tbuckley/cabot-search huggingface dataset:
IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis
Authors: Shuai Yan, Manju Kumari, Haopeng Xiao, Christopher Jacobs, Shihab Kochumon, Mark Jedrychowski, Edward Chouchani, Rasheed Ahmad, Evan D. Rosen
Journal: Journal of Clinical Investigation (2021)

Adipose thermogenesis is repressed in obesity, reducing the homeostatic capacity to compensate for chronic overnutrition. Inflammation inhibits adipose thermogenesis, but little is known about how this occurs. Here we showed that the innate immune transcription factor IRF3 is a strong repressor of thermogenic gene expression and oxygen consumption in adipocytes. IRF3 achieved this by driving expression of the ubiquitin-like modifier ISG15, which became covalently attached to glycolytic enzymes, thus reducing their function and decreasing lactate production. Lactate repletion was able to restore thermogenic gene expression, even when the IRF3/ISG15 axis was activated. Mice lacking ISG15 phenocopied mice lacking IRF3 in adipocytes, as both had elevated energy expenditure and were resistant to diet-induced obesity. These studies provide a deep mechanistic understanding of how the chronic inflammatory milieu of adipose tissue in obesity prevents thermogenic compensation for overnutrition.
Strengthening measurement and performance of HIV prevention programmes
Authors: Charles B Holmes, Nduku Kilonzo, Jinkou Zhao, Leigh F Johnson, Thokozani Kalua, Nina Hasen, Michelle Morrison, Milly Marston, Tyler Smith, Irene Benech, Rachel Baggaley, Anna Carter, Mercy Khasiani, Jacqueline DePasse, Mary Mahy, Caroline Ryan, Geoff P Garnett
Journal: The Lancet HIV (2021)
Combined small-cell lung carcinoma revealed to be an intratumoural metastasis by genetic analysis
Authors: K.D. Lach, M. Sorin, C. Huynh, N.S. Alirezaie, A. Fiore, B. Fiset, R.F. Rayes, S. Camilleri-Broet, R. Fraser, J. Majewski, J.D. Spicer, L.A. Walsh, P.O. Fiset
Journal: Annals of Oncology (2021)
Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from healthcare workers, Israel, December 2020 to January 2021
Authors: Kamal Abu Jabal, Hila Ben-Amram, Karine Beiruti, Yunis Batheesh, Christian Sussan, Salman Zarka, Michael Edelstein
Journal: Eurosurveillance (2021)

The BNT162b2 mRNA COVID-19 vaccine showed high efficacy in clinical trials but observational data from populations not included in trials are needed. We describe immunogenicity 21 days post-dose 1 among 514 Israeli healthcare workers by age, ethnicity, sex and prior COVID-19 infection. Immunogenicity was similar by ethnicity and sex but decreased with age. Those with prior infection had antibody titres one magnitude order higher than naïve individuals regardless of the presence of detectable IgG antibodies pre-vaccination.
Roll-out of the Global Burden of Animal Diseases programme
Authors: J Rushton, B Huntington, W Gilbert, M Herrero, P R Torgerson, A P M Shaw, M Bruce, T L Marsh, D L Pendell, T M Bernardo, D Stacey, D Grace, K Watkins, M Bondad-Reantaso, B Devleesschauwer, D M Pigott, M Stone, S Mesenhowski
Journal: The Lancet (2021)
CMR Diffusion Tensor Imaging Provides Novel Imaging Markers of Adverse Myocardial Remodeling in Aortic Stenosis
Authors: Alexander Gotschy, Constantin von Deuster, Lucas Weber, Mareike Gastl, Martin O. Schmiady, Robbert J.H. van Gorkum, Johanna Stimm, Jochen von Spiczak, Robert Manka, Sebastian Kozerke, Christian T. Stoeck
Journal: JACC. Cardiovascular imaging (2021)
Trends in Total and Out-of-pocket Payments for Noninsulin Glucose-Lowering Drugs Among U.S. Adults With Large-Employer Private Health Insurance From 2005 to 2018
Authors: Hui Shao, Michael Laxy, Stephen R. Benoit, Yiling J. Cheng, Edward W. Gregg, Ping Zhang
Journal: Diabetes Care (2021)

