tbuckley/cabot-search huggingface dataset:
Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants
Authors: Kohei Hamanaka, Noriko Miyake, Takeshi Mizuguchi, Satoko Miyatake, Yuri Uchiyama, Naomi Tsuchida, Futoshi Sekiguchi, Satomi Mitsuhashi, Yoshinori Tsurusaki, Mitsuko Nakashima, Hirotomo Saitsu, Kohei Yamada, Masamune Sakamoto, Hiromi Fukuda, Sachiko Ohori, Ken Saida, Toshiyuki Itai, Yoshiteru Azuma, Eriko Koshimizu, Atsushi Fujita, Biray Erturk, Yoko Hiraki, Gaik-Siew Ch’ng, Mitsuhiro Kato, Nobuhiko Okamoto, Atsushi Takata, Naomichi Matsumoto
Journal: Genome Medicine (2022)

Abstract Background Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. Methods We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). Results We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes ( GLTSCR1 , MARK2 , and UBR3 ). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 “plausible” candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (&gt; 90% true-positive probabilities) candidate genes: HDAC2 , SUPT16H , HECTD4 , CHD5 , XPO1 , GSK3B , NLGN2 , ADGRB1 , CTR9 , BRD3 , and MARK2 . Conclusions We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.
Use of Aspirin to Prevent Cardiovascular Disease
Authors: Jill Jin
Journal: JAMA (2022)

US Preventive Services Task Force; Karina W. Davidson, PhD, MASc; Michael J. Barry, MD; Carol M. Mangione, MD, MSPH; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Alex H. Krist, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD
Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy
Authors: Huai-liang Wu, Yue Gong, Peng Ji, Yi-fan Xie, Yi-Zhou Jiang, Guang-yu Liu
Journal: Journal of Hematology & Oncology (2022)

Abstract Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.
Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis
Authors: Omkar Chaudhary, Diane Trotta, Kaicheng Wang, Xun Wang, Xiuping Chu, Chip Bradley, Jason Okulicz, Ryan C Maves, Karl Kronmann, Christina M Schofield, Jason M Blaylock, Yanhong Deng, Kurt A Schalper, Susan M Kaech, Brian Agan, Anuradha Ganesan, Brinda Emu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background People living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a marker of risk for cancer among HIV-infected virally suppressed patients. Methods A nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point. Results We found that cases have increased expression of PD-1 +CD160+CD244+ (‘triple positive’) on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-bet dim Eomes hi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion. Conclusion In conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-bet dim Eomes hi , that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH.
End-stage Kidney Disease Doubles
Authors: Bridget M. Kuehn
Journal: JAMA (2022)

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Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study
Authors: Luuk Wieske, Koos P J van Dam, Maurice Steenhuis, Eileen W Stalman, Laura Y L Kummer, Zoé L E van Kempen, Joep Killestein, Adriaan G Volkers, Sander W Tas, Laura Boekel, Gerrit J Wolbink, Anneke J van der Kooi, Joost Raaphorst, Mark Löwenberg, R Bart Takkenberg, Geert R A M D'Haens, Phyllis I Spuls, Marcel W Bekkenk, Annelie H Musters, Nicoline F Post, Angela L Bosma, Marc L Hilhorst, Yosta Vegting, Frederike J Bemelman, Alexandre E Voskuyl, Bo Broens, Agner Parra Sanchez, Cécile A C M van Els, Jelle de Wit, Abraham Rutgers, Karina de Leeuw, Barbara Horváth, Jan J G M Verschuuren, Annabel M Ruiter, Lotte van Ouwerkerk, Diane van der Woude, Renée C F Allaart, Y K Onno Teng, Pieter van Paassen, Matthias H Busch, Papay B P Jallah, Esther Brusse, Pieter A van Doorn, Adája E Baars, Dirk Jan Hijnen, Corine R G Schreurs, W Ludo van der Pol, H Stephan Goedee, Sofie Keijzer, Jim B D Keijser, Arend Boogaard, Olvi Cristianawati, Anja Ten Brinke, Niels J M Verstegen, Koos A H Zwinderman, S Marieke van Ham, Taco W Kuijpers, Theo Rispens, Filip Eftimov
Journal: The Lancet Rheumatology (2022)
An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer
Authors: Wenjing Wang, Jianmin Wang, Shuai Liu, Yong Ren, Jingyu Wang, Sen Liu, Wei Cui, Lina Jia, Xing Tang, Jingyu Yang, Chunfu Wu, Lihui Wang
Journal: Molecular Cancer (2022)

Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored.We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance.Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2.Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.
Risk factors for poor humoral response to primary and booster SARS-CoV-2 vaccination in hematologic and oncological outpatients—COVIDOUT study
Authors: Martin Schönlein, Victoria Wrage, Susanne Ghandili, Sibylle C Mellinghoff, Thomas Theo Brehm, Lisa B Leypoldt, Nils Utz, Roland M Schrader, Winfried Alsdorf, Niklas Börschel, Lara Bußmann, Martin Schönrock, Dorothea Perlick, Gerhard Schön, Karl Verpoort, Marc Lütgehetmann, Julian Schulze Zur Wiesch, Katja C Weisel, Carsten Bokemeyer, Philippe Schafhausen, Marianne Sinn
Journal: Cancer Cell (2022)
Variant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2
Authors: Lei Peng, Paul A. Renauer, Arya Ökten, Zhenhao Fang, Jonathan J. Park, Xiaoyu Zhou, Qianqian Lin, Matthew B. Dong, Renata Filler, Qiancheng Xiong, Paul Clark, Chenxiang Lin, Craig B. Wilen, Sidi Chen
Journal: Cell Reports Medicine (2022)

Lipid nanoparticle (LNP)-mRNA vaccines offer protection against COVID-19; however, multiple variant lineages caused widespread breakthrough infections. Here, we generate LNP-mRNAs specifically encoding wild-type (WT), B.1.351, and B.1.617 SARS-CoV-2 spikes, and systematically study their immune responses. All three LNP-mRNAs induced potent antibody and T cell responses in animal models; however, differences in neutralization activity have been observed between variants. All three vaccines offer potent protection against in vivo challenges of authentic viruses of WA-1, Beta, and Delta variants. Single-cell transcriptomics of WT- and variant-specific LNP-mRNA-vaccinated animals reveal a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induces a systemic increase of reactive CD8 T cells and altered gene expression programs in B and T lymphocytes. BCR-seq and TCR-seq unveil repertoire diversity and clonal expansions in vaccinated animals. These data provide assessment of efficacy and direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.
RNAi-based modulation of IFN-γ signaling in skin
Authors: Qi Tang, Jacquelyn Sousa, Dimas Echeverria, Xueli Fan, Ying-Chao Hsueh, Khashayar Afshari, Nicholas MeHugh, David A. Cooper, Lorenc Vangjeli, Kathryn Monopoli, Ken Okamura, Annabelle Biscans, Adam Clauss, John E. Harris, Anastasia Khvorova
Journal: Molecular Therapy (2022)

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases. Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.
Comparison of Estimated Incentives for Preventing Postpartum Depression in Value-Based Payment Models Using the Net Present Value of Care vs Total Cost of Care
Authors: Nathaniel Z. Counts, Margaret R. Kuklinski, Venus Wong, Mark E. Feinberg, Timothy B. Creedon
Journal: JAMA Network Open (2022)

Strong financial incentives are critical to promoting widespread implementation of interventions that prevent postpartum depression. Value-based payment (VBP) approaches could be adapted to capture longer-term value and offer stronger incentives for postpartum depression prevention by sharing the expected future health care savings estimated by reduced postpartum depression incidence with clinicians.
Decitabine increases neoantigen and cancer testis antigen expression to enhance T-cell–mediated toxicity against glioblastoma
Authors: Ruichong Ma, Margarida Rei, Isaac Woodhouse, Katherine Ferris, Sophie Kirschner, Anandhakumar Chandran, Uzi Gileadi, Ji-Li Chen, Mariana Pereira Pinho, Yoanna Ariosa-Morejon, Skirmantas Kriaucionis, Nicola Ternette, Hashem Koohy, Olaf Ansorge, Graham Ogg, Puneet Plaha, Vincenzo Cerundolo
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Despite maximal treatment, median survival remains dismal at 14–24 months. Immunotherapies, such as checkpoint inhibition, have revolutionized management of some cancers but have little benefit for GBM patients. This is, in part, due to the low mutational and neoantigen burden in this immunogenically “cold” tumor. Methods U87MG and patient-derived cell lines were treated with 5-aza-2′-deoxycytidine (DAC) and underwent whole-exome and transcriptome sequencing. Cell lines were then subjected to cellular assays with neoantigen and cancer testis antigen (CTA) specific T cells. Results We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class I in tumor cells, leading to increased neoantigen- and CTA-specific T-cell activation and killing of DAC-treated cancer cells. In addition, we show that patients have endogenous cancer-specific T cells in both tumor and blood, which show increased tumor-specific activation in the presence of DAC-treated cells. Conclusions Our work shows that DAC increases GBM immunogenicity and consequent susceptibility to T-cell responses in vitro. Our results support a potential use of DAC as a sensitizing agent for immunotherapy.
2022 EULAR points to consider for remote care in rheumatic and musculoskeletal diseases
Authors: Annette de Thurah, Philipp Bosch, Andrea Marques, Yvette Meissner, Chetan B Mukhtyar, Johannes Knitza, Aurélie Najm, Nina Østerås, Tim Pelle, Line Raunsbæk Knudsen, Hana Šmucrová, Francis Berenbaum, Meghna Jani, Rinie Geenen, Martin Krusche, Polina Pchelnikova, Savia de Souza, Sara Badreh, Dieter Wiek, Silvia Piantoni, James M Gwinnutt, Christina Duftner, Helena M Canhão, Luca Quartuccio, Nikolay Stoilov, Yeliz Prior, Johannes WJ Bijlsma, Alen Zabotti, Tanja A Stamm, Christian Dejaco
Journal: Annals of the Rheumatic Diseases (2022)

