tbuckley/cabot-search huggingface dataset:
Family history assessment significantly enhances delivery of precision medicine in the genomics era
Authors: Yasmin Bylstra, Weng Khong Lim, Sylvia Kam, Koei Wan Tham, R. Ryanne Wu, Jing Xian Teo, Sonia Davila, Jyn Ling Kuan, Sock Hoai Chan, Nicolas Bertin, Cheng Xi Yang, Steve Rozen, Bin Tean Teh, Khung Keong Yeo, Stuart Alexander Cook, Saumya Shekhar Jamuar, Geoffrey S. Ginsburg, Lori A. Orlando, Patrick Tan
Journal: Genome Medicine (2021)

Abstract Background Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs rendering the value of family history unknown. We evaluated the utility of incorporating family history information for genomic sequencing selection. Methods To ascertain the relationship between family histories on such population-level initiatives, we analysed whole genome sequences of 1750 research participants with no known pre-existing conditions, of which half received comprehensive family history assessment of up to four generations, focusing on 95 cancer genes. Results Amongst the 1750 participants, 866 (49.5%) had high-quality standardised family history available. Within this group, 73 (8.4%) participants had an increased family history risk of cancer (increased FH risk cohort) and 1 in 7 participants ( n = 10/73) carried a clinically actionable variant inferring a sixfold increase compared with 1 in 47 participants ( n = 17/793) assessed at average family history cancer risk (average FH risk cohort) ( p = 0.00001) and a sevenfold increase compared to 1 in 52 participants ( n = 17/884) where family history was not available (FH not available cohort) ( p = 0.00001). The enrichment was further pronounced (up to 18-fold) when assessing only the 25 cancer genes in the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes. Furthermore, 63 (7.3%) participants had an increased family history cancer risk in the absence of an apparent clinically actionable variant. Conclusions These findings demonstrate that the collection and analysis of comprehensive family history and genomic data are complementary and in combination can prioritise individuals for genomic analysis. Thus, family history remains a critical component of health risk assessment, providing important actionable data when implementing genomics screening programs. Trial registration ClinicalTrials.gov NCT02791152 . Retrospectively registered on May 31, 2016.
Author Correction: Exploring the structural distribution of genetic variation in SARS-CoV-2 with the COVID-3D online resource
Authors: Stephanie Portelli, Moshe Olshansky, Carlos H. M. Rodrigues, Elston N. D’Souza, Yoochan Myung, Michael Silk, Azadeh Alavi, Douglas E. V. Pires, David B. Ascher
Journal: Nature Genetics (2021)

A Correction to this paper has been published: https://doi.org/10.1038/s41588-020-00775-x.
Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers
Authors: Peter Georgeson, Bernard J Pope, Christophe Rosty, Mark Clendenning, Khalid Mahmood, Jihoon E Joo, Romy Walker, Ryan A Hutchinson, Susan Preston, Julia Como, Sharelle Joseland, Aung Ko Win, Finlay A Macrae, John L Hopper, Dmitri Mouradov, Peter Gibbs, Oliver M Sieber, Dylan E O'Sullivan, Darren R Brenner, Steve Gallinger, Mark A Jenkins, Ingrid M Winship, Daniel D Buchanan
Journal: Gut (2021)

Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Design Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. Results The combination of mutational signatures SBS18 and SBS36 contributing &gt;30% of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10 -5 ), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Conclusion Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
TS01.02 Novel Anti–CTLA-4 Antibody Quavonlimab Plus Pembrolizumab as First-Line Therapy for NSCLC: Extended Follow-up From a Phase 1 Study
Authors: B.C. Cho, R. Perets, D.W. Rasco, M.-J. Ahn, D.R. Spigel, K. Yoh, D.-W. Kim, M. Gutierrez, D.H. Lee, A. Nagrial, M. Satouchi, D. Kotasek, C. Maurice-Dror, J. Niu, M. Rajasagi, S. Siddiqi, Xiaoyun (Nicole) Li, J. Cyrus, R.A. Altura, J. Bar
Journal: Journal of Thoracic Oncology (2021)
Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling
Authors: Kelsey G. DeFrates, Daniela Franco, Ellen Heber-Katz, Phillip B. Messersmith
Journal: Biomaterials (2021)

