tbuckley/cabot-search huggingface dataset:
CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice
Authors: Hongxia Duan, Lin Jing, Xiaoqing Jiang, Yanbin Ma, Daji Wang, Jianquan Xiang, Xuehui Chen, Zhenzhen Wu, Huiwen Yan, Junying Jia, Zheng Liu, Jing Feng, Mingzhao Zhu, Xiyun Yan
Journal: Journal of Clinical Investigation (2021)

Initiation of T cell receptor (TCR) signaling involves the activation of the tyrosine kinase LCK; however, it is currently unclear how LCK is recruited and activated. Here, we have identified the membrane protein CD146 as an essential member of the TCR network for LCK activation. CD146 deficiency in T cells substantially impaired thymocyte development and peripheral activation, both of which depend on TCR signaling. CD146 was found to directly interact with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain. Interestingly, we found CD146 to be present in both monomeric and dimeric forms in T cells, with the dimerized form increasing after TCR ligation. Increased dimerized CD146 recruited LCK and promoted LCK autophosphorylation. In tumor models, CD146 deficiency dramatically impaired the antitumor response of T cells. Together, our data reveal an LCK activation mechanism for TCR initiation. We also underscore a rational intervention based on CD146 for tumor immunotherapy.
A compendium of uniformly processed human gene expression and splicing quantitative trait loci
Authors: Nurlan Kerimov, James D. Hayhurst, Kateryna Peikova, Jonathan R. Manning, Peter Walter, Liis Kolberg, Marija Samoviča, Manoj Pandian Sakthivel, Ivan Kuzmin, Stephen J. Trevanion, Tony Burdett, Simon Jupp, Helen Parkinson, Irene Papatheodorou, Andrew D. Yates, Daniel R. Zerbino, Kaur Alasoo
Journal: Nature Genetics (2021)

Abstract Many gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue ( https://www.ebi.ac.uk/eqtl ), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.
A Daily-Updated Database and Tools for Comprehensive SARS-CoV-2 Mutation-Annotated Trees
Authors: Jakob McBroome, Bryan Thornlow, Angie S Hinrichs, Alexander Kramer, Nicola De Maio, Nick Goldman, David Haussler, Russell Corbett-Detig, Yatish Turakhia
Journal: Molecular Biology and Evolution (2021)

Abstract The vast scale of SARS-CoV-2 sequencing data has made it increasingly challenging to comprehensively analyze all available data using existing tools and file formats. To address this, we present a database of SARS-CoV-2 phylogenetic trees inferred with unrestricted public sequences, which we update daily to incorporate new sequences. Our database uses the recently proposed mutation-annotated tree (MAT) format to efficiently encode the tree with branches labeled with parsimony-inferred mutations, as well as Nextstrain clade and Pango lineage labels at clade roots. As of June 9, 2021, our SARS-CoV-2 MAT consists of 834,521 sequences and provides a comprehensive view of the virus’ evolutionary history using public data. We also present matUtils—a command-line utility for rapidly querying, interpreting, and manipulating the MATs. Our daily-updated SARS-CoV-2 MAT database and matUtils software are available at http://hgdownload.soe.ucsc.edu/goldenPath/wuhCor1/UShER_SARS-CoV-2/ and https://github.com/yatisht/usher, respectively.
<i>Notes from the Field:</i>Tuberculosis Outbreak Linked to a Contaminated Bone Graft Product Used in Spinal Surgery — Delaware, March–June 2021
Authors: Ruoran Li, W. Wyatt Wilson, Noah G. Schwartz, Alfonso C. Hernandez-Romieu, Janet Glowicz, Emily Hanlin, Malikah Taylor, Heather Pelkey, Carol A. Briody, Lija Gireesh, Mark Eskander, Kenneth Lingenfelter, Sandy P. Althomsons, Rebekah J. Stewart, Rebecca Free, Pallavi Annambhotla, Sridhar V. Basavaraju, Jonathan M. Wortham, Sapna Bamrah Morris, Isaac Benowitz, Maryam B. Haddad, Rick Hong, Marci Drees
Journal: MMWR Morbidity and Mortality Weekly Report (2021)
In persons with obesity, exercise plus liraglutide improved weight-loss maintenance vs. exercise or placebo
Authors: Shohinee Sarma, Lorraine L. Lipscombe
Journal: Annals of Internal Medicine (2021)

ACP Journal ClubSeptember 2021In persons with obesity, exercise plus liraglutide improved weight-loss maintenance vs. exercise or placeboShohinee Sarma, MD, MPH, Lorraine L. Lipscombe, MD, MScShohinee Sarma, MD, MPHUniversity of Toronto, Toronto, Ontario, Canada (S.S., L.L.L.), Lorraine L. Lipscombe, MD, MScUniversity of Toronto, Toronto, Ontario, Canada (S.S., L.L.L.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202109210-102 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med. 2021;384:1719-30. https://pubmed.ncbi.nlm.nih.gov/33951361Clinical Impact RatingsGIM/FP/GP: Endocrinology: Public Health: References1 Johns DJ, Hartmann-Boyce J, Jebb SA. Diet or exercise interventions vs combined behavioral weight management programs: a systematic review and meta-analysis of direct comparisons. J Acad Nutr Diet. 2014;114:1557-68. [PMID: 25257365] Google Scholar2 Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414-25. [PMID: 33755728] Google Scholar3 Look AHEAD Research Group; Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170:1566-75. [PMID: 20876408] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Toronto, Toronto, Ontario, Canada (S.S., L.L.L.)Disclosures: The commentators have reported no disclosures of interest. The forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7320.This article was published at Annals.org on 7 September 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics September 2021Volume 174, Issue 9Page: JC102 ePublished: 7 September 2021 Issue Published: September 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma
Authors: Verena Panitz, Saša Končarević, Ahmed Sadik, Dennis Friedel, Tobias Bausbacher, Saskia Trump, Vadim Farztdinov, Sandra Schulz, Philipp Sievers, Stefan Schmidt, Ina Jürgenson, Stephan Jung, Karsten Kuhn, Irada Pflüger, Suraj Sharma, Antje Wick, Pauline Pfänder, Stefan Selzer, Philipp Vollmuth, Felix Sahm, Andreas von Deimling, Ines Heiland, Carsten Hopf, Peter Schulz-Knappe, Ian Pike, Michael Platten, Wolfgang Wick, Christiane A. Opitz
Journal: Theranostics (2021)

Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma.As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required.Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples.We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age-and sex-matched healthy controls.Tumor volumes were measured in MRI data using an artificial neural network-based approach.MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue.Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma.Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels.Surprisingly, the levels of Trp metabolites were also reduced.The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites.High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival.MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues.Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation.Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset.
PodoSighter: A Cloud-Based Tool for Label-Free Podocyte Detection in Kidney Whole-Slide Images
Authors: Darshana Govind, Jan U. Becker, Jeffrey Miecznikowski, Avi Z. Rosenberg, Julien Dang, Pierre Louis Tharaux, Rabi Yacoub, Friedrich Thaiss, Peter F. Hoyer, David Manthey, Brendon Lutnick, Amber M. Worral, Imtiaz Mohammad, Vighnesh Walavalkar, John E. Tomaszewski, Kuang-Yu Jen, Pinaki Sarder
Journal: Journal of the American Society of Nephrology (2021)

Podocyte depletion precedes progressive glomerular damage in several kidney diseases. However, the current standard of visual detection and quantification of podocyte nuclei from brightfield microscopy images is laborious and imprecise.
Clinical Evidence on “Watchful Waiting” in Basal Cell Carcinoma
Authors: Mackenzie R. Wehner
Journal: JAMA Dermatology (2021)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals 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) 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 Dermatology journal
Covid-19: 80% of young adults in UK are likely to have antibodies, data suggest
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: 80% of young adults in UK are likely to have antibodies, data suggest Jacqui WiseAround eight in ten young adults in the UK are now likely to have SARS-CoV-2 antibodies either from past infection or because they have been vaccinated, the latest survey from the Office for National Statistics has shown. 1 1 Office for National Statistics.Coronavirus (covid-19) infection survey, antibody and vaccination data, UK: 1 September 2021.
Single-cell expression landscape of SARS-CoV-2 receptor ACE2 and host proteases in human lung adenocarcinoma
Authors: G. C. Han, A. Sinjab, K. Hara, W. Treekitkarnmongkol, P. Brennan, K. Chang, E. Bokatenkova, B. Sanchez-Espiridion, C. Behrens, L. M. Solis, B. N. Gao, L. Girard, J. J. Zhang, B. Sepesi, T. Cascone, L. A. Byers, D. L. Gibbons, J. C. Chen, S. J. Moghaddam, E. J. Ostrin, P. Scheet, J. Fujimoto, J. Shay, J. V. Heymach, J. D. Minna, S. Dubinett, Wistuba, Ii, Stevenson, C. S., A. E. Spira, L. H. Wang, H. Kadara
Journal: Cancer Research (2021)
Evaluation of Technology-Enabled Monitoring of Patient-Reported Outcomes to Detect and Treat Toxic Effects Linked to Immune Checkpoint Inhibitors
Authors: Pavlos Msaouel, Clara Oromendia, Arlene O. Siefker-Radtke, Nizar M. Tannir, Sumit K. Subudhi, Jianjun Gao, Yinghong Wang, Bilal A. Siddiqui, Amishi Y. Shah, Ana M. Aparicio, Matthew T. Campbell, Amado J. Zurita, Leah K. Shaw, Lidia P. Lopez, Heather McCord, Sandip N. Chakraborty, Jacqueline Perales, Cong Lu, Michael L. Van Alstine, Michael Elashoff, Christopher Logothetis
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management. <h3>Objective</h3> To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors. <h3>Design, Setting, and Participants</h3> An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020. The median follow-up duration was 63 (interquartile range, 35.5-122) days. Fifty patients with genitourinary cancers treated with immune checkpoint inhibitors were enrolled. <h3>Interventions</h3> A fit-for-purpose electronic platform was developed to enable active patient and care team participation. A smartphone application downloaded onto patients’ personal mobile devices prompted them to report their symptoms at least 3 times per week. The set of symptoms and associated queries were paired with alert thresholds for symptoms requiring clinical action. <h3>Main Outcomes and Measures</h3> The primary end point of this interim analysis was feasibility, as measured by patient and care team adherence, and lack of increase in care team staffing. Operating characteristics were estimated for each symptom alert and used to dynamically adapt the alert thresholds to ensure sensitivity while reducing unnecessary alerts. <h3>Results</h3> Of the 50 patients enrolled, 47 had at least 1 follow-up visit and were included in the analysis. Median age was 65 years (range, 37-86), 39 patients (83%) were men, and 39 patients (83%) had metastatic cancer, with the most common being urothelial cell carcinoma and renal cell carcinoma (22 [47%] patients each). After initial onboarding, no further care team training or additional care team staffing was required. Patients had a median study adherence rate of 74% (interquartile range, 60%-86%) and 73% of automated alerts were reviewed within 3 days by the clinic team. Symptoms with the highest positive predictive value for adverse events requiring acute intervention included dizziness (21%), nausea/vomiting (26%), and shortness of breath (14%). The symptoms most likely to result in unnecessary alerts were arthralgia and myalgia, fatigue, and cough. <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest an acceptable and fiscally sound method can be developed to create a dynamic learning system to detect and manage immune-related toxic effects.
Out-of-specification tisagenlecleucel does not compromise safety or efficacy in pediatric acute lymphoblastic leukemia
Authors: Jenna Rossoff, Christina Baggott, Snehit Prabhu, Holly Pacenta, Christine L. Phillips, Heather Stefanski, Julie-An Talano, Amy Moskop, Steven P. Margossian, Michael R. Verneris, Gary Douglas Myers, Nicole Karras, Patrick A. Brown, Muna Qayed, Michelle Hermiston, Prakash Satwani, Christa Krupski, Amy K. Keating, Rachel Wilcox, Cara A. Rabik, Vanessa A. Fabrizio, Michael Kunicki, Vasant Chinnabhandar, A. Yasemin Goksenin, Kevin J. Curran, Crystal L. Mackall, Theodore W. Laetsch, Liora M. Schultz
Journal: Blood (2021)
AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data
Authors: Asa Thibodeau, Alper Eroglu, Christopher S. McGinnis, Nathan Lawlor, Djamel Nehar-Belaid, Romy Kursawe, Radu Marches, Daniel N. Conrad, George A. Kuchel, Zev J. Gartner, Jacques Banchereau, Michael L. Stitzel, A. Ercument Cicek, Duygu Ucar
Journal: Genome biology (2021)

Abstract Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved.
Mining museums for historical DNA: advances and challenges in museomics
Authors: Christopher J. Raxworthy, Brian Tilston Smith
Journal: Trends in Ecology & Evolution (2021)

Historical DNA (hDNA), obtained from museum and herbarium specimens, has yielded spectacular new insights into the history of organisms. This includes documenting historical genetic erosion and extinction, discovering species new to science, resolving evolutionary relationships, investigating epigenetic effects, and determining origins of infectious diseases. However, the development of best-practices in isolating, processing, and analyzing hDNA remain under-explored, due to the substantial diversity of specimen preparation types, tissue sources, archival ages, and collecting histories. Thus, for hDNA to reach its full potential, and justify the destructive sampling of the rarest specimens, more experimental work using time-series collections, and the development of improved methods to correct for data asymmetries and biases due to DNA degradation are required.
Myeloid-cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice
Authors: Marija Gredic, Cheng-Yu Wu, Stefan Hadzic, Oleg Pak, Rajkumar Savai, Baktybek Kojonazarov, Siddartha Doswada, Astrid Weiss, Andreas Weigert, Andreas Guenther, Ralf P. Brandes, Ralph T. Schermuly, Friedrich Grimminger, Werner Seeger, Natascha Sommer, Simone Kraut, Norbert Weissmann
Journal: European Respiratory Journal (2021)

Background Pulmonary hypertension (PH) is a common complication of COPD, associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. Previously, we identified inducible nitric oxide synthase (iNOS) as an essential enzyme for development and reversal of smoke-induced PH and emphysema, and showed that iNOS expression in bone-marrow-derived cells drives pulmonary vascular remodelling, but not parenchymal destruction. In this study, we aimed to identify the iNOS-expressing cell type driving smoke-induced PH and to decipher pro-proliferative pathways involved. Methods To address this question we used 1) myeloid-cell-specific iNOS knockout mice in chronic smoke exposure and 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMCs) to decipher underlying signalling pathways. Results Myeloid-cell-specific iNOS knockout prevented smoke-induced PH but not emphysema in mice. Moreover, iNOS deletion in myeloid cells ameliorated the increase in expression of CD206, a marker of M2 polarisation, on interstitial macrophages. Importantly, the observed effects on lung macrophages were hypoxia-independent, as these mice developed hypoxia-induced PH. In vitro , smoke-induced PASMC proliferation in co-cultures with M2-polarised macrophages could be abolished by iNOS deletion in phagocytic cells, as well as by extracellular signal-regulated kinase inhibition in PASMCs. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry. Conclusion In summary, our results demonstrate that iNOS deletion in myeloid cells confers protection against PH in smoke-exposed mice and provide evidence for an iNOS-dependent communication between M2-like macrophages and PASMCs in underlying pulmonary vascular remodelling.
Malaria: Combining vaccine with prophylaxis cuts child deaths by 73%, study finds
Authors: Owen Dyer
Journal: BMJ (2021)

Hundreds of thousands of children’s lives could be saved each year in Africa by combining the world’s first effective malaria vaccine with the current recommended approach of giving children prophylactic antimalarials for four months each year, a large study has found.

A study conducted in in Mali and Burkina Faso set out to test whether seasonal use of the vaccine alone, known as RTS,S or Mosquirix, could match the protection offered by seasonal malaria chemoprevention. But although the vaccine and chemoprevention arms of the trial saw roughly equal protective effects, the surprise result came from a third group who received both interventions, a combination that proved greater than the sum of its parts. The findings were published in the New …
Outcomes of pregnancy in autoimmune hepatitis: A population‐based study
Authors: Connie W. Wang, Joshua Grab, Michele M. Tana, Roxanna A. Irani, Monika Sarkar
Journal: Hepatology (2021)

Abstract Background and Aims Autoimmune hepatitis (AIH) disproportionately affects young women, which may have implications in pregnancy. However, data on pregnancy outcomes in women with AIH are limited. Approach and Results Using weighted discharge data from the United States National Inpatient Sample from 2012 to 2016, we evaluated pregnancies after 20 weeks gestation and compared outcomes in AIH to other chronic liver diseases (CLD) or no CLD in pregnancy. The association of AIH with maternal and perinatal outcomes was assessed by logistic regression. Among 18,595,345 pregnancies, 935 (&lt;0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Temporal trends in pregnancies with AIH remained stable from 2008 to 2016 with 1.4–6.8/100,000 pregnancies per year ( p = 0.25). On adjusted analysis, the odds of gestational diabetes (GDM) and hypertensive complications (pre‐eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2, 95% CI: 1.5–3.9, p &lt; 0.001; hypertensive complications: OR: 1.8, 95% CI: 1.0–3.2, p = 0.05) and also compared to no CLD in pregnancy (GDM: OR: 2.4, 95% CI: 1.6–3.6, p &lt; 0.001; hypertensive complications: OR: 2.4, 95% CI: 1.3–4.1, p = 0.003). AIH was also associated with preterm births when compared with women without CLD (OR: 2.0, 95% CI: 1.2–3.5, p = 0.01). AIH was not associated with postpartum hemorrhage, maternal, or perinatal death. Conclusions Rates of pregnancy in women with AIH have remained stable in recent years, although AIH is associated with notable maternal and perinatal risks, such as GDM, hypertensive complications, and preterm birth. Whether these risks are influenced by steroid use and/or AIH disease activity warrants evaluation. These data support a low risk of postpartum hemorrhage and favorable survival of mothers and infants.