tbuckley/cabot-search huggingface dataset:
Identification of Functional Variant Enhancers Associated With Atrial Fibrillation
Authors: Antoinette F. van Ouwerkerk, Fernanda M. Bosada, Jia Liu, Juan Zhang, Karel van Duijvenboden, Mark Chaffin, Nathan R. Tucker, Daniel Pijnappels, Patrick T. Ellinor, Phil Barnett, Antoine A.F. de Vries, Vincent M. Christoffels
Journal: Circulation Research (2020)

Rationale: Genome-wide association studies have identified a large number of common variants (single-nucleotide polymorphisms) associated with atrial fibrillation (AF). These variants are located mainly in noncoding regions of the genome and likely include variants that modulate the function of transcriptional regulatory elements (REs) such as enhancers. However, the actual REs modulated by variants and the target genes of such REs remain to be identified. Thus, the biological mechanisms by which genetic variation promotes AF has thus far remained largely unexplored. Objective: To identify REs in genome-wide association study loci that are influenced by AF-associated variants. Methods and Results: We screened 2.45 Mbp of human genomic DNA containing 12 strongly AF-associated loci for RE activity using self-transcribing active regulatory region sequencing and a recently generated monoclonal line of conditionally immortalized rat atrial myocytes. We identified 444 potential REs, 55 of which contain AF-associated variants ( P &lt;10 −8 ). Subsequently, using an adaptation of the self-transcribing active regulatory region sequencing approach, we identified 24 variant REs with allele-specific regulatory activity. By mining available chromatin conformation data, the possible target genes of these REs were mapped. To define the physiological function and target genes of such REs, we deleted the orthologue of an RE containing noncoding variants in the Hcn4 (potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4) locus of the mouse genome. Mice heterozygous for the RE deletion showed bradycardia, sinus node dysfunction, and selective loss of Hcn4 expression. Conclusions: We have identified REs at multiple genetic loci for AF and found that loss of an RE at the HCN4 locus results in sinus node dysfunction and reduced gene expression. Our approach can be broadly applied to facilitate the identification of human disease-relevant REs and target genes at cardiovascular genome-wide association studies loci.
David Oliver: Silencing NHS staff who speak out is sheer stupidity
Authors: David Oliver
Journal: BMJ (2020)

BerkshireAmid a global pandemic, which is putting our health services and frontline staff under immense strain and personal risk, is it right to suppress their free speech?On 31 March the media reported on a dossier from the Doctors' Association UK detailing numerous instances of medical and nursing staff being warned, disciplined, threatened, monitored, and gagged for speaking out on social or mainstream media. 1 Their concerns included a lack of personal protective equipment and testing for covid-19-putting them, their families, and their patients at risk. 2 The staff also highlighted what they saw as inconsistent and unconvincing guidance from their employers and national authorities.
A fatal case of COVID-19 pneumonia occurring in a patient with severe acute ulcerative colitis
Authors: Stefano Mazza, Andrea Sorce, Flora Peyvandi, Maurizio Vecchi, Flavio Caprioli
Journal: Gut (2020)

Since December 2019, a novel coronavirus referred to as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)1 was identified as the causative agent of a respiratory syndrome named COVID-19.2 Since February 2020, an outbreak of COVID-19 has developed in Lombardy, in northern Italy, posing serious challenges to healthcare system. As reported, COVID-19 severity directly correlates with patient’s age and several comorbidities,3 but no data are currently available regarding clinical outcome in inflammatory bowel diseases (IBD). Recently, the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) recommended a reduction of corticosteroid therapy in IBD patients, while maintaining thiopurines and biologics,4 even if Authors recognised that specific IBD research on COVID-19 is lacking.

On 12 February 2020, days before this outbreak was recognised, an 80-year-old female with a 3-year history of left-sided ulcerative colitis (UC), in maintenance with mesalamine, …
<i>LAG3</i>(<i>LAG-3</i>,<i>CD223</i>) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma
Authors: Niklas Klümper, Damian J Ralser, Emma Grace Bawden, Jenny Landsberg, Romina Zarbl, Glen Kristiansen, Marieta Toma, Manuel Ritter, Michael Hölzel, Jörg Ellinger, Dimo Dietrich
Journal: Journal for ImmunoTherapy of Cancer (2020)

Lymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation of LAG3 in KIRC by methylation.We correlated quantitative LAG3 methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzed LAG3 methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.We found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore, LAG3 methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+ immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.Our data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testing LAG3 DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.
Reinforcement of antitumor effect of micelles containing anticancer drugs by binding of an anti-tissue factor antibody without direct cytocidal effects
Authors: Hiroki Takashima, Yoshikatsu Koga, Ryo Tsumura, Masahiro Yasunaga, Masami Tsuchiya, Tadashi Inoue, Eriko Negishi, Mitsunori Harada, Sei Yoshida, Yasuhiro Matsumura
Journal: Journal of Controlled Release (2020)

It has been preclinically and clinically proven that anticancer agent-incorporating (ACA-incorporating) polymeric micelles selectively accumulate in tumor via the enhanced permeability and retention (EPR) effect, yielding a wider therapeutic window and greater safety than conventional low-molecular weight ACAs. To increase the antitumor effect of these safer micelle formulations, epirubicin-incorporating polymer micelles (NC-6300) conjugated with monoclonal antibodies (mAbs) have been prepared. In this study, we used two types of mAb: an anti-tissue factor (TF) mAb that does not exert a direct cytocidal effect, and an anti-HER2 mAb that has a direct cytocidal effect. We compared the antitumor effects and pharmacological properties of the two types of antibody conjugated to NC-6300. Immunomicelles conjugated to anti-TF mAb exerted greater antitumor activity toward TF-positive stomach cancer than the combination of anti-TF mAb and NC-6300, and were distributed more uniformly throughout TF-positive tumor tissue than NC-6300. On the other hand, immunomicelles conjugated to anti-HER2 mAb did not exert significant antitumor activity toward HER2-positive stomach cancer relative to the combined use of anti-HER2 mAb and NC-6300. Thus, this immunomicelle-based strategy may be useful for antibodies that target cancer as pilot molecules even when the antibodies themselves do not have an antitumor effect.
Deployment of convalescent plasma for the prevention and treatment of COVID-19
Authors: Evan M. Bloch, Shmuel Shoham, Arturo Casadevall, Bruce S. Sachais, Beth Shaz, Jeffrey L. Winters, Camille van Buskirk, Brenda J. Grossman, Michael Joyner, Jeffrey P. Henderson, Andrew Pekosz, Bryan Lau, Amy Wesolowski, Louis Katz, Hua Shan, Paul G. Auwaerter, David Thomas, David J. Sullivan, Nigel Paneth, Eric Gehrie, Steven Spitalnik, Eldad A. Hod, Lewis Pollack, Wayne T. Nicholson, Liise-anne Pirofski, Jeffrey A. Bailey, Aaron A.R. Tobian
Journal: Journal of Clinical Investigation (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS–CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource.
Fit to fight – from military hygiene to wellbeing in the British Army
Authors: Martin C. M. Bricknell, Colonel David A. Ross
Journal: Military Medical Research (2020)

Abstract This paper reviews the historical evolution of the language and organization surrounding the health of personnel in the British Army from ‘hygiene’ through to ‘wellbeing’. It starts by considering the health of the army in the mid-nineteenth century and the emergence of military hygiene as a professional subject. It continues by looking at advances in military hygiene in the two world wars. Hygiene was replaced by the term ‘health’ in the 1950s as the collective noun used by professionals working in this field. This unity split when the professions of occupational medicine and public health established separate faculties and training pathways. However, the health issues for the armed forces remain fundamentally unchanged. Going forward, the term ‘wellbeing’ is helping to refresh the close relationships between executives, their medical advisers and those within the population of health professions charged with keeping the British Army healthy. The core theme is the collaborations between civil society, executive leadership and medical services in maximizing the health of the military population from recruitment through to life as a veteran.
Deterministic paracrine repair of injured myocardium using microfluidic-based cocooning of heart explant-derived cells
Authors: Pushpinder Kanda, Ainara Benavente-Babace, Sandrine Parent, Michie Connor, Nicholas Soucy, Alexander Steeves, Aizhu Lu, Nicholas David Cober, David Courtman, Fabio Variola, Emilio I. Alarcon, Wenbin Liang, Duncan J. Stewart, Michel Godin, Darryl R. Davis
Journal: Biomaterials (2020)
Medicare Enrollment Among Patients With End-Stage Kidney Disease Receiving Dialysis in Outpatient Facilities Between 2005 and 2016
Authors: Abby Hoffman, Caroline E. Sloan, Matthew L. Maciejewski, Virginia Wang
Journal: JAMA (2020)