OBJECTIVE To estimate trends in total payment and patients’ out-of-pocket (OOP) payments of noninsulin glucose-lowering drugs by class from 2005 to 2018. RESEARCH DESIGN AND METHODS We analyzed data for 53 million prescriptions from adults aged &amp;gt;18 years with type 2 diabetes under fee-for-service plans from the 2005–2018 IBM MarketScan Commercial Databases. The total payment was measured as the amount that the pharmacy received, and the OOP payment was the sum of copay, coinsurance, and deductible paid by the beneficiaries. We applied a joinpoint regression to evaluate nonlinear trends in cost between 2005 and 2018. We further conducted a decomposition analysis to explore the drivers for total payment change. RESULTS Total annual payments for older drug classes, including metformin, sulfonylurea, meglitinide, α-glucosidase inhibitors, and thiazolidinedione, declined during 2005–2018, ranging from −$271 (−53.8%) for metformin to −$2,406 (−92.2%) for thiazolidinedione. OOP payments for these drug classes also reduced. In the same period, the total annual payments for the newer drug classes, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium–glucose cotransporter 2 inhibitors, increased by $2,181 (88.4%), $3,721 (77.6%), and $1,374 (37.0%), respectively. OOP payment for these newer classes remained relatively unchanged. Our study findings indicate that switching toward the newer classes for noninsulin glucose-lowering drugs was the main driver that explained the total payment increase. CONCLUSIONS Average annual payments and OOP payment for noninsulin glucose-lowering drugs increased significantly from 2005 to 2018. The uptake of newer drug classes was the main driver.
Autoantibodies May Drive COVID-19 Blood Clots
Authors: Tracy Hampton
Journal: JAMA (2021)

Ana Blasco, MD, PhD; María-José Coronado, PhD; Fernando Hernández-Terciado, MD; Paloma Martín, MD, PhD; Ana Royuela, PhD; Elvira Ramil, PhD; Diego García, MLT; Javier Goicolea, MD; María Del Trigo, MD, PhD; Javier Ortega, MD; Juan M. Escudier, MD, PhD; Lorenzo Silva, MD; Carmen Bellas, MD, PhD
Rates of Peanut Discontinuation After Introduction Among High-Risk Infants
Authors: Abhilasha Banerjee, Michael Pistiner, Wayne Shreffler, Robert Wood, Joan Dunlop, Jennifer Dantzer, Mihaela Plesa, Daria Szelag, Roger Peng, Alkis Togias, Corinne Keet
Journal: Journal of Allergy and Clinical Immunology (2021)
Exploiting Allosteric Properties of RAF and MEK Inhibitors to Target Therapy-Resistant Tumors Driven by Oncogenic BRAF Signaling
Authors: Christos Adamopoulos, Tamer A. Ahmed, Maxwell R. Tucker, Peter M.U. Ung, Min Xiao, Zoi Karoulia, Angelo Amabile, Xuewei Wu, Stuart A. Aaronson, Celina Ang, Vito W. Rebecca, Brian D. Brown, Avner Schlessinger, Meenhard Herlyn, Qi Wang, David E. Shaw, Poulikos I. Poulikakos
Journal: Cancer Discovery (2021)

Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF) but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAFV600E therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical well-being in a patient with stage IV colorectal cancer. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAFV600E tumors. SIGNIFICANCE: This work identifies a new class of RAFi that are selective for dBRAF over mBRAF and determines the basis of their selectivity. A rationally designed combination of RAF and MEK inhibitors based on their conformation selectivity achieved increased efficacy and a high therapeutic index when used to target BRAFV600E tumors.See related commentary by Zhang and Bollag, p. 1620.This article is highlighted in the In This Issue feature, p. 1601.
European Respiratory Society guidelines for the management of children and adolescents with bronchiectasis
Authors: Anne B. Chang, Rebecca Fortescue, Keith Grimwood, Efthymia Alexopoulou, Leanne Bell, Jeanette Boyd, Andrew Bush, James D. Chalmers, Adam T. Hill, Bulent Karadag, Fabio Midulla, Gabrielle B. McCallum, Zena Powell, Deborah Snijders, Woo-Jung Song, Thomy Tonia, Christine Wilson, Angela Zacharasiewicz, Ahmad Kantar
Journal: European Respiratory Journal (2021)

