tbuckley/cabot-search huggingface dataset:
MGMT Promoter Methylation as a Target In Metastatic Colorectal Cancer: Rapid Turnover and Use of Folates Alter its Study—Response
Authors: Giovanni Randon, Filippo Pagani, Filippo Pietrantonio
Journal: Clinical Cancer Research (2020)

We agree with Ottaiano and Caraglia that the heterogeneity and dynamic evolution of MGMT status might cause temozolomide resistance related to MGMT reexpression/ MGMT demethylation in patients with metastatic colorectal cancer. In phase II trials ([1–5][1]) and pooled analyses ([6–8][2]) of
Exploring neighborhoods in large metagenome assembly graphs using spacegraphcats reveals hidden sequence diversity
Authors: C. Titus Brown, Dominik Moritz, Michael P. O’Brien, Felix Reidl, Taylor Reiter, Blair D. Sullivan
Journal: Genome biology (2020)

Abstract Genomes computationally inferred from large metagenomic data sets are often incomplete and may be missing functionally important content and strain variation. We introduce an information retrieval system for large metagenomic data sets that exploits the sparsity of DNA assembly graphs to efficiently extract subgraphs surrounding an inferred genome. We apply this system to recover missing content from genome bins and show that substantial genomic sequence variation is present in a real metagenome. Our software implementation is available at https://github.com/spacegraphcats/spacegraphcats under the 3-Clause BSD License.
Patterns of farm exposure are associated with reduced incidence of atopic dermatitis in early life
Authors: Cheryl A. Steiman, Michael D. Evans, Kristine E. Lee, Michael R. Lasarev, Ronald E. Gangnon, Brent F. Olson, Kathrine L. Barnes, Casper G. Bendixsen, Christine M. Seroogy, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2020)
Potential of regulatory T-cell-based therapies in the management of severe COVID-19
Authors: Emmanuel Stephen-Victor, Mrinmoy Das, Anupama Karnam, Bruno Pitard, Jean-François Gautier, Jagadeesh Bayry
Journal: European Respiratory Journal (2020)

<b>In view of dysregulated immune response, "cytokine storm" and inflammation-induced lung damage in severely ill COVID-19 patients, we propose that CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> regulatory T-cell-based therapies could be considered for patient management</b>https://bit.ly/3eKqWPo
The health of private insurance in the US during covid-19
Authors: Bob Roehr
Journal: BMJ (2020)

The health of private insurance in the US during covid-19In an insurance based health system, it's insurers who foot the bill for pandemic care.Bob Roehr finds that the pandemic is further complicating an already complicated system Bob RoehrEarly in the pandemic, US health insurers planned to treat covid-19 just like any other medical condition: in general, people pay a percentage of costs that their plan deems legitimate.
Population-based estimates of healthy working life expectancy in England at age 50 years: analysis of data from the English Longitudinal Study of Ageing
Authors: Marty Parker, Milica Bucknall, Carol Jagger, Ross Wilkie
Journal: The Lancet Public Health (2020)

