tbuckley/cabot-search huggingface dataset:
Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly
Authors: Roel P. H. De Maeyer, Rachel C. van de Merwe, Rikah Louie, Olivia V. Bracken, Oliver P. Devine, Daniel R. Goldstein, Mohib Uddin, Arne N. Akbar, Derek W. Gilroy
Journal: Nature Immunology (2020)
Letting the GENIE Out of Its Bottle: Examining the Potential of Real-World Clinicogenomic Data
Authors: Emily Castellanos, Shrujal S. Baxi
Journal: Cancer Discovery (2020)

In this issue, Smyth and colleagues investigate the natural history of AKT1-mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic data. A rare subset of tumors, AKT1-mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as AKT1-wild-type tumors, but a longer duration of therapy on mTOR inhibitors.See related article by Smyth et al., p. 526.
Serum zinc levels and multiple health outcomes: Implications for zinc-based biomaterials
Authors: Xinhua Qu, Hongtao Yang, Zhifeng Yu, Bo Jia, Han Qiao, Yufeng Zheng, Kerong Dai
Journal: Bioactive Materials (2020)

Zinc-based biomaterials, including biodegradable metal, nanoparticles, and coatings used in medical implants release zinc ions that may increase the whole-body and serum zinc concentrations. The impact of serum zinc concentrations on major health outcomes can provide insights for device design and clinical transformation of zinc-based biomaterials.This nationally representative cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (NHANES, 2011-2014) including 3607 participants. Using unadjusted and multivariate-adjusted logistic regression analyses, two-piecewise linear regression model with a smoothing function and threshold level analysis, we evaluated the associations between elevated serum zinc levels and major health outcomes.Elevated serum zinc levels were significantly associated with an increase in total spine and total femur bone mineral density (BMD). Every 10 μg/dL increase was associated with a 1.12-fold increase in diabetes mellitus (DM) and 1.23-fold and 1.29-fold increase in cardiovascular diseases (CVD) and coronary heart disease (CHD), in participants with serum zinc levels ≥ 100 μg/dL. It had no significant linear or nonlinear associations with risk of fractures, congestive heart failure, heart attack, thyroid disease, arthritis, osteoarthritis, rheumatoid arthritis, dyslipidemia and cancer.Serum zinc levels are significantly associated with increased BMD in the total spine and total femur, and risk of DM, and CVD/CHD among participants with serum zinc levels ≥100 μg/dL.
Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers
Authors: Chirag Bavishi, Thomas M. Maddox, Franz H. Messerli
Journal: JAMA Cardiology (2020)

This Viewpoint discusses recommendations for angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use in patients with or at risk of contracting coronavirus disease 2019 (COVID-19).
Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Gleason Score 6 Prostate Cancer
Authors: Daniel W. Kim, Ming-Hui Chen, Hartwig Huland, Markus Graefen, Derya Tilki, Anthony V. D’Amico
Journal: JAMA Network Open (2020)

distinguishing men of older vs younger age; however, life expectancy using a validated metric, such as the Adult Comorbidity Evaluation-27, 6 may be preferred rather than a specific age cutoff.These findings suggest that men older than 65 years with biopsy-confirmed Gleason score 6 prostate cancer may benefit from additional testing, such as multiparametric magnetic resonance imaging and targeted biopsy before proceeding with active surveillance.If higher grade or stage disease is detected, this information could be used to guide the use and duration of androgen deprivation therapy in men considering radiotherapy.
Fructose Production and Metabolism in the Kidney
Authors: Takahiko Nakagawa, Richard J. Johnson, Ana Andres-Hernando, Carlos Roncal-Jimenez, Laura G. Sanchez-Lozada, Dean R. Tolan, Miguel A. Lanaspa
Journal: Journal of the American Society of Nephrology (2020)

Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.
Health‐related quality of life and long‐term related conditions in survivors of epidermal necrolysis: a study of 57 patients
Authors: S. Ingen‐Housz‐Oro, A. Alves, A. Colin, R. Ouedraogo, R. Layese, F. Canoui‐Poitrine, O. Chosidow, A. Mekontso‐Dessap, P. Wolkenstein, N. Prost
Journal: British Journal of Dermatology (2020)

Epidermal necrolysis (EN), including Stevens‐Johnson syndrome and toxic epidermal necrolysis (or Lyell syndrome), are life‐threatening drug reactions which cause blistering and sloughing of skin and mucous membranes. They represent a single disease with a spectrum of severity. Mortality (death) rate at the acute, meaning more severe, phase varies from 15 to 30%. Supportive care is the cornerstone of treatment. Some patients need care in an intensive care unit (ICU) or burn unit. The aim of the current study was to investigate the long‐term health‐related quality of life (HR‐QoL) of EN survivors, and other conditions they later experienced as a result of EN (known as sequelae). We conducted a study of patients admitted to a hospital for EN between 2010 and 2017. HR‐QoL was assessed during a phone interview by using different ways of measuring a person's quality of life: the SF‐36 questionnaire, Hospital Anxiety and Depression (HAD) scale, Impact of Event Scale‐Revised (IES‐R), and general QoL outcomes, including specific sequelae. The primary (main) outcome measure was the physical component summary (PCS) score of the SF‐36. In this, higher scores show higher (or better) quality of life, while lower scores show a worse quality of life. In total, 57 EN survivors, including 19 who had been admitted in the ICU, were phone‐interviewed at a median of 3.6 years after hospital discharge. The median SF36 physical component score (PCS) was below that of the age‐sex‐matched reference population (meaning people of the same age and sex but who had not had EN), and was significantly lower for EN survivors admitted versus not admitted to the ICU. The proportion of patients with high anxiety and depression scores was 54% and 21%, respectively. Reported specific sequelae were cutaneous, meaning they affected the skin (77%), ocular (eyes, 70%), psychological (60%), dental/oral (49%), genital (30%) and respiratory (breathing/ lungs, 18%). Our study confirms the major burden and long‐term impact of EN on quality of life of survivors and emphasizes the need for prolonged close follow‐up after the acute phase of EN. This is a summary of the study: Health‐related quality of life and long‐term sequelae in survivors of epidermal necrolysis: an observational study of 57 patients
The Impact of Medicare's Alternative Payment Models on the Value of Care
Authors: Joshua M. Liao, Amol S. Navathe, Rachel M. Werner
Journal: Annual Review of Public Health (2020)

Over the past decade, the Centers for Medicare and Medicaid Services (CMS) have led the nationwide shift toward value-based payment. A major strategy for achieving this goal has been to implement alternative payment models (APMs) that encourage high-value care by holding providers financially accountable for both the quality and the costs of care. In particular, the CMS has implemented and scaled up two types of APMs: population-based models that emphasize accountability for overall quality and costs for defined patient populations, and episode-based payment models that emphasize accountability for quality and costs for discrete care. Both APM types have been associated with modest reductions in Medicare spending without apparent compromises in quality. However, concerns about the unintended consequences of these APMs remain, and more work is needed in several important areas. Nonetheless, both APM types represent steps to build on along the path toward a higher-value national health care system.
Minimal clinically important difference in quality of life scores for patients with heart failure and reduced ejection fraction
Authors: Javed Butler, Muhammad Shahzeb Khan, Claudio Mori, Gerasimos S. Filippatos, Piotr Ponikowski, Josep Comin‐Colet, Bernard Roubert, John A. Spertus, Stefan D. Anker
Journal: European Journal of Heart Failure (2020)
Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs
Authors: Chiara Porta, Francesca Maria Consonni, Sara Morlacchi, Sabina Sangaletti, Augusto Bleve, Maria Grazia Totaro, Paola Larghi, Monica Rimoldi, Claudio Tripodo, Laura Strauss, Stefania Banfi, Mariangela Storto, Tiziana Pressiani, Lorenza Rimassa, Silvia Tartari, Alessandro Ippolito, Andrea Doni, Giulia Soldà, Stefano Duga, Viviana Piccolo, Renato Ostuni, Gioacchino Natoli, Vincenzo Bronte, Fiorella Balzac, Emilia Turco, Emilio Hirsch, Mario P. Colombo, Antonio Sica
Journal: Cancer Research (2020)

Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFNγ, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-κB in M-MDSCs, diverting their response to IFNγ toward NO-mediated immunosuppression and reducing TNFα expression. At the genome level, p50 NF-κB promoted binding of STAT1 to regulatory regions of selected IFNγ-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2low/TNFαhigh phenotype, restoring the in vivo antitumor activity of IFNγ. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy. SIGNIFICANCE: Tumor-derived PGE2-mediated induction of nuclear p50 NF-κB epigenetically reprograms the response of monocytic cells to IFNγ toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFNγ. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2874/F1.large.jpg.
Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes
Authors: Pavel N. Zakharov, Hao Hu, Xiaoxiao Wan, Emil R. Unanue
Journal: The Journal of Experimental Medicine (2020)

