tbuckley/cabot-search huggingface dataset:
Somatic mutational landscapes of adherens junctions and their functional consequences in cutaneous melanoma development
Authors: Praveen Kumar Korla, Chih-Chieh Chen, Daniel Esguerra Gracilla, Ming-Tsung Lai, Chih-Mei Chen, Huan Yuan Chen, Tritium Hwang, Shih-Yin Chen, Jim Jinn-Chyuan Sheu
Journal: Theranostics (2020)

Cell-cell interaction in skin homeostasis is tightly controlled by adherens junctions (AJs). Alterations in such regulation lead to melanoma development. However, mutations in AJs and their functional consequences are still largely unknown. Methods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts. Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software. Neo-antigen prediction was carried out using NetMHCpan tool. Cell-based fluorescence reporter assay was used to validate β-catenin activity in the presence of cadherin mutations. Clinical significance was analyzed using datasets from TCGA and other non-TCGA cohorts. Targeted gene exon sequencing and immunofluorescence staining on melanoma tissues were performed to confirm the in silico findings. Results: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca2+-binding and cell-cell contacts. Mutational co-occurrence and physical dynamics analyses placed CDH6 at the center of the top-four mutated cadherins (core CDHs; all type-II), suggesting altered heterophilic interactions in melanoma development. Mutations in the intracellular domains significantly disturbed CDH6/β-catenin complex formation, resulting in β-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/β-catenin signaling. Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type. Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy. Conclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development. Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times.
A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease
Authors: Juan M. Bustamante, Fernando Sanchez-Valdez, Angel M. Padilla, Brooke White, Wei Wang, Rick L. Tarleton
Journal: Science Translational Medicine (2020)

A modified regimen of benznidazole prevents Trypanosoma cruzi dormancy-dependent treatment failure in several mouse models of Chagas disease.
Evaluation of Minimal Residual Disease (MRD) Negativity in Patients with Relapsed or Refractory Multiple Myeloma Treated in the Candor Study
Authors: Ola Landgren, Katja Weisel, Laura Rosinol Dachs, Philippe Moreau, Mehmet Turgut, Roman Hajek, Peter Mollee, Jin Seok Kim, Jianqi Zhang, Ning Go, Christopher L. Morris, Saad Z. Usmani
Journal: Blood (2020)
Abstract MP155: Oxidized Lipids Diet Causes Pulmonary Hypertension Through T-cell Dependent Endothelial Cell Apoptosis
Authors: Gregoire Ruffenach, Ellen O'connor, Mylene Vaillancourt, JASON HONG, Victor R Grijalva, Christine M Cunningham, shuchita tiwari, Frederic Perros, Xia YANG, Aldrin V Gomes, Srinivasa T Reddy, Mansoureh Eghbali
Journal: Circulation Research (2020)

Background: Pulmonary hypertension (PH) is a fatal disease characterized by an increased mean pulmonary arterial pressure above 25mmHg. This increased pressure is, at least in part, due to thickening of the distal pulmonary arteries. Recently, numerous studies demonstrated an increased plasma concentration of oxidized lipids in PH and in diseases where secondary PH developed. Furthermore, 15-hydroxyeicosatetraenoic acid (15-HETE) an oxidized lipid and a major metabolite of arachidonic acid in the lung, has been implicated in dysregulation of major biological pathways in PH. However, the mechanisms involved in the causal role of 15-HETE in pulmonary hypertension development are not known. Methods and Results: To study the role of 15-HETE in PH development, we fed C57BL6/J mice a diet supplemented with 15-HETE for 3 weeks with no other insults. After 3 weeks on the diet with added 15-HETE, C57BL6/J mice had increased concentrations of not only 15-HETE but also of other oxidized lipids (5-, 11- and 12-HETE) in plasma and lung, and they developed PH. RNA-seq analysis revealed the activation of pathways involved in antigen processing and presentation, and with evidence of T cell mediated cytotoxicity in lungs of mice fed 15-HETE. Transcriptomic profiling of lung tissues obtained from patients with pulmonary arterial hypertension (PAH) demonstrated activation of pathways similar to those seen mice. In mice fed a 15-HETE diet, there was an increase in the number of CD8/CD69 double positive cells, as well as an increase in pulmonary arterial endothelial cell (PAEC) apoptosis. Furthermore, PAEC exposed to 15-HETE were more prone to apoptosis when exposed to CD8 cells. Adding Tg6F, an apoA-I mimetic peptide to the 15-HETE diet prevented and rescued PH in C57BL6/J mice, in part, by inhibiting PAEC apoptosis. Conclusions: 15-HETE diet induced PH in C57Bl6/J mice by triggering PAEC death in a T-cell dependent mechanism. The apoA-I mimetic peptide Tg6F was able to prevent and rescue PH induced by 15-HETE.
Choosing Wisely in the Workup of Primary Hyperaldosteronism
Authors: Gerard M. Doherty, Rajshri M. Gartland, Quan-Yang Duh
Journal: JAMA Surgery (2020)