Historically, the field of regenerative medicine has aimed to heal damaged tissue through the use of biomaterials scaffolds or delivery of foreign progenitor cells. Despite 30 years of research, however, translation and commercialization of these techniques has been limited. To enable mammalian regeneration, a more practical approach may instead be to develop therapies that evoke endogenous processes reminiscent of those seen in innate regenerators. Recently, investigations into tadpole tail regrowth, zebrafish limb restoration, and the super-healing Murphy Roths Large (MRL) mouse strain, have identified ancient oxygen-sensing pathways as a possible target to achieve this goal. Specifically, upregulation of the transcription factor, hypoxia-inducible factor one alpha (HIF-1α) has been shown to modulate cell metabolism and plasticity, as well as inflammation and tissue remodeling, possibly priming injuries for regeneration. Since HIF-1α signaling is conserved across species, environmental or pharmacological manipulation of oxygen-dependent pathways may elicit a regenerative response in non-healing mammals. In this review, we will explore the emerging role of HIF-1α in mammalian healing and regeneration, as well as attempts to modulate protein stability through hyperbaric oxygen treatment, intermittent hypoxia therapy, and pharmacological targeting. We believe that these therapies could breathe new life into the field of regenerative medicine.
MO01.07 Incidence of Aggressive End of Life Measures in a Retrospective Cohort of High-Risk Patients with Advanced Lung Cancer Receiving Immunotherapy
Authors: A. Singh, J. Lantz, N. Roberts, G. Russell, D. Margalski, V. Aggarwal, K. Kannan, A. Dothard, T. Lycan
Journal: Journal of Thoracic Oncology (2021)
Clinical Characteristics and Outcomes of Hospitalized Women Giving Birth With and Without COVID-19
Authors: Karola S. Jering, Brian L. Claggett, Jonathan W. Cunningham, Ning Rosenthal, Orly Vardeny, Michael F. Greene, Scott D. Solomon
Journal: JAMA Internal Medicine (2021)

stedt that courts must weigh the health benefit of a law that regulates abortion against the harm it imposes in terms of constrained access.A law with no demonstrated benefit, and that restricted access to abortion services, was deemed unconstitutional.However, the Court's current conservative majority has put in question the future of this balancing test and the protection of the fundamental right to choose to have an abortion.The worrisome increase in state-level restriction on abortions is part of a larger trend of politicians ignoring science and the views of medical experts in favor of ideology and partisan politics.This pattern has been seen during the coronavirus disease 2019 (COVID-19) pandemic as well.If states refuse to issue orders that require masks or enforce social distancing, the federal government should be more assertive in protecting public health.Similarly, the federal government should protect people from state laws that impose restrictions on access to abortion care.Politicized responses to health care challenges are harmful and undermine public health and well-being.This is just as true for reproductive health as it is for responding to COVID-19.
Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection
Authors: Cheleka A. M. Mpande, Munyaradzi Musvosvi, Virginie Rozot, Boitumelo Mosito, Timothy D. Reid, Constance Schreuder, Tessa Lloyd, Nicole Bilek, Huang Huang, Gerlinde Obermoser, Mark M. Davis, Morten Ruhwald, Mark Hatherill, Thomas J. Scriba, Elisa Nemes, Hassan Mahomed, Willem A. Hanekom, Fazlin Kafaar, Leslie Workman, Humphrey Mulenga, Rodney Ehrlich, Mzwandile Erasmus, Deborah Abrahams, Anthony Hawkridge, E. Jane Hughes, Sizulu Moyo, Sebastian Gelderbloem, Michele Tameris, Hennie Geldenhuys, Gregory Hussey
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 mo) and persistent (QuantiFERON-TB+ for >1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+ TNF+Mycobacterium tuberculosis-specific T cells and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19; 0.99; 0.96-1.00); and tuberculosis progressors (n = 22) and nonprogressors (n = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.
The PanPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the NATIVE Phase 2b trial
Authors: Sven Francque, Pierre Bedossa, Vlad Ratziu, Quentin Anstee, Elisabetta Bugianesi, Arun Sanyal, Rohit Loomba, Stephen A Harrison, Rozalina Ivanova Balabanska, Lyudmila Mateva, Nicolas Lanthier
Journal: Hepatology (2020)
Graft Versus Leukemia: Current Status and Future Perspectives
Authors: Aideen T. O'Neill, Ronjon Chakraverty
Journal: Journal of Clinical Oncology (2021)