Tissue-specific autoimmune diseases are driven by activation of diverse immune cells in the target organs. However, the molecular signatures of immune cell populations over time in an autoimmune process remain poorly defined. Using single-cell RNA sequencing, we performed an unbiased examination of diverse islet-infiltrating cells during autoimmune diabetes in the nonobese diabetic mouse. The data revealed a landscape of transcriptional heterogeneity across the lymphoid and myeloid compartments. Memory CD4 and cytotoxic CD8 T cells appeared early in islets, accompanied by regulatory cells with distinct phenotypes. Surprisingly, we observed a dramatic remodeling in the islet microenvironment, in which the resident macrophages underwent a stepwise activation program. This process resulted in polarization of the macrophage subpopulations into a terminal proinflammatory state. This study provides a single-cell atlas defining the staging of autoimmune diabetes and reveals that diabetic autoimmunity is driven by transcriptionally distinct cell populations specialized in divergent biological functions.
Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non–Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling
Authors: Jon Zugazagoitia, Swati Gupta, Yuting Liu, Kit Fuhrman, Scott Gettinger, Roy S. Herbst, Kurt A. Schalper, David L. Rimm
Journal: Clinical Cancer Research (2020)

Only a minority of patients with advanced non-small cell lung cancer (NSCLC) truly benefits from single-agent PD-1 checkpoint blockade, and more robust predictive biomarkers are needed.
Tuberculosis in 2020 — New Approaches to a Continuing Global Health Crisis
Authors: Ahmad Zaheen, Barry R. Bloom
Journal: New England Journal of Medicine (2020)

The World Health Organization estimates that in 2018, 1.5 million people died from tuberculosis — higher mortality than that caused by any other single infectious agent. This interactive graphic provides a guide to the history, epidemiology, and clinical characteristics of tuberculosis and highlights the obstacles to and strategies for containing infection.
HLA loci predisposing to immune TTP in Japanese: potential role of the shared ADAMTS13 peptide bound to different HLA-DR
Authors: Kazuya Sakai, Masataka Kuwana, Hidenori Tanaka, Kazuyoshi Hosomichi, Atsushi Hasegawa, Hiroki Uyama, Kenji Nishio, Takashi Omae, Masakatsu Hishizawa, Masashi Matsui, Koji Iwato, Akinao Okamoto, Kazuki Okuhiro, Yukiko Yamashita, Masataka Itoh, Hanae Kumekawa, Naoki Takezako, Noriaki Kawano, Toshihiro Matsukawa, Haruna Sano, Kazuiku Ohshiro, Kunio Hayashi, Yasunori Ueda, Toshiki Mushino, Yoshiyuki Ogawa, Yuji Yamada, Mitsuru Murata, Masanori Matsumoto
Journal: Blood (2020)
Rights, interests and expectations: Indigenous perspectives on unrestricted access to genomic data
Authors: Maui Hudson, Nanibaa’ A. Garrison, Rogena Sterling, Nadine R. Caron, Keolu Fox, Joseph Yracheta, Jane Anderson, Phil Wilcox, Laura Arbour, Alex Brown, Maile Taualii, Tahu Kukutai, Rodney Haring, Ben Te Aika, Gareth S. Baynam, Peter K. Dearden, David Chagné, Ripan S. Malhi, Ibrahim Garba, Nicki Tiffin, Deborah Bolnick, Matthew Stott, Anna K. Rolleston, Leah L. Ballantyne, Ray Lovett, Dominique David-Chavez, Andrew Martinez, Andrew Sporle, Maggie Walter, Jeff Reading, Stephanie Russo Carroll
Journal: Nature Reviews Genetics (2020)
Multi-institutional analysis of synchronous prostate and rectosigmoid cancers.
Authors: Corbin Jacobs, Jacob Trotter, Manisha Palta, Yuan Wu, Christopher Willett, W. Robert Lee, Brian G. Czito
Journal: Journal of Clinical Oncology (2019)