Retirement ages are rising in many countries to offset the challenges of population ageing, but people's capacity to work for more years in their later working life (>50 years) is unclear. We aimed to estimate healthy working life expectancy in England.This analysis included adults aged 50 years and older from six waves (2002-13) of the English Longitudinal Study of Ageing (ELSA), with linked mortality data. Healthy working life expectancy was defined as the average number of years expected to be spent healthy (no limiting long-standing illness) and in paid work (employment or self-employment) from age 50 years. Healthy working life expectancy was estimated for England overall and stratified by sex, educational attainment, deprivation level, occupation type, and region by use of interpolated Markov chain multi-state modelling.There were 15 284 respondents (7025 men and 8259 women) with survey and mortality data for the study period. Healthy working life expectancy at age 50 years was on average 9·42 years (10·94 years [95% CI 10·65-11·23] for men and 8·25 years [7·92-8·58] for women) and life expectancy was 31·76 years (30·05 years for men and 33·49 years for women). The number of years expected to be spent unhealthy and in work from age 50 years was 1·84 years (95% CI 1·74-1·94) in England overall. Population subgroups with the longest healthy working life expectancy were the self-employed (11·76 years [95% CI 10·76-12·76]) or those with non-manual occupations (10·32 years [9·95-10·69]), those with a tertiary education (11·27 years [10·74-11·80]), those living in southern England (10·73 years [10·16-11·30] in the South East and 10·51 years [9·80-11·22] in the South West), and those living in the least deprived areas (10·53 years [10·06-10·99]).Healthy working life expectancy at age 50 years in England is below the remaining years to State Pension age. Older workers of lower socioeconomic status and in particular regions in England might benefit from proactive approaches to improve health, workplace environments, and job opportunities to improve their healthy working life expectancy. Continued monitoring of healthy working life expectancy would provide further examination of the success of such approaches and that of policies to extend working lives.Economic and Social Research Council.
The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages
Authors: Marta Lourenço, Lorenzo Chaffringeon, Quentin Lamy-Besnier, Thierry Pédron, Pascal Campagne, Claudia Eberl, Marion Bérard, Bärbel Stecher, Laurent Debarbieux, Luisa De Sordi
Journal: Cell Host & Microbe (2020)
Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift
Authors: Kevin D. Deane, V. Michael Holers
Journal: Arthritis & Rheumatology (2020)

Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today.
Erratum for the Research Article: “The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females” by Y. Chen, A. Moutal, E. Navratilova, C. Kopruszinski, X. Yue, M. Ikegami, M. Chow, I. Kanazawa, S. S. Bellampalli, J. Xie, A. Patwardhan, K. Rice, H. Fields, A. Akopian, V. Neugebauer, D. Dodick, R. Khanna, F. Porreca
Journal: Science Translational Medicine (2020)
Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5
Authors: Yang Liu, Xiaojia Liu, Na Zhang, Mingxiao Yin, Jingwen Dong, Qingxuan Zeng, Genxiang Mao, Danqing Song, Lu Liu, Hongbin Deng
Journal: Acta Pharmaceutica Sinica B (2020)

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer
Authors: Debarati Banik, Satish Noonepalle, Melissa Hadley, Erica Palmer, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Namratta Manhas, Hayk Simonyan, Colin N. Young, Anastas Popratiloff, Katherine B. Chiappinelli, Rohan Fernandes, Eduardo M. Sotomayor, Alejandro Villagra
Journal: Cancer Research (2020)

Despite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new noncanonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial-mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pretreatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of breast cancer with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi. SIGNIFICANCE: Ultraselective HDAC6 inhibitors can reduce tumor growth and invasiveness of breast cancer by noncanonical mechanisms unrelated to the previously cytotoxic properties attributed to HDAC inhibitors.
Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older
Authors: Ariela R. Orkaby, Jane A. Driver, Yuk-Lam Ho, Bing Lu, Lauren Costa, Jacqueline Honerlaw, Ashley Galloway, Jason L. Vassy, Daniel E. Forman, J. Michael Gaziano, David R. Gagnon, Peter W. F. Wilson, Kelly Cho, Luc Djousse
Journal: JAMA (2020)

<h3>Importance</h3> Data are limited regarding statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults 75 years and older. <h3>Objective</h3> To evaluate the role of statin use for mortality and primary prevention of ASCVD in veterans 75 years and older. <h3>Design, Setting, and Participants</h3> Retrospective cohort study that used Veterans Health Administration (VHA) data on adults 75 years and older, free of ASCVD, and with a clinical visit in 2002-2012. Follow-up continued through December 31, 2016. All data were linked to Medicare and Medicaid claims and pharmaceutical data. A new-user design was used, excluding those with any prior statin use. Cox proportional hazards models were fit to evaluate the association of statin use with outcomes. Analyses were conducted using propensity score overlap weighting to balance baseline characteristics. <h3>Exposures</h3> Any new statin prescription. <h3>Main Outcomes and Measures</h3> The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included a composite of ASCVD events (myocardial infarction, ischemic stroke, and revascularization with coronary artery bypass graft surgery or percutaneous coronary intervention). <h3>Results</h3> Of 326 981 eligible veterans (mean [SD] age, 81.1 [4.1] years; 97% men; 91% white), 57 178 (17.5%) newly initiated statins during the study period. During a mean follow-up of 6.8 (SD, 3.9) years, a total 206 902 deaths occurred including 53 296 cardiovascular deaths, with 78.7 and 98.2 total deaths/1000 person-years among statin users and nonusers, respectively (weighted incidence rate difference [IRD]/1000 person-years, –19.5 [95% CI, –20.4 to –18.5]). There were 22.6 and 25.7 cardiovascular deaths per 1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, –3.1 [95 CI, –3.6 to –2.6]). For the composite ASCVD outcome there were 123 379 events, with 66.3 and 70.4 events/1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, –4.1 [95% CI, –5.1 to –3.0]). After propensity score overlap weighting was applied, the hazard ratio was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers. <h3>Conclusions and Relevance</h3> Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all-cause and cardiovascular mortality. Further research, including from randomized clinical trials, is needed to more definitively determine the role of statin therapy in older adults for primary prevention of ASCVD.
Addressing Burnout—Focus on Systems, Not Resilience
Authors: Allan H. Goroll
Journal: JAMA Network Open (2020)