Article Tools REVIEW ARTICLES Immunotherapy for Hematologic Malignancies Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.20.01801 Journal of Clinical Oncology - published online before print January 12, 2021 PMID: 33434054 Graft Versus Leukemia: Current Status and Future Perspectives Aideen T. O'Neill, MBBS, MRCP, FRCPath1xAideen T. O'NeillSearch for articles by this author and Ronjon Chakraverty, MBChB, MRCP, FRCPath, PhD1xRonjon ChakravertySearch for articles by this author Show More 1MRC Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom https://doi.org/10.1200/JCO.20.01801 First Page Full Text PDF Figures and Tables Supplements © 2021 by American Society of Clinical OncologyCONTEXTKey ObjectiveRelapse of hematologic malignancy is the major reason for treatment failure after allogeneic stem cell transplantation.Knowledge GeneratedGraft-versus-leukemia (GVL) responses are critical to prevent relapse but may fail as a result of tumor immune evasion, for example through antigen loss or T cell dysfunction. In silico pipelines for the discovery of tumor-expressed antigens and novel therapies that target immune evasion mechanisms (small molecule, biological, immune cell transfer) are potential strategies to sustain or reimpose GVL.RelevanceA key challenge will be how experimental therapies to enhance GVL can progress from first-in-human trials to prospective, controlled trials that evaluate efficacy and lead to regulatory approval.AUTHOR CONTRIBUTIONSConception and design: All authorsCollection and assembly of data: All authorsData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTGraft Versus Leukemia: Current Status and Future PerspectivesThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Ronjon ChakravertyConsulting or Advisory Role: NovartisNo other potential conflicts of interest were reported.
新規診断された慢性骨髄性白血病のイマチニブに対する早期分子応答の長期予後的意義:インターフェロンおよびSTI571の多国間無作為化試験(IRIS)から得られた解析結果
Authors: P Hughes Timothy, Hochhaus Andreas, Branford Susan, C Mueller Martin, S Kaeda Jaspal, Foroni Letizia, J Druker Brian, Guilhot Francois, A Larson Richard, G O’Brien Stephen, S Rudoltz Marc, Mone Manisha, Wehrle Elisabeth, Modur Vijay, M Goldman John, P Radich Jerald
Journal: Blood (2010)
Author Correction: A global survey of potential acceptance of a COVID-19 vaccine
Authors: Jeffrey V. Lazarus, Scott C. Ratzan, Adam Palayew, Lawrence O. Gostin, Heidi J. Larson, Kenneth Rabin, Spencer Kimball, Ayman El-Mohandes
Journal: Nature Medicine (2021)

A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01226-0
Circulating collagen neo-epitopes and their role in the prediction of fibrosis in patients with systemic sclerosis: a multicentre cohort study
Authors: Rucsandra Dobrota, Suzana Jordan, Pernille Juhl, Britta Maurer, Lukas Wildi, Anne-Christine Bay-Jensen, Morten Asser Karsdal, Ariane L Herrick, Jörg H W Distler, Yannick Allanore, Anna-Maria Hoffmann-Vold, Anne Sofie Siebuhr, Oliver Distler
Journal: The Lancet Rheumatology (2021)
An investigation of calcium carbonate core-shell particles for incorporation of 225Ac and sequester of daughter radionuclides: in vitro and in vivo studies
Authors: Albert R. Muslimov, Dmitrii Antuganov, Yana V. Tarakanchikova, Timofey E. Karpov, Mikhail V. Zhukov, Mikhail V. Zyuzin, Alexander S. Timin
Journal: Journal of Controlled Release (2021)
Reducing Post-Myocardial Infarction Mortality in the Elderly: The Power and Promise of Secondary Prevention⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: William E. Boden, David J. Maron
Journal: Journal of the American College of Cardiology (2008)
Removing the Reliability Bottleneck in Functional Magnetic Resonance Imaging Research to Achieve Clinical Utility
Authors: Michael P. Milham, Joshua Vogelstein, Ting Xu
Journal: JAMA Psychiatry (2021)

