tbuckley/cabot-search huggingface dataset:
Genomic Risk Score for Advanced Osteoarthritis in Older Adults
Authors: Paul Lacaze, Yuanyuan Wang, Galina Polekhina, Andrew Bakshi, Moeen Riaz, Alice Owen, Angus Franks, Jawad Abidi, Jane Tiller, John McNeil, Flavia Cicuttini
Journal: Arthritis & Rheumatology (2022)

Prevention of osteoarthritis (OA) remains important, as there are no disease-modifying treatments. A personalized approach has the potential to better target prevention strategies. In the present study, we used recently identified genetic risk variants from genome-wide association analysis for advanced OA to calculate polygenic risk scores (PRS) for knee and hip OA and assessed PRS performance in an independent population of older community-dwelling adults.PRS were calculated in 12,093 individuals of European genetic descent ages ≥70 years who were enrolled in the Aspirin in Reducing Events in the Elderly trial. The outcome measure was knee and hip replacement (hospitalizations during the trial and self-reported joint replacements before enrollment). PRS were considered as continuous (per SD) and categorical (low risk [0-20%], medium risk [21-80%], high risk [81-100%]) variables. Logistic regression was used to examine associations between PRS and risk of joint replacement, adjusted for age, sex, body mass index, and socioeconomic status.Among the participants, 1,422 (11.8%) had knee replacements and 1,297 (10.7%) had hip replacements. PRS (per SD) were associated with a risk of knee replacement (odds ratio [OR] 1.13 [95% confidence interval (95% CI) 1.07-1.20]) and hip replacement (OR 1.23 [95% CI 1.16-1.30]). Participants with high PRS had an increased risk of knee replacement (OR 1.44 [95% CI 1.20-1.73]) and hip replacement (OR 1.88 [95% CI 1.56-2.26]), compared to those with low PRS. Associations were stronger for PRS and hip replacement risk in women than in men. Associations were similar in sensitivity analyses that examined joint replacements before and during the trial separately.PRS have the potential to improve prevention of severe knee and hip OA by providing a personalized approach and identifying individuals who may benefit from early intervention.
High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura
Authors: Pablo Canales-Herrerias, Etienne Crickx, Matteo Broketa, Aurélien Sokal, Guilhem Chenon, Imane Azzaoui, Alexis Vandenberghe, Angga Perima, Bruno Iannascoli, Odile Richard-Le Goff, Carlos Castrillon, Guillaume Mottet, Delphine Sterlin, Ailsa Robbins, Marc Michel, Patrick England, Gael A. Millot, Klaus Eyer, Jean Baudry, Matthieu Mahevas, Pierre Bruhns
Journal: Journal of Clinical Investigation (2022)

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti-integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.
Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells
Authors: Nicola Lockwood, Silvia Martini, Ainara Lopez-Pardo, Katharina Deiss, Hendrika A. Segeren, Robert K. Semple, Ian Collins, Dimitra Repana, Mathias Cobbaut, Tanya Soliman, Francesca Ciccarelli, Peter J. Parker
Journal: Cancer Research (2022)

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.The identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality.
Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer
Authors: Peter Weber, Axel Künstner, Julia Hess, Kristian Unger, Sebastian Marschner, Christian Idel, Julika Ribbat-Idel, Philipp Baumeister, Olivier Gires, Christoph Walz, Sibylle Rietzler, Laura Valeanu, Timm Herkommer, Lisa Kreutzer, Olena Klymenko, Guido Drexler, Thomas Kirchner, Cornelius Maihöfer, Ute Ganswindt, Axel Walch, Michael Sterr, Heiko Lickert, Martin Canis, Dirk Rades, Sven Perner, Mauricio Berriel Diaz, Stefan Herzig, Kirsten Lauber, Barbara Wollenberg, Hauke Busch, Claus Belka, Horst Zitzelsberger
Journal: Clinical Cancer Research (2021)

The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations.From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data.Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin.Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.
High-performance microbial opsins for spatially and temporally precise perturbations of large neuronal networks
Authors: Savitha Sridharan, Marta A. Gajowa, Mora B. Ogando, Uday K. Jagadisan, Lamiae Abdeladim, Masato Sadahiro, Hayley A. Bounds, William D. Hendricks, Toby S. Turney, Ian Tayler, Karthika Gopakumar, Ian Antón Oldenburg, Stephen G. Brohawn, Hillel Adesnik
Journal: Neuron (2022)

The biophysical properties of existing optogenetic tools constrain the scale, speed, and fidelity of precise optogenetic control. Here, we use structure-guided mutagenesis to engineer opsins that exhibit very high potency while retaining fast kinetics. These new opsins enable large-scale, temporally and spatially precise control of population neural activity. We extensively benchmark these new opsins against existing optogenetic tools and provide a detailed biophysical characterization of a diverse family of opsins under two-photon illumination. This establishes a resource for matching the optimal opsin to the goals and constraints of patterned optogenetics experiments. Finally, by combining these new opsins with optimized procedures for holographic photostimulation, we demonstrate the simultaneous coactivation of several hundred spatially defined neurons with a single hologram and nearly double that number by temporally interleaving holograms at fast rates. These newly engineered opsins substantially extend the capabilities of patterned illumination optogenetic paradigms for addressing neural circuits and behavior.
Rotating Night Shift Work and Healthy Aging After 24 Years of Follow-up in the Nurses' Health Study
Authors: Hongying Shi, Tianyi Huang, Eva S. Schernhammer, Qi Sun, Molin Wang
Journal: JAMA Network Open (2022)