Colin P. West, MD, PhD; Liselotte N. Dyrbye, MD, MHPE; Christine Sinsky, MD; Mickey Trockel, MD, PhD; Michael Tutty, PhD; Laurence Nedelec, PhD; Lindsey E. Carlasare, MBA; Tait D. Shanafelt, MD
Mannose-Binding Lectin and Risk of Cardiovascular Events and Mortality in Type 2 Diabetes: A Danish Cohort Study
Authors: Anne Gedebjerg, Mette Bjerre, Alisa Devedzic Kjaergaard, Rudi Steffensen, Jens Steen Nielsen, Jørgen Rungby, Søren Gunnar Friborg, Ivan Brandslund, Steffen Thiel, Henning Beck-Nielsen, Henrik Toft Sørensen, Troels Krarup Hansen, Reimar Wernich Thomsen
Journal: Diabetes Care (2020)

OBJECTIVE Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS In a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and all-cause mortality. The association with outcomes was examined by spline and Cox regression analyses. RESULTS Serum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34–2.46) for the low-MBL category and 1.48 (95% CI 1.14–1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87–2.25) for the low-expression genotype and 1.44 (95% CI 1.01–2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality. CONCLUSIONS Both serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population.
Clinical correlates of rhinovirus infection in preschool asthma
Authors: Tuomas Jartti, Unna Liimatainen, Paraskevi Xepapadaki, Tero Vahlberg, Claus Bachert, Susetta Finotto, Marek L Kowalski, Anna Sobanska, Heikki Lukkarinen, Maria Pasioti, Tytti Vuorinen, Nan Zhang, Theodor Zimmermann, Nikolaos G Papadopoulos
Journal: Allergy (2020)

Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group.To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome.A total of 130 asthmatic children aged 4-6 years from the multinational PreDicta cohort were prospectively followed for a 12-month period. Allergy tests and a standard health questionnaire were carried out at study entry. Respiratory virus presence in nasopharyngeal washes was studied at illness visits and at 3 scheduled visits.At study entry, mean age of the children was 5.3 years. Of 571 visits, 54% were positive for any virus and 39% for RV. Patient characteristics were only assessed with RV infection due to low number of other viruses. The use of supplementary vitamin D was inversely associated with RV infection (P < .05). RV infection was associated with more severe course of acute illness in terms of more severe nighttime coughing, more sleep disturbances, and more days with runny nose (all P < .05). RV infection was also associated with more severe disease course during the 12-month follow-up in terms of more nights with awakenings and more days of exercise-related symptoms (both P < .05).Vitamin D supplementation may have an anti-rhinovirus effect. Both short- and medium-term outcomes suggest RV infection to be an important clinical marker of instable preschool asthma.
A Replication-Competent Vesicular Stomatitis Virus for Studies of SARS-CoV-2 Spike-Mediated Cell Entry and Its Inhibition
Authors: M. Eugenia Dieterle, Denise Haslwanter, Robert H. Bortz, Ariel S. Wirchnianski, Gorka Lasso, Olivia Vergnolle, Shawn A. Abbasi, J. Maximilian Fels, Ethan Laudermilch, Catalina Florez, Amanda Mengotto, Duncan Kimmel, Ryan J. Malonis, George Georgiev, Jose Quiroz, Jason Barnhill, Liise-anne Pirofski, Johanna P. Daily, John M. Dye, Jonathan R. Lai, Andrew S. Herbert, Kartik Chandran, Rohit K. Jangra
Journal: Cell Host & Microbe (2020)
Unique skin abnormality in patients with peanut allergy but no atopic dermatitis
Authors: Evgeny Berdyshev, Elena Goleva, Irina Bronova, Anna-Sofia Bronoff, Bryce C. Hoffman, Marco A. Ramirez-Gama, Shannon L. Garcia, Debra Crumrine, Peter M. Elias, Christine B. Cho, Donald Y.M. Leung
Journal: Journal of Allergy and Clinical Immunology (2020)
Global burden of oesophageal and gastric cancer by histology and subsite in 2018
Authors: Melina Arnold, Jacques Ferlay, Mark I van Berge Henegouwen, Isabelle Soerjomataram
Journal: Gut (2020)