33 Background: Synchronous prostate cancer (PC) and rectosigmoid (RS) cancer (RSC) is a challenging clinical situation. Methods: A retrospective review of Duke University and Durham VA charts was performed for men with adenocarcinomas of the prostate and RS colon from 1988-2017. Synchronous presentation was defined as symptoms, diagnosis (dx), or treatment (tx) of PC/RSC within 12 months. The primary endpoint was overall survival (OS), calculated from latest dx date. Univariate and multivariate (MVA) Cox regression was performed using STATA 15.1. Results: Among 31,883 men with PC identified, 330 (1%) also had RSC. 54 (16%) were considered synchronous (median age 67, IQR 62-72). PC was more commonly the first dx (59%), and 15 (28%) underwent prostatectomy (n=13) or radiotherapy (RT, n=2) before a dx of synchronous RSC. 26%, 57%, and 17% had stage I, II-III, and IV RSC, respectively. Prostatectomy, LAR, APR, and combined surgery for both PC/RSC was performed in 17 (31%), 24 (44%), 10 (19%), and 2 (4%) men, respectively. 35 (65%) received RT with median RS dose of 50.4 Gy (IQR 50.4-54 Gy) and prostate boost to 66 Gy (IQR 61-72 Gy). 34 (63%) received 5-FU based chemotherapy, 23 (43%) received ADT, and 9 (17%) received no PC-specific tx. After a median follow up of 43 (IQR 21-93) months, there were 34 deaths: 18 (53%) due to RSC, 2 (6%) due to PC, 3 (9%) due to grade 5 toxicity, 7 (21%) due to another malignancy, and 4 (12%) due to unknown cause without recurrence. Grade 5 toxicities resulted from sequential hepatectomy/LAR, combined prostatectomy/APR, and myocardial infarction while on ADT. Crude late grade ≥3 toxicities include 9 (17%) GI and 6 (11%) GU. Two anastomotic leaks &lt;2.3 years after LAR occurred in men who received neoadjuvant prostate RT boost of 70.6-76.4 Gy. Stages II-III (HR 4.3, p=0.02) and IV (HR 16, p&lt;0.01) for RSC but only stage IV (HR 31, p&lt;0.01) for PC were significantly associated with OS on MVA. Among 30 men with stage II-III RSC and non-metastatic PC, 5-FU based chemotherapy (HR 0.34, p=0.04) but no PC-specific tx was significantly associated with OS on MVA. Conclusions: Synchronous RSC is a greater contributor to mortality than PC. Men aged ≥50 with localized PC should undergo colorectal cancer screening prior to tx to evaluate for synchronous RSC.
Rapid Accumulation of Mutations in Growing Mycelia of a Hypervariable Fungus Schizophyllum commune
Authors: Aleksandra V Bezmenova, Elena A Zvyagina, Anna V Fedotova, Artem S Kasianov, Tatiana V Neretina, Aleksey A Penin, Georgii A Bazykin, Alexey S Kondrashov
Journal: Molecular Biology and Evolution (2020)

Abstract The basidiomycete Schizophyllum commune has the highest level of genetic polymorphism known among living organisms. In a previous study, it was also found to have a moderately high per-generation mutation rate of 2×10−8, likely contributing to its high polymorphism. However, this rate has been measured only in an experiment on Petri dishes, and it is unclear how it translates to natural populations. Here, we used an experimental design that measures the rate of accumulation of de novo mutations in a linearly growing mycelium. We show that S. commune accumulates mutations at a rate of 1.24×10−7 substitutions per nucleotide per meter of growth, or ∼2.04×10−11 per nucleotide per cell division. In contrast to what has been observed in a number of species with extensive vegetative growth, this rate does not decline in the course of propagation of a mycelium. As a result, even a moderate per-cell-division mutation rate in S. commune can translate into a very high per-generation mutation rate when the number of cell divisions between consecutive meiosis is large.
Is the Environment Associated With Preterm Birth?
Authors: Ruth A. Etzel
Journal: JAMA Network Open (2020)

Yu Zhang, BA; Vicente Mustieles, PhD; Jennifer Yland, SM; Joseph M. Braun, PhD; Paige L. Williams, PhD; Jill A. Attaman, MD; Jennifer B. Ford, RN; Antonia M. Calafat, PhD; Russ Hauser, MD, ScD; Carmen Messerlian, PhD
Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas
Authors: William D. Tap, Andrew J. Wagner, Patrick Schöffski, Javier Martin-Broto, Anders Krarup-Hansen, Kristen N. Ganjoo, Chueh-Chuan Yen, Albiruni R. Abdul Razak, Alexander Spira, Akira Kawai, Axel Le Cesne, Brian A. Van Tine, Yoichi Naito, Se Hoon Park, Alexander Fedenko, Zsuzsanna Pápai, Victoria Soldatenkova, Ashwin Shahir, Gary Mo, Jennifer Wright, Robin L. Jones
Journal: JAMA (2020)

Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy.Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations.Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%).In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.ClinicalTrials.gov Identifier: NCT02451943.
Unsupervised learning in a BCI chess application using label proportions and expectation-maximization
Authors: David Hübner, Albrecht Schall, Michael Tangermann
Journal: Brain-Computer Interfaces (2020)

ABSTRACT The online usage of brain-computer interfaces (BCI) generates unlabeled data. This data in combination with the rich structure contained in BCI applications based on event-related potentials allow to design novel unsupervised classification approaches like learning from label proportions (LLP) or its combination with expectation-maximization (EM) into a mixed model. In this work, we explore the feasibility of unsupervised classification in a BCI chess application. We propose an LLP extension based on weighted least squares regression. It requires randomization of timing parameters but overcomes the dependency on additional symbols. Simulations on electroencephalogram data obtained from six subjects playing BCI-controlled chess show that a combination of unsupervised LLP with EM (despite not using any labels) by constant adaptation quickly reaches and on the long run outperforms the average performance level of non-adaptive supervised classifiers. With our contribution, we increase the scope for which unsupervised learning methods can successfully be applied in BCI.