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Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans
Authors: Jennifer A. Jenks, Cody S. Nelson, Hunter K. Roark, Matthew L. Goodwin, Robert F. Pass, David I. Bernstein, Emmanuel B. Walter, Kathryn M. Edwards, Dai Wang, Tong-Ming Fu, Zhiqiang An, Cliburn Chan, Sallie R. Permar
Journal: Science Translational Medicine (2020)

Protection against CMV correlates with gB/MF59 vaccine-elicited IgG that binds cell-associated gB.
AB0030 INCREASED CIRCULATING CD19+CD24HICD38HI REGULATORY B CELLS ARE BIOMARKERS OF RESPONSE TO METHOTREXATE IN EARLY RHEUMATOID ARTHRITIS
Authors: P. Fortea-Gordo, A. Villalba, L. Nuño, M. J. Santos-Bornez, D. Peiteado, I. Monjo, A. Puig-Kröger, P. Sanchez-Mateos, E. Martín-Mola, A. Balsa, M. E. Miranda-Carus
Journal: Annals of the Rheumatic Diseases (2020)

Background: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional B cells (cTrB) have been described in patients with longstanding RA. Objectives: To examine the frequency and evolution of cTrB cells in the peripheral blood of early RA (ERA) patients. Methods: Freshly isolated PBMCs from 48 steroid and DMARD-naïve ERA patients with a disease duration below 24 weeks and 48 healthy controls (HC) were examined by flow cytometry. Cocultures of isolated memory B cells were established with autologous T cells, in the absence or presence of TrB cells. Results: As compared with HC, ERA patients demonstrated an increased frequency of cTrB cells. cTrBs of ERA and HC displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFNγ and IL-21 production, together with ACPA secretion in autologous B/T cell cocultures. Basal frequencies of cTrBs above the median value observed in HC were associated with a good EULAR response to MTX at 12 months (RR=2.91; 95% CI, 1.37-6.47). A significant reduction of cTrBs was observed 12 months after initiating MTX, when the cTrB cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone. Conclusion: An increased frequency of regulatory cTrB cells is apparent in untreated ERA, and the baseline cTrB cell frequency is associated with the clinical response to MTX at 12 months. References: [1]Matsushita T, et al. J Clin Invest. 2008;118:342. Flores-Borja F, et al. Sci Transl Med. 2013;5:173ra23. Disclosure of Interests: Paula Fortea-Gordo Grant/research support from: BMS, Alejandro Villalba: None declared, Laura Nuño: None declared, Maria-Jose Santos-Bornez Grant/research support from: BMS, Diana Peiteado: None declared, Irene Monjo: None declared, Amaya Puig-Kröger: None declared, Paloma Sanchez-Mateos: None declared, Emilio Martín-Mola Grant/research support from: BMS, Roche, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Roche
Untargeted Metabolomic Fingerprinting As a Potential Tool in the Diagnostic Evaluation of Diamond Blackfan Anemia
Authors: Birgit Van Dooijeweert, Melissa H. Broeks, Simon T. Grootendorst, Nanda M. Verhoeven, Wouter W. van Solinge, Edward E.S. Nieuwenhuis, Judith J. Jans, Richard van Wijk, Marije Bartels
Journal: Blood (2020)
Association of Sleep Disorders With Physician Burnout
Authors: Matthew D. Weaver, Rebecca Robbins, Stuart F. Quan, Conor S. O’Brien, Natalie C. Viyaran, Charles A. Czeisler, Laura K. Barger
Journal: JAMA Network Open (2020)

This cross-sectional study evaluates the association between sleep disorders and burnout symptoms among faculty and staff at a large teaching hospital.
Abstract 462: Cardiac-specific LMCD1/dyxin-knockout in Mice Blunts Pressure Overload-induced Activation of Calcineurin Signaling
Authors: Lucia S Kilian, Jakob Voran, Nesrin Schmiedel, Katharina Stiebeling, Julika Richter, Norbert Frey, Derk Frank
Journal: Circulation Research (2020)