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Proportion, Type, and Characteristics of Physician Entrepreneurship in Massachusetts
Authors: Wesley H. Greenblatt
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although there have been signs of increasing interest in entrepreneurship among physicians as well as claims of a paucity of entrepreneurial activity in health care in general, there is little systematic evidence of the extent, type, and characteristics of entrepreneurship by physicians. Physician involvement in entrepreneurship may result in more innovative and financially successful health care companies. <h3>Objective</h3> To evaluate the proportion and characteristics of physicians who founded new businesses and the types of businesses that they started. <h3>Design, Setting, and Participants</h3> This cross-sectional study was conducted by matching all 33 770 physicians holding a Massachusetts medical license in 2017 with the Massachusetts new business registration records from 1960 to 2017 to identify companies founded by physicians. Data were analyzed from September 2017 to December 2019. <h3>Main Outcomes and Measures</h3> The number of physician-founded companies in Massachusetts and the types of businesses as characterized by the stated purpose at the time of founding. <h3>Results</h3> Among the 33 770 physicians holding a Massachusetts license in 2017, 13 839 (41.0%) were women and 8029 (23.8%) were international medical graduates; the median year of graduation from medical school was 1994 (interquartile range, 1983-2004). A total of 6494 (19.2%) physicians had founded at least 1 new business, and 831 of the 2448 physicians (33.9%) who graduated from medical school between 1974 and 1978 had founded a business. A total of 9501 companies were founded, of which 6267 (66.0%) were clinical practice, real estate, or practice management companies; 703 companies (7.4%) were in the public interest, including advocacy, public health, and philanthropy; 533 (5.6%) were biotechnology, health care information technology, or medical device companies; and 1759 (18.5%) were other business pursuits. For physician entrepreneurs, the mean (SD) time from medical school graduation to company founding was 20.2 (9.8) years. Regression analysis suggested that female physicians founded companies at lower rates than male physicians (odds ratio [OR], 0.529; 95% CI, 0.494-0.567) and that there was an association between attending a top-10 medical school by National Institutes of Health research funding and starting a clinical practice (OR, 0.687; 95% CI, 0.616-0.766) or biotechnology company (OR, 4.326; 95% CI, 2.951-6.344). <h3>Conclusions and Relevance</h3> The findings of this cross-sectional study suggest that physicians may be substantially involved in entrepreneurship, although there may be disparities by sex. Facilitation of physician entrepreneurship by policy makers, educators, and institutions may enhance medical innovation and public health.
Whole-exome Sequencing in Penile Squamous Cell Carcinoma Uncovers Novel Prognostic Categorization and Drug Targets Similar to Head and Neck Squamous Cell Carcinoma
Authors: Jad Chahoud, Frederico O. Gleber-Netto, Barrett Z. McCormick, Priya Rao, Xin Lu, Ming Guo, Maggaret B. Morgan, Randy A. Chu, Magaly Martinez-Ferrer, Agda Karina Eterovic, Curtis R. Pickering, Curtis A. Pettaway
Journal: Clinical Cancer Research (2021)

Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets.PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC-enriched mutational patterns based on their association with the Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies.We identified that most PSCC samples showed enrichment for Notch pathway (n = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased tumor mutation burden (TMB; CC, 0.71; P < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13-92.9); P = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC-enriched subset [HR, 2.41 (1.11-6.77); P = 0.042].This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications.See related commentary by McGregor and Sonpavde, p. 2375.
MO01.34 Patients with Solid Tumors Harboring NRG1 Gene Fusions: A Real-World Feasibility Study
Authors: A. Gajra, A.J. Klink, J. Kaufman, J. Laney, A. Cseh, K. Fernamberg, B. Moehring, S. Jonna
Journal: Journal of Thoracic Oncology (2021)