Journal: The Lancet Neurology (2018)