Objectives To provide updated estimates of the global burden of oesophageal and gastric cancer by subsite and type. Methods Using data from population-based cancer registries, proportions of oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC) out of all oesophageal as well as cardia gastric cancer (CGC) and non-CGC (NCGC) out of all gastric cancer cases were computed by country, sex and age group. Proportions were subsequently applied to the estimated numbers of oesophageal and gastric cancer cases from GLOBOCAN 2018. Age-standardised incidence rates (ASR) were calculated. Results In 2018, there were an estimated 572 000 new cases of oesophageal cancer worldwide, 85 000 OACs (ASR 0.9 per 100 000, both sexes combined) and 482 000 OSCCs (ASR 5.3). Out of 1.03 million gastric cancers, there were an estimated 181 000 cases of CGC (ASR 2.0) and 853 000 cases of NCGC (ASR 9.2). While the highest incidence rates of OSCC, CGC and NCGC were observed in Eastern Asia (ASRs 11.1, 4.4 and 17.9, respectively), rates of OAC were highest in Northern Europe (ASR 3.5). While globally OSCC and NCGC remain the most common types of oesophageal and gastric cancer, respectively, rates of OAC exceed those of OSCC in an increasing number of high-income countries. Conclusions These updated estimates of the global burden of oesophageal and gastric cancer by subtype and site suggest an ongoing transition in epidemiological patterns. This work will serve as a cornerstone for policy-making and will aid in developing appropriate cancer control strategies.
Tongue Ulceration from Cytomegalovirus Infection
Authors: Ryo Nishioka, Mitsuhiro Kawano
Journal: New England Journal of Medicine (2020)

A 78-year-old man with end-stage renal disease and microscopic polyangiitis, for which he was taking glucocorticoids, presented with fever, taste abnormalities, and a painful ulceration of the tongue. Biopsy of the lesion confirmed a diagnosis of cytomegalovirus infection.
Association Between Atrial Fibrillation and Sudden Cardiac Death
Authors: Victor Waldmann, Xavier Jouven, Kumar Narayanan, Olivier Piot, Sumeet S. Chugh, Christine M. Albert, Eloi Marijon
Journal: Circulation Research (2020)

Emerging evidence suggests that atrial fibrillation (AF) may be associated with an increased risk of sudden cardiac death (SCD). However, AF shares risk factors with numerous cardiac conditions, including coronary heart disease and heart failure—the 2 most common substrates for SCD—making the AF-SCD relationship particularly challenging to address. A careful consideration of confounding factors is essential, since interventions for AF will be effective in reducing SCD only if there is a causal association between these 2 conditions. In this translational review, we detail the plausible underlying pathophysiological mechanisms through which AF may promote or lead to SCD, as well as the existing epidemiological evidence supporting an association between AF and SCD. While the role of AF in predicting SCD in the general population appears limited and not established, AF might be integrated to improve risk stratification in some specific phenotypes. Optimal AF management, including that of its associated conditions, appears to be of interest to prevent AF-related SCD, especially because the AF-SCD relationship is in part driven by heart failure.