Rotating night shift work is associated with higher mortality. Whether it is also associated with overall health among those who survive to older ages remains unclear.
Comparison of Socioeconomic Disparities in Pump Uptake Among Children With Type 1 Diabetes in 2 Canadian Provinces With Different Payment Models
Authors: Jennifer M. Ladd, Atul Sharma, Elham Rahme, Kristine Kroeker, Marjolaine Dubé, Marc Simard, Céline Plante, Claudia Blais, Marni Brownell, Celia Rodd, Meranda Nakhla
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Insulin pumps improve glycemic control and quality of life in children with type 1 diabetes (T1D). Canada's provinces have implemented universal pediatric programs to improve access. However, these programs provide differing financial coverage, allowing for unique cross-jurisdictional comparisons. <h3>Objective</h3> To evaluate possible socioeconomic status (SES) disparities in pump uptake in Québec, where pumps are fully funded, with those in Manitoba, where pumps are partially funded. <h3>Design, Setting, and Participants</h3> Using health administrative databases and a clinical registry, parallel, population-based cohort studies of children with diabetes were conducted from April 1, 2011, in Québec, and April 1, 2012, in Manitoba, until March 31, 2017. In analysis conducted from July 1, 2019, to November 30, 2021, multivariable Cox proportional hazards regression models were applied to study the association between pump uptake and SES, defined using validated area-based material and social deprivation indices. Children aged 1 to 17 years with T1D were identified using a validated definition in administrative data (Québec) and a clinical registry (Manitoba). Those using pumps before the initiation of provincial programs were excluded. <h3>Exposures</h3> Socioeconomic status. <h3>Main Outcomes and Measures</h3> Insulin pump uptake. <h3>Results</h3> A total of 2919 children with T1D were identified in Québec: 1550 male (53.1%), mean (SD) age at diagnosis, 8.3 (4.4) years, and 1067 (36.6%) were using a pump. In Manitoba, 636 children were identified: 364 male (57.2%), mean (SD) age at diagnosis, 8.8 (4.4) years, and 106 (16.7%) were using a pump. In Québec, the mean age at diagnosis of T1D was lower in children using the pump compared with those not using a pump (7.6 [4.1] vs 8.7 [4.5] years); sex distribution was similar (562 [52.7%] vs 988 [53.3%] male). No differences in mean (SD) age at diagnosis (8.8 [4.4] vs 8.8 [4.3] years) or sex (57 [53.8%] vs 307 [57.9%] male) were noted in both groups in Manitoba. Increasing material deprivation was associated with decreased pump uptake in both Québec (adjusted hazard ratio [aHR] 0.89; 95% CI, 0.85-0.93) and Manitoba (aHR, 0.70; 95% CI, 0.60-0.82). Inclusion of ethnic concentration did not change this association. Socioeconomic disparities in pump uptake were greater in Manitoba than Québec (<i>P</i> = .006 by<i>t</i>test; Cochran<i>Q</i>, 8.15;<i>P</i> = .004;<i>I</i><sup>2</sup> = 87.7%; 95% CI, 52.5%-96.8%). <h3>Conclusions and Relevance</h3> The results of this study suggest that the program of full coverage for pumps available in Québec partially mitigates observed SES disparities in uptake and may be a model to improve access for all children with T1D.
Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma
Authors: Bethany L. Mundy-Bosse, Christoph Weigel, Yue-Zhong Wu, Salma Abdelbaky, Youssef Youssef, Susana Beceiro Casas, Nicholas Polley, Gabrielle Ernst, Karen A. Young, Kathleen K. McConnell, Ansel P. Nalin, Kevin G. Wu, Megan Broughton, Matthew R. Lordo, Ekaterina Altynova, Everardo Hegewisch-Solloa, Daniel Y. Enriquez-Vera, Daniela Dueñas, Carlos Barrionuevo, Shan-Chi Yu, Atif Saleem, Carlos J. Suarez, Edward L. Briercheck, Hernan Molina-Kirsch, Thomas P. Loughran, Dieter Weichenhan, Christoph Plass, John C. Reneau, Emily M. Mace, Fabiola Valvert Gamboa, David M. Weinstock, Yasodha Natkunam, Michael A. Caligiuri, Anjali Mishra, Pierluigi Porcu, Robert A. Baiocchi, Jonathan E. Brammer, Aharon G. Freud, Christopher C. Oakes
Journal: Blood Cancer Discovery (2022)