There is increasing awareness of bronchiectasis in children and adolescents, a chronic pulmonary disorder associated with poor quality of life for the child/adolescent and their parents, recurrent exacerbations, and costs to the family and health systems. Optimal treatment improves clinical outcomes. Several national guidelines exist, but there are no international guidelines. The European Respiratory Society (ERS) Task Force for the management of paediatric bronchiectasis sought to identify evidence-based management (investigation and treatment) strategies. It used the ERS standardised methodology that included a systematic review of the literature and application of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to define the quality of the evidence and level of recommendations. A multidisciplinary team of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, immunology, methodology, patient advocacy and parents of children/adolescents with bronchiectasis considered the most relevant clinical questions (for both clinicians and patients) related to managing paediatric bronchiectasis. 14 key clinical questions (seven PICO (Patient, Intervention, Comparison, Outcome) and seven narrative) were generated. The outcomes for each PICO were decided by voting by the panel and parent/patient advisory group. This guideline addresses the definition, diagnostic approach and antibiotic treatment of exacerbations, pathogen eradication, long-term antibiotic therapy, asthma-type therapies (inhaled corticosteroids and bronchodilators), mucoactive drugs, airway clearance, investigation of underlying causes of bronchiectasis, disease monitoring, factors to consider before surgical treatment, and the reversibility and prevention of bronchiectasis in children/adolescents. Benchmarking quality of care for children/adolescents with bronchiectasis to improve clinical outcomes and evidence gaps for future research could be based on these recommendations.
Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
Authors: Elsa Bernard, Yasuhito Nannya, Robert P. Hasserjian, Sean M. Devlin, Heinz Tuechler, Juan S. Medina-Martinez, Tetsuichi Yoshizato, Yusuke Shiozawa, Ryunosuke Saiki, Luca Malcovati, Max F. Levine, Juan E. Arango, Yangyu Zhou, Francesc Solé, Catherine A. Cargo, Detlef Haase, Maria Creignou, Ulrich Germing, Yanming Zhang, Gunes Gundem, Araxe Sarian, Arjan A. van de Loosdrecht, Martin Jädersten, Magnus Tobiasson, Olivier Kosmider, Matilde Y. Follo, Felicitas Thol, Ronald F. Pinheiro, Valeria Santini, Ioannis Kotsianidis, Jacqueline Boultwood, Fabio P. S. Santos, Julie Schanz, Senji Kasahara, Takayuki Ishikawa, Hisashi Tsurumi, Akifumi Takaori-Kondo, Toru Kiguchi, Chantana Polprasert, John M. Bennett, Virginia M. Klimek, Michael R. Savona, Monika Belickova, Christina Ganster, Laura Palomo, Guillermo Sanz, Lionel Ades, Matteo Giovanni Della Porta, Alexandra G. Smith, Yesenia Werner, Minal Patel, Agnès Viale, Katelynd Vanness, Donna S. Neuberg, Kristen E. Stevenson, Kamal Menghrajani, Kelly L. Bolton, Pierre Fenaux, Andrea Pellagatti, Uwe Platzbecker, Michael Heuser, Peter Valent, Shigeru Chiba, Yasushi Miyazaki, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H. Jansen, José Cervera, Yoshiko Atsuta, Norbert Gattermann, Benjamin L. Ebert, Rafael Bejar, Peter L. Greenberg, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Elli Papaemmanuil
Journal: Nature Medicine (2021)
Abstract PR003: Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility
Authors: Tracy A. O'Mara, Pik Fang Kho, Gabriel Cuellar Partida, Amanda B. Spurdle, Dylan M. Glubb
Journal: Clinical Cancer Research (2021)

Abstract To date, genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic risk regions; however, candidate susceptibility genes at these regions are yet to be confirmed. We performed a transcriptome-wide association study (TWAS) to identify candidate endometrial cancer susceptibility genes and provide evidence to support previously identified candidate genes. To maximise statistical power, we used a multi-tissue TWAS approach, integrating the largest endometrial cancer GWAS (12,906 cases and 108,979 controls of European ancestry) with cis-expression quantitative trait loci (eQTLs) from 48 tissues. Identified genes were prioritised by colocalisation analysis to reduce false positive findings. We found seven candidate endometrial cancer susceptibility genes, six of which had previously been identified as candidate susceptibility genes by parallel functional analyses. The remaining identified gene was a lncRNA located at a potentially novel endometrial cancer genetic risk region. Using phenome-wide association approaches, we found these genes associate with traits related to endometrial cancer risk factors, including cardiovascular phenotypes, diabetes, and hormone levels. This analysis additionally identified associations with traits related to bone health, haematopoiesis and liver function, providing avenues for future study. Comparing genetically predicted endometrial cancer gene expression with drug-induced gene expression profiles from the Connectivity Map database, we identified 14 drug repurposing candidates including tubulin inhibitors, a drug class already in use for treatment of advanced endometrial cancer. In summary, using TWAS we have identified candidate endometrial cancer susceptibility genes and provided evidence to prioritise existing candidates. Follow-up analyses have revealed further potential risk factors for endometrial cancer and compounds that could be repurposed for endometrial cancer treatment. Citation Format: Tracy A. O'Mara, Pik Fang Kho, Gabriel Cuellar Partida, Amanda B. Spurdle, Dylan M. Glubb. Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR003.
Abstract PO008: ARID1A prevents H3K27-hyperacetylation at active super-enhancers
Authors: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler
Journal: Clinical Cancer Research (2021)

Abstract Mutations in the multi-subunit SWI/SNF (BAF) chromatin remodeling complex are observed in nearly all types of cancer. The most highly mutated subunit across cancer is ARID1A, which occurs in roughly half of uterine endometrial cancer cases. ARID1A mutations and loss of expression are also common in endometriosis. We have previously demonstrated that ARID1A loss drives transcriptional alterations leading to invasive phenotypes through multiple model systems. Yet, how ARID1A regulates transcription through chromatin regulation is poorly understood. We have generated genome-wide profiles of seven chromatin features associated with transcriptional regulation in human endometrial epithelial cells, in both the presence and absence of ARID1A, in order to identify a mechanism by which ARID1A regulates chromatin. Unbiased genome segmentation using these features revealed that ARID1A interacts with chromatin at highly active and accessible enhancers genome-wide. Out of all tested chromatin features, ARID1A most strongly co-localizes with H3K27ac, a mark of transcriptional activation at proximal and distal enhancers. ARID1A depletion also displayed the greatest effect on genomic H3K27ac as opposed to other histone modifications, H3K18ac, H3K4me1, H3K4me3, and H3K27me3. While the majority of typical enhancers had reduced H3K27ac with ARID1A loss, super-enhancers marked by high basal H3K27ac levels displayed hyperacetylation following ARID1A loss. Moreover, increasing H3K27ac was also associated with heightened eRNA transcription, indicating enhancer hyperactivation. Finally, RNA-seq revealed that genes associated with active super-enhancers were preferentially dysregulated following ARID1A loss. These results suggest that ARID1A-SWI/SNF differentially regulate typical enhancers vs. super-enhancers in the endometrial epithelium, and ARID1A may normally restrict super-enhancer hyperactivation to maintain epithelial identity and prevent endometrial invasion. Citation Format: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler. ARID1A prevents H3K27-hyperacetylation at active super-enhancers [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO008.
Abstract #4222: Characterization of the promoter region of the ORF11 gene of Kaposi's sarcoma-associated herpesvirus
Authors: Lei Chen
Journal: Cancer Research (2009)

Open reading frame 11 (ORF11) of Kaposi\#8217;s sarcoma-associated herpesvirus belongs to a herpesviral homologous protein family that is conserved among members of the gamma-herpesvirus subfamily. Little is known about the function of ORF11 and how this viral gene is regulated in KSHV life cycle. In this study, we have characterized the major transcript of the ORF11 gene, which is located adjacent and in the opposite orientation to a well-characterized viral IL-6 gene. Northern blot analysis revealed that the ORF11 gene is lytic viral gene with delayed-early expression kinetics. We have determined the 5\#8217; and 3\#8217; untranslated region of the unspliced ORF11 transcript and identified both the transcription start site and the transcription termination site. Core promoter region, representing ORF11 promoter activity, was mapped to a 160nt fragment 5\#8217; most proximal to the transcription start site. A functional TATA box was identified in the core promoter region. We also found that the characterized ORF11 gene promoter region is not responsive to Rta, the KSHV lytic switch protein. Our data help to elucidate transcription regulation of the KSHV ORF11 gene and to understand the biology of ORF11 in KSHV life cycle.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4222.
Depression: EU approves expanded use of esketamine for rapid reduction of symptoms
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Esketamine nasal spray—sold under the name Spravato—has been approved by the European Commission as a short term treatment for adults with a moderate to severe episode of major depressive disorder.1

The spray, which must be given alongside an oral antidepressant, has been approved for use in situations deemed a psychiatric emergency, to reduce depressive symptoms rapidly.

