tbuckley/cabot-search huggingface dataset:
New hints towards a precision medicine strategy for IDH wild-type glioblastoma
Authors: K. White, K. Connor, J. Clerkin, B.M. Murphy, M. Salvucci, A.C. O'Farrell, M. Rehm, D. O'Brien, J.H.M. Prehn, S.P. Niclou, M.L.M. Lamfers, M. Verreault, A. Idbaih, R. Verhaak, A. Golebiewska, A.T. Byrne
Journal: Annals of Oncology (2020)

•Studying IDH-wt GBM subtype specific differences across the TME may reveal novel contexts of vulnerability.•Knowledge gained from diverse molecular profiling should direct future targeted therapeutic strategies.•Stratifying patients based on immune contexture may guide novel immune therapy approaches for IDH-wt patients.•Due to the heterogeneous nature of GBM, future trials should consider a stratified, 'subtype-specific' design.•We propose an integrated multi-omic discovery strategy to establish improved precision targeting in the IDH-wt GBM setting Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches. Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.
Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti–Interleukin 12/23p40 Antibody Ustekinumab
Authors: Florence Poizeau, Emmanuel Nowak, Sandrine Kerbrat, Béranger Le Nautout, Catherine Droitcourt, Milou-Daniel Drici, Emilie Sbidian, Bernard Guillot, Hervé Bachelez, Hafid Ait-Oufella, André Happe, Emmanuel Oger, Alain Dupuy
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> Ustekinumab, a monoclonal antibody targeting interleukin 12/23p40 (IL-12/23p40), is effective in the treatment of moderate to severe psoriasis, psoriatic arthritis, and Crohn disease. In 2011, a meta-analysis of randomized clinical trials reported a potential risk of severe cardiovascular events (SCEs) within the first few months after the initiation of anti–IL-12/23p40 antibodies. <h3>Objective</h3> To assess whether the initiation of ustekinumab treatment is associated with increased risk of SCEs. <h3>Design, Setting, and Participants</h3> This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018. <h3>Exposure</h3> The initiation of ustekinumab treatment was screened during the risk and reference periods. <h3>Main Outcomes and Measures</h3> Odds ratios for the risk of SCE after the initiation of ustekinumab treatment were calculated. <h3>Results</h3> Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke). Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59). Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13). <h3>Conclusions and Relevance</h3> This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk. In line with the current mechanistic models for atherosclerotic disease, the period after the initiation of anti–IL-12/23p40 may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17. Although the study interpretation is limited by its observational design, these results suggest that caution may be needed in the prescription of ustekinumab to patients at high cardiovascular risk.
Estimating the quality of eukaryotic genomes recovered from metagenomic analysis with EukCC
Authors: Paul Saary, Alex L. Mitchell, Robert D. Finn
Journal: Genome biology (2020)

Abstract Microbial eukaryotes constitute a significant fraction of biodiversity and have recently gained more attention, but the recovery of high-quality metagenomic assembled eukaryotic genomes is limited by the current availability of tools. To help address this, we have developed EukCC, a tool for estimating the quality of eukaryotic genomes based on the automated dynamic selection of single copy marker gene sets. We demonstrate that our method outperforms current genome quality estimators, particularly for estimating contamination, and have applied EukCC to datasets derived from two different environments to enable the identification of novel eukaryote genomes, including one from the human skin.
Subgroup analysis of the ASPirin in Reducing Events in the Elderly randomized clinical trial suggests aspirin did not improve outcomes in older adults with chronic kidney disease
Authors: Rory Wolfe, James B. Wetmore, Robyn L. Woods, John J. McNeil, Hugh Gallagher, Paul Roderick, Rowan Walker, Mark R. Nelson, Christopher M. Reid, Raj C. Shah, Michael E. Ernst, Jessica E. Lockery, Andrew M. Tonkin, Walter P. Abhayaratna, Peter Gibbs, Erica M. Wood, Suzanne E. Mahady, Jeff D. Williamson, Geoffrey A. Donnan, Geoffrey C. Cloud, Anne M. Murray, Kevan R. Polkinghorne
Journal: Kidney International (2020)
Abstract 9824: S1p2 Receptor Antagonist Attenuates Endothelial Dysfunction and Inhibits Atherogenesis in Apolipoprotein-e-deficient Mice
Authors: Byambasuren Ganbaatar, Daiju Fukuda, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Masataka Sata
Journal: Circulation (2019)

Background and Aims: The bioactive lipid, sphingosine-1-phosphate (S1P) has various roles in the physiology and pathophysiology of many diseases including atherosclerosis. S1P exerts its biological...
iGMDR: Integrated Pharmacogenetic Resource Guide to Cancer Therapy and Research
Authors: Xiang Chen, Yi Guo, Xin Chen
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Current pharmacogenetic studies have obtained many genetic models that can predict the therapeutic efficacy of anticancer drugs. Although some of these models are of crucial importance and have been used in clinical practice, these very valuable models have not been well adopted into cancer research to promote the development of cancer therapies due to the lack of integration and standards for the existing data of the pharmacogenetic studies. For this purpose, we built a resource investigating genetic model of drug response (iGMDR), which integrates the models from in vitro and in vivo pharmacogenetic studies with different omics data from a variety of technical systems. In this study, we introduced a standardized process for all integrations, and described how users can utilize these models to gain insights into cancer. iGMDR is freely accessible at https://igmdr.modellab.cn.
Abstract 15427: Sociodemographic Disparities in Influenza Vaccination Among Adults With Atherosclerotic Cardiovascular Disease in the United States
Authors: Gowtham R Grandhi, Javier Valero-Elizondo, Reed Mszar, Rohan Khera, Nihar R Desai, Michael J Blaha, Ron Blankstein, Salim S Virani, Harlan M Krumholz, Saad B Omer, Khurram Nasir
Journal: Circulation (2019)

Introduction: Vaccination against influenza is an effective strategy for preventing vaccine-preventable mortality and morbidity for individuals with atherosclerotic cardiovascular disease (ASCVD). ...
To achieve “zero covid” we need to include the controlled, careful acquisition of population (herd) immunity
Authors: Raj S Bhopal
Journal: BMJ (2020)

Torjesen asks whether the UK should aim for zero covid.1 Of course it should, but how? My suggested strategy includes herd immunity, which I rename population immunity given the antipathy to the word herd, evoking animals.2

On 7 April 2020 Martin McKee wrote to the covid-19 global researchers email group “seeking sensible thoughts about coming out of lockdown.” I responded with an eight point plan, the last point being that in the absence of a vaccine …
Chromosome 20 loss is characteristic of breast implant–associated anaplastic large cell lymphoma
Authors: G. Tjitske Los-de Vries, Mintsje de Boer, Erik van Dijk, Phylicia Stathi, Nathalie J. Hijmering, Margaretha G. M. Roemer, Matias Mendeville, Daniel M. Miedema, Jan Paul de Boer, Hinne A. Rakhorst, Flora E. van Leeuwen, René R. W. J. van der Hulst, Bauke Ylstra, Daphne de Jong
Journal: Blood (2020)
Reply to Dr. Vincenzo Patella et al. Could anti‐tubercular vaccination protect against COVID‐19 infection?
Authors: Cevdet Ozdemir, Umut C. Kucuksezer, Zeynep Ülker Tamay
Journal: Allergy (2020)

The authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Reconfiguring Medical Education
Authors: George D. Everett, Michael Muszynski
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Inhibition of IRF5 hyperactivation protects from lupus onset and severity
Authors: Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes
Journal: Journal of Clinical Investigation (2020)

The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.
Association of<i>GATA3</i>Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia
Authors: Hui Zhang, Anthony Pak-Yin Liu, Meenakshi Devidas, Shawn HR Lee, Xueyuan Cao, Deqing Pei, Michael Borowitz, Brent Wood, Julie M Gastier-Foster, Yunfeng Dai, Elizabeth Raetz, Eric Larsen, Naomi Winick, W Paul Bowman, Seth Karol, Wenjian Yang, Paul L Martin, William L Carroll, Ching-Hon Pui, Charles G Mullighan, William E Evans, Cheng Cheng, Stephen P Hunger, Mary V Relling, Mignon L Loh, Jun J Yang
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on interpatient variability in MRD. Methods A genome-wide association study was performed on 2597 children on the Children’s Oncology Group AALL0232 trial for high-risk B-cell ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863 370 single nucleotide polymorphisms (SNPs), adjusting for genetic ancestry and treatment strata. Top variants were further evaluated in a validation cohort of 491 patients from the Children’s Oncology Group P9905 and 6 ALL trials. The independent prognostic value of single nucleotide polymorphisms was determined in multivariable analyses. All statistical tests were 2-sided. Results In the discovery genome-wide association study, we identified a genome-wide significant association at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84; P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count, and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively). Conclusion Inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of germline variants in upfront risk stratification in ALL.
<i>QuickStats:</i> Prevalence of Obesity* and Severe Obesity<sup>†</sup> Among Persons Aged 2–19 Years — National Health and Nutrition Examination Survey, 1999–2000 through 2017–2018
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

prevalence of obesity among persons aged 2-19 years increased from 13.9% to 19.3%, and the prevalence of severe obesity increased from 3.6% to 6.1%.
Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease
Authors: Israt S. Alam, Federico Simonetta, Lukas Scheller, Aaron T. Mayer, Surya Murty, Ophir Vermesh, Tomomi W. Nobashi, Juliane K. Lohmeyer, Toshihito Hirai, Jeanette Baker, Kenneth H. Lau, Robert Negrin, Sanjiv S. Gambhir
Journal: Cancer Research (2020)