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.
MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination
Authors: Yeonsu Kim, Xiaoyan Zheng, Kathrin Eschke, M. Zeeshan Chaudhry, Federico Bertoglio, Adriana Tomić, Astrid Krmpotić, Markus Hoffmann, Yotam Bar-On, Julia Boehme, Dunja Bruder, Thomas Ebensen, Linda Brunotte, Stephan Ludwig, Martin Messerle, Carlos Guzman, Ofer Mandelboim, Michael Hust, Stefan Pöhlmann, Stipan Jonjić, Luka Čičin-Šain
Journal: Cellular and Molecular Immunology (2022)

Abstract Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8 + T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMV HA ) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMV S ). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMV HA -vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.
Clarification of Conflict of Interest Disclosures
Authors: Sean Mackey
Journal: JAMA Surgery (2022)

Jennifer Hah, MD, MS; Sean C. Mackey, MD, PhD; Peter Schmidt, MD; Rebecca McCue, BS; Keith Humphreys, PhD; Jodie Trafton, PhD; Bradley Efron, PhD; Debra Clay, BSN, RN; Yasamin Sharifzadeh, BS; Gabriela Ruchelli, BS; Stuart Goodman, MD, PhD; James Huddleston, MD; William J. Maloney, MD; Frederick M. Dirbas, MD; Joseph Shrager, MD; John G. Costouros, MD; Catherine Curtin, MD; Ian Carroll, MD, MS
Cerebrovascular Complications of COVID-19 and COVID-19 Vaccination
Authors: Manuela De Michele, Joshua Kahan, Irene Berto, Oscar G. Schiavo, Marta Iacobucci, Danilo Toni, Alexander E. Merkler
Journal: Circulation Research (2022)

The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.
Laparoscopic Anatomical Versus Non-anatomical hepatectomy in the Treatment of Hepatocellular Carcinoma: A randomised controlled trial
Authors: Kexi Liao, Kaijin Yang, Li Cao, Yao Lu, Bowen Zheng, Xuesong Li, Xiaojun Wang, Jianwei Li, Jian Chen, Shuguo Zheng
Journal: International Journal of Surgery (2022)
Y-Chromosome Gene, <i>Uty</i>, Protects Against Pulmonary Hypertension by Reducing Proinflammatory Chemokines
Authors: Christine M. Cunningham, Min Li, Gregoire Ruffenach, Mitali Doshi, Laila Aryan, Jason Hong, John Park, Haley Hrncir, Lejla Medzikovic, Soban Umar, Arthur P. Arnold, Mansoureh Eghbali
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Idiopathic pulmonary arterial hypertension (PAH) is a terminal pulmonary vascular disease characterized by increased pressure, right ventricular failure, and death. PAH exhibits a striking sex bias and is up to four times more prevalent in females. Understanding the molecular basis behind sex differences could help uncover novel therapies. Objectives: We previously discovered that the Y chromosome is protective against hypoxia-induced experimental pulmonary hypertension (PH), which may contribute to sex differences in PAH. Here, we identify the gene responsible for Y-chromosome protection, investigate key downstream autosomal genes, and demonstrate a novel preclinical therapy. Methods: To test the effect of Y-chromosome genes on PH development, we knocked down each Y-chromosome gene expressed in the lung by means of intratracheal instillation of siRNA in gonadectomized male mice exposed to hypoxia and monitored changes in right ventricular and pulmonary artery hemodynamics. We compared the lung transcriptome of Uty knockdown mouse lungs to those of male and female PAH patient lungs to identify common downstream pathogenic chemokines and tested the effects of these chemokines on human pulmonary artery endothelial cells. We further inhibited the activity of these chemokines in two preclinical pulmonary hypertension models to test the therapeutic efficacy. Measurements and Main Results: Knockdown of the Y-chromosome gene Uty resulted in more severe PH measured by increased right ventricular pressure and decreased pulmonary artery acceleration time. RNA sequencing revealed an increase in proinflammatory chemokines Cxcl9 and Cxcl10 as a result of Uty knockdown. We found CXCL9 and CXCL10 significantly upregulated in human PAH lungs, with more robust upregulation in females with PAH. Treatment of human pulmonary artery endothelial cells with CXCL9 and CXCL10 triggered apoptosis. Inhibition of Cxcl9 and Cxcl10 expression in male Uty knockout mice and CXCL9 and CXCL10 activity in female rats significantly reduced PH severity. Conclusions:Uty is protective against PH. Reduction of Uty expression results in increased expression of proinflammatory chemokines Cxcl9 and Cxcl10, which trigger endothelial cell death and PH. Inhibition of CLXC9 and CXLC10 rescues PH development in multiple experimental models.
Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease
Authors: Andrea Beaton, Emmy Okello, Joselyn Rwebembera, Anneke Grobler, Daniel Engelman, Juliet Alepere, Lesley Canales, Jonathan Carapetis, Alyssa DeWyer, Peter Lwabi, Mariana Mirabel, Ana O. Mocumbi, Meghna Murali, Miriam Nakitto, Emma Ndagire, Maria C.P. Nunes, Isaac O. Omara, Rachel Sarnacki, Amy Scheel, Nigel Wilson, Meghan Zimmerman, Liesl Zühlke, Ganesan Karthikeyan, Craig A. Sable, Andrew C. Steer
Journal: New England Journal of Medicine (2021)

Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown.