tbuckley/cabot-search huggingface dataset:
DNA Methylation Profiling of Human Hepatocarcinogenesis
Authors: Gabriela Hernandez‐Meza, Johann von Felden, Edgar E. Gonzalez‐Kozlova, Teresa Garcia‐Lezana, Judit Peix, Anna Portela, Amanda J. Craig, Sergi Sayols, Myron Schwartz, Bojan Losic, Vincenzo Mazzaferro, Manel Esteller, Josep M. Llovet, Augusto Villanueva
Journal: Hepatology (2020)

Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue.Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology.Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
Micra Transcatheter Pacing System Implant under Direct Visualization During Minimally Invasive Tricuspid Valve Surgery
Authors: Mohamad Sinno
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Atrioventricular nodal conduction abnormalities are common after open heart surgery and more so during or after valve surgery. The incidence of atrioventricular (AV) block after tricuspid valve (TV) surgery is higher than what is observed following coronary artery bypass surgery or left sided valve interventions due to the proximity of the TV annulus to the AV node and hence requirements for cardiac pacing are high. However, the mechanical interference between pacing leads and TV leaflet mobility and coaptation can result in regurgitation rendering such an approach counterintuitive. We report a case of Micra Transcatheter pacing system (TPS) implant under direct visualization at the time of tricuspid valve surgery performed via a right mini-thoracotomy approach.
13462 Elucidating the role of innate immunity involving interleukin-1 cytokines and inflammasome signaling pathways in the pathogenesis of psoriasis
Authors: Sophie Carrie Shan Cai, Kim Robinson, Eugene Sern-Ting Tan, Hong Liang Tey, Bruno Reversade, Franklin Zhong
Journal: Journal of the American Academy of Dermatology (2020)
New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies
Authors: Zhenfeng Zhang, Stephan Urban
Journal: Journal of Hepatology (2020)

Chronic hepatitis D (CHD), a global health problem, manifests as the most severe form of viral hepatitis. The causative agent, HDV, is the smallest known human virus; it replicates its circular single-stranded RNA genome in the nucleus of hepatocytes. HDV requires HBV-encoded envelope proteins for dissemination and de novo cell entry. However, HDV can also spread through cell division. Following entry into hepatocytes, replicative intermediates of HDV RNA are sensed by the pattern recognition receptor MDA5 (melanoma differentiation antigen 5) resulting in interferon (IFN)-β/λ induction. This IFN response strongly suppresses cell division-mediated spread of HDV genomes, however, it only marginally affects HDV RNA replication in already infected, resting hepatocytes. Monotherapy with IFN-α/λ shows efficacy but rarely results in HDV clearance. Recent molecular insights into key determinants of HDV persistence and the accelerated development of specifically acting antivirals that interfere with the replication cycle have revealed promising new therapeutic perspectives. In this review, we briefly summarise our knowledge on replication/persistence of HDV, the newly discovered HDV-like agents, and the interplay of HDV with the IFN response and its consequences for persistence. Finally, we discuss the possible role of IFNs in combination with upcoming therapies aimed at HDV cure.
370P Bespoke circulating tumour DNA assay for the detection of minimal residual disease in esophageal adenocarcinoma patients
Authors: E. Ococks, A. Ng, G. Devonshire, S. Dashner, W-C. Chan, S. Sharma, H-T. Wu, A. Redmond, A. Northrop, N. Grehan, H. Sethi, B. Zimmermann, E. Smyth, A. Aleshin, R. Fitzgerald
Journal: Annals of Oncology (2020)
A mindful response to doctors’ mental health
Authors: Vishal Patel, Hirah Rizki, Jajini Varghese
Journal: BMJ (2020)

Half of those recently surveyed by the BMA (43%) said that they were currently experiencing work related depression, anxiety, stress, burnout, emotional distress, or other mental health condition and that it was worse than it had been before the pandemic.1 Indeed, the recent General Medical Council survey of doctors in …
Race/Ethnicity Among Children With COVID-19–Associated Multisystem Inflammatory Syndrome
Authors: Ellen H. Lee, Kelsey L. Kepler, Anita Geevarughese, Rachel Paneth-Pollak, Marie S. Dorsinville, Stephanie Ngai, Kathleen H. Reilly
Journal: JAMA Network Open (2020)

This cohort study describes the distribution of race/ethnicity among cases of coronavirus disease 2019 (COVID-19)–associated multisystem inflammatory syndrome in children reported to the New York City Department of Health and Mental Hygiene.
Abstract 23088: GLP-1 Loading During Percutaneous Coronary Intervention (GOLD PCI) trial
Authors: Joel P Giblett, Sophie Clarke, Liam M McCormick, Tian Zhao, Denise Braganza, Cameron G Densem, Michael O'Sullivan, Nick E West, Stephen P Hoole
Journal: Circulation (2017)

Introduction: Glucagon-like peptide 1 (7-36) amide (GLP-1) is an incretin hormone, which has been shown to protect against non-lethal cardiac ischemia-reperfusion injury. We sought to investigate whether GLP-1 protected against PCI-induced myocardial infarction (PMI) and attenuate cardiac troponin I (cTnI) release after elective PCI. Methods: A double-blind, randomised, placebo-control trial, stratified for diabetes mellitus, conducted in a single UK centre, administered an intravenous infusion of GLP-1 (1.2pmol/Kg/min) or saline to patients approximately 30-minutes before elective PCI. The primary endpoint was PMI defined as a cTnI elevation &gt; 5xURL at 6-hours post-PCI. Secondary endpoints include, intra-procedural chest pain, TIMI flow and blush grade after PCI, rise in cTnI elevation and creatinine at 6-hours post-PCI and major adverse cardiovascular and cerebrovascular events (MACCE) at six months. Results: A CONSORT diagram for the study is shown in Figure 1. Of the 192 patients randomized, 152 (79%) were male, mean age 68.1±8.9 years. Patient demographics were similar between the groups. There was no inter-group difference in the incidence of PMI: GLP-1 9 (9.8%) vs. saline 8 (8.3%), p=0.28. Median [IQR] cTnI elevation between the groups was also similar: GLP-1 20 [0-88.5] vs. saline 10 [0-58.5] ng/L, p=0.28. Renal function was not impaired at 6 hours. Δ Creatinine was not significantly different. (GLP-1 -2.78±9.04 vs. saline -1.75±8.74 μmol/L, p=0.73). Other secondary end-point data will be available at time of presentation. Conclusion: GLP-1 did not confer cardioprotection against PMI after elective PCI, although the incidence of PMI in contemporary PCI is low.
Low-Dose Computed Tomography Coronary Angiography With Prospective Triggering: A Promise for the Future⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Philipp A. Kaufmann
Journal: Journal of the American College of Cardiology (2008)
Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020
Authors: Kristina L. Bajema, Ryan E. Wiegand, Kendra Cuffe, Sadhna V. Patel, Ronaldo Iachan, Travis Lim, Adam Lee, Davia Moyse, Fiona P. Havers, Lee Harding, Alicia M. Fry, Aron J. Hall, Kelly Martin, Marjorie Biel, Yangyang Deng, William A. Meyer, Mohit Mathur, Tonja Kyle, Adi V. Gundlapalli, Natalie J. Thornburg, Lyle R. Petersen, Chris Edens
Journal: JAMA Internal Medicine (2020)

Case-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely underestimates the true prevalence of infections. Large-scale seroprevalence surveys can better estimate infection across many geographic regions.To estimate the prevalence of persons with SARS-CoV-2 antibodies using residual sera from commercial laboratories across the US and assess changes over time.This repeated, cross-sectional study conducted across all 50 states, the District of Columbia, and Puerto Rico used a convenience sample of residual serum specimens provided by persons of all ages that were originally submitted for routine screening or clinical management from 2 private clinical commercial laboratories. Samples were obtained during 4 collection periods: July 27 to August 13, August 10 to August 27, August 24 to September 10, and September 7 to September 24, 2020.Infection with SARS-CoV-2.The proportion of persons previously infected with SARS-CoV-2 as measured by the presence of antibodies to SARS-CoV-2 by 1 of 3 chemiluminescent immunoassays. Iterative poststratification was used to adjust seroprevalence estimates to the demographic profile and urbanicity of each jurisdiction. Seroprevalence was estimated by jurisdiction, sex, age group (0-17, 18-49, 50-64, and ≥65 years), and metropolitan/nonmetropolitan status.Of 177 919 serum samples tested, 103 771 (58.3%) were from women, 26 716 (15.0%) from persons 17 years or younger, 47 513 (26.7%) from persons 65 years or older, and 26 290 (14.8%) from individuals living in nonmetropolitan areas. Jurisdiction-level seroprevalence over 4 collection periods ranged from less than 1% to 23%. In 42 of 49 jurisdictions with sufficient samples to estimate seroprevalence across all periods, fewer than 10% of people had detectable SARS-CoV-2 antibodies. Seroprevalence estimates varied between sexes, across age groups, and between metropolitan/nonmetropolitan areas. Changes from period 1 to 4 were less than 7 percentage points in all jurisdictions and varied across sites.This cross-sectional study found that as of September 2020, most persons in the US did not have serologic evidence of previous SARS-CoV-2 infection, although prevalence varied widely by jurisdiction. Biweekly nationwide testing of commercial clinical laboratory sera can play an important role in helping track the spread of SARS-CoV-2 in the US.
Peanut‐induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry
Authors: Ioana Maris, Sabine Dölle‐Bierke, Jean‐Marie Renaudin, Lars Lange, Alice Koehli, Thomas Spindler, Jonathan Hourihane, Kathrin Scherer, Katja Nemat, C. Kemen, Irena Neustädter, Christian Vogelberg, Thomas Reese, Ismail Yildiz, Zsolt Szepfalusi, Hagen Ott, Helen Straube, Nikolaos G. Papadopoulos, Susanne Hämmerling, Ute Staden, Michael Polz, Tihomir Mustakov, Ewa Cichocka‐Jarosz, Renata Cocco, Alessandro Giovanni Fiocchi, Montserrat Fernandez‐Rivas, Margitta Worm
Journal: Allergy (2020)

Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.
The copper chaperone Atox1 is involved in the intracellular sequestration of cisplatin
Authors: Roohangiz Safaei, Michael Rasmussen, Karen Francisco, Stephen Howell
Journal: Cancer Research (2007)

5631  The role of copper (Cu) in the etiology of cancer is widely recognized and recent findings link the expression of Cu transporters directly to the development of resistance to platinum drugs particularly cisplatin (DDP). The Cu chaperone Atox1 is essential for the efflux of Cu and is known to exchange Cu with the importer Ctr1 and the exporters Atp7a and Atp7b. We studied the uptake, efflux and Pt-DNA adduct formation in fibroblast cell lines from Atox1-/- transgenic and wild type (Atox1+/+) mice following 24 h exposure to 2 µM DDP and performed parallel experiments with 64Cu to define the mechanisms by which Atox1 contributes to the intracellular transport of DDP (all values are mean ± SEM). The whole cell accumulation of DDP in the Atox1-/- cells was reduced to 62% of that in the Atox1+/+ cells (167.03 ± 18.15 and 103.32 ± 23.41 picomol/mg protein (p = 0.03) in the Atox1+/+ and Atox1-/- cells, respectively). In contrast, following a 24 h exposure to 2 µM 64Cu the Cu level was 86% higher in the Atox1-/- than in the Atxo1+/+ cells (174.02 ± 3.73 and 324.45 ± 16.00 picomol /mg protein in the Atox1+/+ and Atox1-/- cells, respectively (p = 0.00001)). Efflux of DDP was similar in the 2 cell lines but that of 64Cu was more rapid in the Atox1+/+ cells (p= 0.05). At the end of a 60 min efflux period 44.68 ± 0.91% of the 64Cu remained in the Atox1+/+ cells whereas 82.74 ± 11.50 % persisted in the Atox1-/- cells The extent of Pt-DNA adduct formation in the Atox1-/- cells was only 55% of that in the Atox1+/+ cells (18.77 ± 5.50 and 34.38 ± 6.72 and picomol/mg DNA, p
16455 Treatment patterns among patients with atopic dermatitis using advanced therapies in the united states: Analysis of a retrospective claims database
Authors: Lawrence F. Eichenfield, Marco DiBonaventura, Jason Xenakis, Marie-Helene Lafeuille, Mei Sheng Duh, Jennifer W. Wu, Mark Levenberg, Joseph C. Cappelleri, Vanja Sikirica
Journal: Journal of the American Academy of Dermatology (2020)
Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients
Authors: Mireia García-López, Sabela Lens, Laura J. Pallett, Barbara Testoni, Sergio Rodríguez-Tajes, Zoe Mariño, Concepción Bartres, Ester García-Pras, Thais Leonel, Elena Perpiñán, Juan José Lozano, Francisco Rodríguez-Frías, George Koutsoudakis, Fabien Zoulim, Mala K. Maini, Xavier Forns, Sofía Pérez-del-Pulgar
Journal: Journal of Hepatology (2020)

Factors associated with a successful outcome upon nucleos(t)ide analogue (NA) treatment withdrawal in HBeAg-negative chronic hepatitis B (CHB) patients have yet to be clarified. The objective of this study was to analyse the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation.Twenty-seven patients without cirrhosis with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analysed at baseline and longitudinally throughout follow-up.After a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1,000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses.Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal.Nucleos(t)ide analogue therapy can be discontinued in a high proportion of chronic hepatitis B patients without cirrhosis. The strength of HBV-specific immune T cell responses may contribute to successful viral control after antiviral treatment interruption. Our comprehensive study provides in-depth data on virological and immunological factors than can help guide individualised therapy in patients with chronic hepatitis B.
Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation
Authors: Omar Y. Mousa, Brian D. Juran, Bryan M. McCauley, Mette N. Vesterhus, Trine Folseraas, Coleman T. Turgeon, Ahmad H. Ali, Erik M. Schlicht, Elizabeth J. Atkinson, Chang Hu, Denise Harnois, Elizabeth J. Carey, Andrea A. Gossard, Devin Oglesbee, John E. Eaton, Nicholas F. LaRusso, Gregory J. Gores, Tom H. Karlsen, Konstantinos N. Lazaridis
Journal: Hepatology (2020)

Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility.Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86).Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.