Abstract Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring. Significance: OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.
Obesity and Hypertension in the Time of COVID-19
Authors: Griffin P. Rodgers, Gary H. Gibbons
Journal: JAMA (2020)

Paul Muntner, PhD; Shakia T. Hardy, PhD; Lawrence J. Fine, MD; Byron C. Jaeger, PhD; Gregory Wozniak, PhD; Emily B. Levitan, ScD; Lisandro D. Colantonio, MD, PhD
Time series analysis of microbiome and metabolome at multiple body sites in steady long-term isolation confinement
Authors: Qiang Feng, Xiang Lan, Xiaoli Ji, Meihui Li, Shili Liu, Jianghui Xiong, Yanbo Yu, Zhipeng Liu, Zi Xu, Li He, Ying Chen, Haisheng Dong, Pu Chen, Bin Chen, Kunlun He, Yinghui Li
Journal: Gut (2020)

We read the article by Flemer et al ,1 which suggests that the combined analysis of the oral and faecal microbiota may have significant value in the detection of colorectal cancer, with great interest. The oral and intestinal microbiomes are distant anatomic populations that highly abundant, with distinct microbiota and metabolomes, but microbes from the two sites interact with each other.2 External factors, such as residence changes, bacterial infections, irregular diet and circadian rhythm alterations, can lead to a shift in the microbial ecosystem.3 Therefore, understanding the dynamic changes of the microbiome and metabolic profile of faeces and saliva in steady long-term isolation confinement can establish the change rule of human microbiome and the possible disease risk in a long time space travel.

In this study, we examined the human microbiome and metabolome with a time series from multiple body sites to evaluate the stability of the microbial ecosystem and its connection with the human metabolome. The salivary and faecal microbiome and the plasmatic, urinary and faecal metabolome of four simulated astronauts were investigated at a total of 18 time points and were compared with before, during and after 180 days of a test of living in the well-controlled ecological life support system (CELSS) (figure 1 and online supplementary file).### Supplementary data

[gutjnl-2020-320666supp001.pdf]



Figure 1 
Overview of the study design and sample collection (saliva (S), faeces (F) and plasma …
Association of Infections and Use of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection
Authors: Yaa-Hui Dong, Chia-Hsuin Chang, Jiun-Ling Wang, Li-Chiu Wu, Jou-Wei Lin, Sengwee Toh
Journal: JAMA Internal Medicine (2020)

Prior observational studies have suggested that fluoroquinolone use may be associated with more than 2-fold increased risk of aortic aneurysm or aortic dissection (AA/AD). These studies, however, did not fully consider the role of coexisting infections and the risk of fluoroquinolones relative to other antibiotics.To estimate the risk of AA/AD associated with infections and to assess the comparative risk of AA/AD associated with fluoroquinolones vs other antibiotics with similar indication profiles among patients with the same types of infections.This nested case-control study identified 21 651 176 adult patients from a nationwide population-based health insurance claims database from January 1, 2009, to November 30, 2015. Each incident case of AA/AD was matched with 10 control individuals by age, sex, and follow-up duration in the database using risk-set sampling. Analysis of the data was conducted from April 2019 to March 2020.Infections and antibiotic use within a 60-day risk window before the occurrence of AA/AD.Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% CIs comparing infections for which fluoroquinolones are commonly used with no infection within a 60-day risk window before outcome occurrence, adjusting for baseline confounders and concomitant antibiotic use. The adjusted ORs comparing fluoroquinolones with antibiotics with similar indication profiles within patients with indicated infections were also estimated.A total of 28 948 cases and 289 480 matched controls were included (71.37% male; mean [SD] age, 67.41 [15.03] years). Among these, the adjusted OR of AA/AD for any indicated infections was 1.73 (95% CI, 1.66-1.81). Septicemia (OR, 3.16; 95% CI, 2.63-3.78) and intra-abdominal infection (OR, 2.99; 95% CI, 2.45-3.65) had the highest increased risk. Fluoroquinolones were not associated with an increased AA/AD risk when compared with combined amoxicillin-clavulanate or combined ampicillin-sulbactam (OR, 1.01; 95% CI, 0.82-1.24) or with extended-spectrum cephalosporins (OR, 0.88; 95% CI, 0.70-1.11) among patients with indicated infections. The null findings for fluoroquinolone use remained robust in different subgroup and sensitivity analyses.These results highlight the importance of accounting for coexisting infections while examining the safety of antibiotics using real-world data; the findings suggest that concerns about AA/AD risk should not deter fluoroquinolone use for patients with indicated infections.