The treatment was initially approved by the …
Effect of Clinical Decision Support on Diagnostic Imaging for Pediatric Appendicitis
Authors: Anupam B. Kharbanda, Gabriela Vazquez-Benitez, Dustin W. Ballard, David R. Vinson, Uli K. Chettipally, Steven P. Dehmer, Heidi Ekstrom, Adina S. Rauchwerger, Brianna McMichael, Dale M. Cotton, Mamata V. Kene, Laura E. Simon, Jingyi Zhu, E. Margaret Warton, Patrick J. O’Connor, Elyse O. Kharbanda
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Appendicitis is the most common pediatric surgical emergency. Efforts to improve efficiency and quality of care have increased reliance on computed tomography (CT) and ultrasonography (US) in children with suspected appendicitis. <h3>Objective</h3> To evaluate the effectiveness of an electronic health record–linked clinical decision support intervention, AppyCDS, on diagnostic imaging, health care costs, and safety outcomes for patients with suspected appendicitis. <h3>Design, Setting, and Participants</h3> In this parallel, cluster randomized trial, 17 community-based general emergency departments (EDs) in California, Minnesota, and Wisconsin were randomized to the AppyCDS intervention group or usual care (UC) group. Patients were aged 5 to 20 years, presenting for an ED visit with right-sided or diffuse abdominal pain lasting 5 days or less. We excluded pregnant patients, those with a prior appendectomy, those with selected comorbidities, and those with traumatic injuries. The trial was conducted from October 2016 to July 2019. <h3>Interventions</h3> AppyCDS prompted data entry at the point of care to estimate appendicitis risk using the pediatric appendicitis risk calculator (pARC). Based on pARC estimates, AppyCDS recommended next steps in care. <h3>Main Outcomes and Measures</h3> Primary outcomes were CT, US, or any imaging (CT or US) during the index ED visit. Safety outcomes were perforations, negative appendectomies, and missed appendicitis. Costs were a secondary outcome. Ratio of ratios (RORs) for primary and safety outcomes and differences by group in cost were used to evaluate effectiveness of the clinical decision support tool. <h3>Results</h3> We enrolled 3161 patients at intervention EDs and 2779 patients at UC EDs. The mean age of patients was 11.9 (4.6) years and 2614 (44.0%) were boys or young men. RORs for CT (0.94; 95% CI, 0.75-1.19), US (0.98; 95% CI, 0.84-1.14), and any imaging (0.96; 95% CI, 0.86-1.07) did not differ by study group. In an exploratory analysis conducted in 1 health system, AppyCDS was associated with a reduction in any imaging (ROR, 0.82; 95% CI, 0.73- 0.93) for patients with pARC score of 15% or less and a reduction in CT (ROR, 0.58; 95% CI, 0.45-0.74) for patients with a pARC score of 16% to 50%. Perforations, negative appendectomies, and cases of missed appendicitis by study phase did not differ significantly by study group. Costs did not differ overall by study group. <h3>Conclusions and Relevance</h3> In this study, AppyCDS was not associated with overall reductions in diagnostic imaging; exploratory analysis revealed more appropriate use of imaging in patients with a low pARC score. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02633735
Abstract 11345: Both Leanness and Obesity Were Associated With Cardiovascular Events in Patients With More Than 65 Years Old: The Japan Morning Surge Home Blood Pressure (J-HOP) Study
Authors: Shinichi Toriumi, Tomoyuki Kabutoya, Satoshi Hoshide, Kazuomi Kario
Journal: Circulation (2019)

Introduction: Whether age-related differences exist in the association between leanness and cardiovascular events remains unclear. Hypothesis: We hypothesized that the association between leanness ...
Endothelial cell-driven regulation of CD9 or motility related protein-1 (MRP-1) expression in the murine 5T33 multiple myeloma cells
Authors: Elke De Bruyne, Thomas Levin Andersen, Hendrik De Raeve, Els Van Valckenborgh, Jo Caers, Benjamin Van Camp, Jean-Marie Délaisse, Ivan Van Riet, Karin Vanderkerken
Journal: Leukemia (2006)