Background Remote care and telehealth have the potential to expand healthcare access, and the COVID-19 pandemic has called for alternative solutions to conventional face-to-face follow-up and monitoring. However, guidance is needed on the integration of telehealth into clinical care of people with rheumatic and musculoskeletal diseases (RMD). Objective To develop EULAR points to consider (PtC) for the development, prioritisation and implementation of telehealth for people with RMD. Methods A multidisciplinary EULAR task force (TF) of 30 members from 14 European countries was established, and the EULAR standardised operating procedures for development of PtC were followed. A systematic literature review was conducted to support the TF in formulating the PtC. The level of agreement among the TF was established by anonymous online voting. Results Four overarching principles and nine PtC were formulated. The use of telehealth should be tailored to patient’s needs and preferences. The healthcare team should have adequate equipment and training and have telecommunication skills. Telehealth can be used in screening for RMD as preassessment in the referral process, for disease monitoring and regulation of medication dosages and in some non-pharmacological interventions. People with RMD should be offered training in using telehealth, and barriers should be resolved whenever possible. The level of agreement to each statement ranged from 8.5 to 9.8/10. Conclusion The PtC have identified areas where telehealth could improve quality of care and increase healthcare access. Knowing about drivers and barriers of telehealth is a prerequisite to successfully establish remote care approaches in rheumatologic clinical practice.
Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer
Authors: Janelle M. Guirguis-Blake, Corinne V. Evans, Leslie A. Perdue, Sarah I. Bean, Caitlyn A. Senger
Journal: JAMA (2022)

<h3>Importance</h3> Low-dose aspirin is used for primary cardiovascular disease prevention and may have benefits for colorectal cancer prevention. <h3>Objective</h3> To review the benefits and harms of aspirin in primary cardiovascular disease prevention and colorectal cancer prevention to inform the US Preventive Services Task Force. <h3>Data Sources</h3> MEDLINE, PubMed, Embase, and the Cochrane Central Register of Controlled Trials through January 2021; literature surveillance through January 21, 2022. <h3>Study Selection</h3> English-language randomized clinical trials (RCTs) of low-dose aspirin (≤100 mg/d) compared with placebo or no intervention in primary prevention populations. <h3>Data Extraction and Synthesis</h3> Single extraction, verified by a second reviewer. Quantitative synthesis using Peto fixed-effects meta-analysis. <h3>Main Outcomes and Measures</h3> Cardiovascular disease events and mortality, all-cause mortality, colorectal cancer incidence and mortality, major bleeding, and hemorrhagic stroke. <h3>Results</h3> Eleven RCTs (N = 134 470) and 1 pilot trial (N = 400) of low-dose aspirin for primary cardiovascular disease prevention were included. Low-dose aspirin was associated with a significant decrease in major cardiovascular disease events (odds ratio [OR], 0.90 [95% CI, 0.85-0.95]; 11 RCTs [n = 134 470];<i>I2</i> = 0%; range in absolute effects, −2.5% to −0.1%). Results for individual cardiovascular disease outcomes were significant, with similar magnitude of benefit. Aspirin was not significantly associated with reductions in cardiovascular disease mortality or all-cause mortality. There was limited trial evidence on benefits for colorectal cancer, with the findings highly variable by length of follow-up and statistically significant only when considering long-term observational follow-up beyond randomized trial periods. Low-dose aspirin was associated with significant increases in total major bleeding (OR, 1.44 [95% CI, 1.32-1.57]; 10 RCTs [n = 133 194];<i>I2</i> = 4.7%; range in absolute effects, 0.1% to 1.0%) and in site-specific bleeding, with similar magnitude. <h3>Conclusions and Relevance</h3> Low-dose aspirin was associated with small absolute risk reductions in major cardiovascular disease events and small absolute increases in major bleeding. Colorectal cancer results were less robust and highly variable.