We and others have shown that LMCD1 expression levels are upregulated in various in vitro and in vivo models of hypertrophy and that LMCD1 is necessary and sufficient to induce cardiomyocyte hypertrophy in vitro . We successfully generated a new mouse line with a conditional cardiac knockout of LMCD1. We performed echocardiographic, morphometric, and molecular analysis in these LMCD1-deficient and appropriate control-mice under basic conditions as well as 14 days after transverse aortic banding (TAC)-induced left ventricular (LV) pressure overload. Our aim was to investigate the hypothesis of potential beneficial effects of LMCD1-downregulation in vivo . These knockout (KO)-mice revealed under basic conditions a significant reduction of LMCD1 in the heart to &lt;10% on protein level compared to control (WT)-mice (females and males n=5 each, p&lt;0.001), while anatomic and functional parameters of the heart as well as LMCD1 levels in all other tested organs remained unchanged. Sham-operated KO-mice also showed significantly reduced level of LMCD1 in the LV compared to Sham-operated WT-mice (protein level &lt;20%, p&lt;0.001, n=8). No significant increase of LMCD1 in TAC- compared to Sham-operated KO-mice was found. TAC-operated KO-mice showed no significant differences in heart anatomy and function when compared to TAC-operated WT-mice. However, we determined a consistent trend toward improved heart function (ejection fraction and fractional shortening). Furthermore, TAC-operated KO-mice showed reduced activation of the fetal gene program in LV-tissue compared to TAC-operated WT-mice: mRNA levels of the hypertrophic markers NppA, NppB, and Rcan1-4 were all decreased (WT-TAC n=8 vs. KO-TAC n=10: NppA 8.5±2.0 vs. 5.1±1.5, p&lt;0.05; NppB 1.9±0.2 vs. 1.7±0.3, p=0.093; Rcan1-4 6.0±0.2 vs. 3.2 vs. 0.7, p&lt;0.05), suggesting a protective role of LMCD1-knockout. The reduction of calcineurin (CnA)-responsive Rcan1-4 specifically suggests a protective role of LMCD1-knockout in CnA-dependent signaling. Taken together, our preliminary data reveals protective effects of LMCD1-knockout against TAC-induced hypertrophic signaling. Ongoing experiments focus on effects of LMCD1-knockout on apoptosis and fibrosis and its role in Angiotensin-induced hypertrophy.
Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement
Authors: Peter Nash, Andreas Kerschbaumer, Thomas Dörner, Maxime Dougados, Roy M Fleischmann, Klaus Geissler, Iain McInnes, Janet E Pope, Désirée van der Heijde, Michaela Stoffer-Marx, Tsutomu Takeuchi, Michael Trauner, Kevin L Winthrop, Maarten de Wit, Daniel Aletaha, Xenofon Baraliakos, Wolf-Henning Boehncke, Paul Emery, John D Isaacs, Joel Kremer, Eun Bong Lee, Walter P Maksymowych, Marieke Voshaar, Lai-Shan Tam, Yoshiya Tanaka, Filip van den Bosch, René Westhovens, Ricardo Xavier, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2020)

Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.
Ocular Health of Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Baseline Data from the DREAMM-2 Trial of Belantamab Mafodotin (Belamaf)
Authors: Rakesh Popat, Aikaterini Kazantzi, Asim Farooq, Praneetha Thulasi, Sagar Lonial, Andrzej Jakubowiak, Ashraf Z. Badros, Bennie H. Jeng, Joanna Opalinska, January Baron, Trisha Piontek, Julie Byrne, Lynsey Womersley, Ira Gupta, Simona Degli Esposti
Journal: Blood (2020)
The Outcome of Diffuse Large B-Cell Lymphoma with CNS Involvement at Diagnosis, Single-Center Experience
Authors: Mubarak A Almansour, Saif Saif, Ziyad Alhrbi, Abdulrhamn Alhwaity, Ahmed Almasrahi, Waleed Alnejadi, Mohammed anwar Khan, Sarah surur Hussain, Ahmad Absi
Journal: Blood (2020)
The landscape of host genetic factors involved in immune response to common viral infections
Authors: Linda Kachuri, Stephen S. Francis, Maike L. Morrison, George A. Wendt, Yohan Bossé, Taylor B. Cavazos, Sara R. Rashkin, Elad Ziv, John S. Witte
Journal: Genome Medicine (2020)

Abstract Background Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. Methods We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. Results Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response ( P &lt; 5.0 × 10 −8 ), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR : P = 5.0 × 10 −15 (MCV), NTN5 : P = 1.1 × 10 −9 (BKV), and P2RY13 : P = 1.1 × 10 −8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. Conclusions Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
Biallelic Loss of BCMA Triggers Resistance to Anti-BCMA CAR T Cell Therapy in Multiple Myeloma
Authors: Mehmet K. Samur, Mariateresa Fulciniti, Anil Aktas-Samur, Abdul Hamid Bazarbachi, Yu-Tzu Tai, Timothy B. Campbell, Fabio Petrocca, Kristen Hege, Shari Kaiser, Kenneth Anderson, Nikhil C. Munshi
Journal: Blood (2020)
Antimicrobial resistance point-of-care testing for gonorrhoea treatment regimens: cost-effectiveness and impact on ceftriaxone use of five hypothetical strategies compared with standard care in England sexual health clinics
Authors: Emma M Harding-Esch, Susie E Huntington, Michael J Harvey, Georgie Weston, Claire E Broad, Elisabeth J Adams, S Tariq Sadiq
Journal: Eurosurveillance (2020)

Background Widespread ceftriaxone antimicrobial resistance (AMR) threatens Neisseria gonorrhoeae (NG) treatment, with few alternatives available. AMR point-of-care tests (AMR POCT) may enable alternative treatments, including abandoned regimens, sparing ceftriaxone use. We assessed cost-effectiveness of five hypothetical AMR POCT strategies: A-C included a second antibiotic alongside ceftriaxone; and D and E consisted of a single antibiotic alternative, compared with standard care (SC: ceftriaxone and azithromycin). Aim Assess costs and effectiveness of AMR POCT strategies that optimise NG treatment and reduce ceftriaxone use. Methods The five AMR POCT treatment strategies were compared using a decision tree model simulating 38,870 NG-diagnosed England sexual health clinic (SHC) attendees; A micro-costing approach, representing cost to the SHC (for 2015/16), was employed. Primary outcomes were: total costs; percentage of patients given optimal treatment (regimens curing NG, without AMR); percentage of patients given non-ceftriaxone optimal treatment; cost-effectiveness (cost per optimal treatment gained). Results All strategies cost more than SC. Strategy B (azithromycin and ciprofloxacin (azithromycin preferred); dual therapy) avoided most suboptimal treatments (n = 48) but cost most to implement (GBP 4,093,844 (EUR 5,474,656)). Strategy D (azithromycin AMR POCT; monotherapy) was most cost-effective for both cost per optimal treatments gained (GBP 414.67 (EUR 554.53)) and per ceftriaxone-sparing treatment (GBP 11.29 (EUR 15.09)) but with treatment failures (n = 34) and suboptimal treatments (n = 706). Conclusions AMR POCT may enable improved antibiotic stewardship, but require net health system investment. A small reduction in test cost would enable monotherapy AMR POCT strategies to be cost-saving.
Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts
Authors: Philippe Moreau, Ajai Chari, Mathias Haenel, Albert Oriol, Paula Rodriguez-Otero, Helen McCarthy, Kenshi Suzuki, Vania T. M. Hungria, Anna Sureda Balari, Lauriane Clement-Filliatre, Cyrille Hulin, Hila Magen, Shinsuke Iida, Vladimir Maisnar, Lionel Karlin, Luděk Pour, Cyrille Touzeau, Shiyi Yang, Michele Kosh, Maria Delioukina, Christoph Heuck, Hartmut Goldschmidt
Journal: Blood (2020)
Assessing the Feasibility and Limitations of Cultured Skin Fibroblasts for Germline Genetic Testing in Hematologic Disorders
Authors: Lia DeRoin, Marcela Cavalcante De Andrade Silva, Kristin Petras, Kelly Arndt, Nathaniel Phillips, Pankhuri Wanjari, Hari Prasanna Subramanian, David Montes, Soma Das, Lucy A. Godley, Jeremy Segal, Daniela del Gaudio, Carrie Fitzpatrick, Jane E. Churpek
Journal: Blood (2020)
Five thousand years of minimal access surgery: 1990–present: organisational issues and the rise of the robots
Authors: Rachel Hargest
Journal: Journal of the Royal Society of Medicine (2020)

The last 30 years have seen a revolution in the provision of minimal access surgery for many conditions, and technological advances are increasing exponentially. Many instruments are superseded by improved versions before the NHS and publicly funded health services can offer widespread coverage. Although we tend to think of minimal access surgery as a modern concept, Parts I and II of this series have shown that there is a 5000-year history to this specialty and our predecessors laid down many principles which still apply today. During the 19th and early 20th centuries, minimal access surgery was driven forward by visionary individuals, often in the face of opposition from colleagues and the medical establishment. However, in the last 30 years, innovation has been driven more in partnerships between healthcare, scientific, financial, educational and charitable organisations. There are far too many individuals involved to detail every contribution here, but this third part of the series will concentrate on some of the important themes in the development of minimal access surgery to its current status.