This study characterizes annual changes in enrollment of Medicare and non-Medicare patients treated at dialysis facilities before and after 2011 payment reforms and 2014 Affordable Care Act changes that influenced reimbursements.
Did Introducing a New Category of Thyroid Tumors (Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features) Decrease the Risk of Malignancy for the Diagnostic Categories in the Bethesda System for Reporting Thyroid Cytopathology?
Authors: Janusz Kopczyński, Agnieszka Suligowska, Kornelia Niemyska, Iwona Pałyga, Agnieszka Walczyk, Danuta Gąsior-Perczak, Artur Kowalik, Kinga Hińcza, Ryszard Mężyk, Stanisław Góźdź, Aldona Kowalska
Journal: Endocrine Pathology (2020)
Better Understanding the Importance of Palliative Care for Pediatric Patients
Authors: Emily E. Johnston, Abby R. Rosenberg
Journal: JAMA Oncology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
“We Signed Up for This!” — Student and Trainee Responses to the Covid-19 Pandemic
Authors: Thomas H. Gallagher, Anneliese M. Schleyer
Journal: New England Journal of Medicine (2020)

“We Signed Up for This!” Students and trainees are experiencing intense anxiety, uncertainty, and anticipatory loss during the Covid-19 pandemic. Many are facing new ethical dilemmas and practical ...
Association between age and clinical characteristics and outcomes of COVID-19
Authors: Yang Liu, Bei Mao, Shuo Liang, Jia-Wei Yang, Hai-Wen Lu, Yan-Hua Chai, Lan Wang, Li Zhang, Qiu-Hong Li, Lan Zhao, Yan He, Xiao-Long Gu, Xiao-Bin Ji, Li Li, Zhi-Jun Jie, Qiang Li, Xiang-Yang Li, Hong-Zhou Lu, Wen-Hong Zhang, Yuan-Lin Song, Jie-Ming Qu, Jin-Fu Xu
Journal: European Respiratory Journal (2020)

<b>Age significantly determined the clinical features and prognosis of COVID-19. The prognosis was worse in patients older than 60 years, calling for clinicians to pay more attention to patients of this age.</b>https://bit.ly/34DTI05
A Cross-sectional Comparison of Magnetic Resonance Imaging Findings and Clinical Assessment in Patients With Morphea
Authors: Laila F. Abbas, Jack C. O’Brien, Shauna Goldman, Parham Pezeshk, Majid Chalian, Avneesh Chhabra, Heidi T. Jacobe
Journal: JAMA Dermatology (2020)

0-4 scale for 5 categories [maximum score, 20]) as reported by patients.
Effect of L-arginine on intestinal water and sodium absorption Reply
Authors: C D HOLDSWORTH, M D HELLIER, R A WAPNIR, M A WINGERTZAHN, S TEICHBERG
Journal: Gut (1997)

Phospholipase A 2 in inflammatory bowel disease EDITOR,-Increased release of proinflammatory eicosanoids such as prostaglandin E 2 and thromboxane B 2 from mononuclear cells occurs during relapse in patients with inflammatory bowel disease (IBD). 1 The key enzyme in eicosanoid synthesis is phospholipase A 2 (PLA 2 ).Raised serum concentrations of the PLA 2 group II isoenzyme can be detected by immunoassay during the acute stages of IBD. 2 We read with interest the recent article by Peterson et al about the role of a phospholipase A 2 activating protein, PLAP (Gut 1996; 39: 698-704).The authors showed clearly that PLAP can be detected in monocytes and granulocytes originating from intestinal mucosa of patients with Crohn's disease and ulcerative colitis.In addition to this finding, extracellular deposits of PLAP antigen were associated with blood vessels and oedematous fluid from the inflamed tissue.Peterson et al postulated that PLAP may be involved in increasing PLA 2 activity with consecutive eicosanoid generation in IBD.We propose a further possible mechanism of PLA 2 activation during acute IBD in which the pro-inflammatory cytokine interleukin-6 (IL-6) is a key mediator.Peripheral blood concentrations of this cytokine are raised during acute IBD. 3 We showed recently that recombinant human IL-6 alone can increase serum concentrations of PLA 2 group II isoenzyme in humans. 4 Therefore, we suggest that increased IL-6 concentrations during relapse of IBD are also able to induce PLA 2 by a diVerent mechanism from PLA 2 activation via PLAP.The important role of cytokines in the induction of PLA 2 was confirmed by Crowl et al, 5 who showed that IL-6 could induce PLA 2 in vitro.The molecular mechanism of this induction was further elucidated by detection of an IL-6 response element in the promoter region of the PLA 2 gene. 5 In conclusion, activation of PLA 2 by PLAP could be a possible mechanism for increased eicosanoid synthesis in IBD but direct induction of PLA 2 gene transcription by pro-inflammatory cytokines should be taken into account.Therefore, we suggest a study with parallel measurements of IL-6 and PLA 2 serum concentrations during acute relapse of IBD to correlate these parameters and to determine the profiles of occurrence of these inflammation markers.We have developed a radiometric assay which may be useful as a sensitive and reliable method for absolute measurements of the true PLA 2 group II enzyme activity in serum. 6 Parallel measurements using a PLA 2 group II immunoassay may also indicate whether activation or inhibitory factors of PLA 2 are also present in peripheral blood.
Abstract 13414: Patients With Repaired Tetralogy of Fallot Have Increased Aortic Kinetic Energy Loss and Suboptimal Flow Hemodynamics Independent of Aortic Stiffness and Left Ventricular Function
Authors: Michal Schafer, Uyen Truong, Lorna Browne, Alex Barker, James Jaggers, David Campbell, Gareth Morgan, Michael DiMaria, Brian Fonseca, Ladonna Malone, Dunbar Ivy, Max Mitchell
Journal: Circulation (2018)

Introduction: Tetralogy of Fallot (TOF) aortopathy is characterized by aortic stiffness, dilation and reduced left ventricular (LV) function. TOF repair in infancy normalizes aortic dimensions, but...
Orchiectomy in transgender individuals: A motivation analysis and report of surgical outcomes
Authors: Wouter B. van der Sluis, Thomas D. Steensma, Mark-Bram Bouman
Journal: International Journal of Transgender Health (2020)

Background: Different surgical procedures are available for transgender women wishing to undergo genital gender-affirming surgery.Aim: To assess preoperative motivations, the frequency of orchiectomy procedures, and postoperative outcomes of orchiectomy in transgender individuals.Methods: All transgender individuals who underwent orchiectomy in the period between January 2012 and January 2020 at our institution were retrospectively identified. A chart study was conducted, recording motivations, demographics, perioperative characteristics and surgical outcomes. The frequency of orchiectomy and vaginoplasty procedures during the study period were determined and compared.Results: During the study period, an increase of performed orchiectomy procedures was observed. The orchiectomy/vaginoplasty ratio was 0.01–0.07 in the period 2012–2018 and 0.24 in 2019. A total of 43 transgender individuals were retrospectively identified. Sixteen (37%) initially wished to undergo a vaginoplasty, but did not meet institutional requirements (nonsmoker, BMI < 30kg/m2) or were not eligible for vaginoplasty surgery because of interfering somatic or mental health issues. Fourteen (33%) individuals who underwent orchiectomy regarded it as a preceding step to a future vaginoplasty procedure. Out of these fourteen, one person is now on the waiting list for vaginoplasty surgery. Thirteen (30%) others did not report a desire to pursue vaginoplasty in the future. This was mostly motivated by the absence of genital dysphoria or motivations related to their gender identity, with a desire to discontinue anti-testosterone treatment. The postoperative course was uncomplicated in 39 (91%) individuals.Conclusion: In the Netherlands, especially in the last year, the frequency of orchiectomy procedures has increased. Reasons that people chose to undergo this procedure include: not being eligible for a vaginoplasty procedure, seeing it as a preceding step to a possible future vaginoplasty or other identity-related motivations (i.e., non-binary gender identification or absence of genital dysphoria).
Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model
Authors: Asante Hatcher, Kwanha Yu, Jochen Meyer, Isamu Aiba, Benjamin Deneen, Jeffrey L Noebels
Journal: Journal of Clinical Investigation (2020)

Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmaco-resistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting MapT suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.