tbuckley/cabot-search huggingface dataset:
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
Authors: Benjamin Watkins, Muna Qayed, Courtney McCracken, Brandi Bratrude, Kayla Betz, Yvonne Suessmuth, Alison Yu, Shauna Sinclair, Scott Furlan, Steven Bosinger, Victor Tkachev, James Rhodes, Audrey Grizzle Tumlin, Alexandria Narayan, Kayla Cribbin, Scott Gillespie, Ted A. Gooley, Marcelo C. Pasquini, Kyle Hebert, Urvi Kapoor, Andre Rogatko, Mourad Tighiouart, Sungjin Kim, Catherine Bresee, Sung W. Choi, Jeffrey Davis, Christine Duncan, Roger Giller, Michael Grimley, Andrew C. Harris, David Jacobsohn, Nahal Lalefar, Maxim Norkin, Nosha Farhadfar, Michael A. Pulsipher, Shalini Shenoy, Aleksandra Petrovic, Kirk R. Schultz, Gregory A. Yanik, Edmund K. Waller, John E. Levine, James L. Ferrara, Bruce R. Blazar, Amelia Langston, John T. Horan, Leslie S. Kean
Journal: Journal of Clinical Oncology (2021)

Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers
Authors: Zhiyuan Hu, Paula Cunnea, Zhe Zhong, Haonan Lu, Oloruntoba I. Osagie, Leticia Campo, Mara Artibani, Katherine Nixon, Jennifer Ploski, Laura Santana Gonzalez, Abdulkhaliq Alsaadi, Nina Wietek, Stephen Damato, Sunanda Dhar, Sarah P. Blagden, Christopher Yau, Joanna Hester, Ashwag Albukhari, Eric O. Aboagye, Christina Fotopoulou, Ahmed Ahmed
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P &amp;lt; 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation
Authors: Bing Wu, Song Zhang, Zengli Guo, Yanmin Bi, Mingxia Zhou, Ping Li, Maryamsadat Seyedsadr, Xiaojiang Xu, Jian-liang Li, Silva Markovic-Plese, Yisong Y. Wan
Journal: Immunity (2021)
IM01.01 4-Year Survival in Randomised Phase II (POPLAR) and Phase III (OAK) Studies of Atezolizumab vs. Docetaxel in 2L+ NSCLC
Authors: J. Mazieres, A. Rittmeyer, S.M. Gadgeel, T. Hida, D. Gandara, D. Cortinovis, F. Barlesi, W. Yu, C. Matheny, M. Ballinger, K. Park
Journal: Journal of Thoracic Oncology (2021)
Peripheral airways type 2 inflammation, neutrophilia and microbial dysbiosis in severe asthma
Authors: Adnan Azim, Ben Green, Laurie Lau, Hitasha Rupani, Nivenka Jayasekera, Kenneth Bruce, Peter Howarth
Journal: Allergy (2021)

Abstract Background IL‐13 is considered an archetypal T2 cytokine central to the clinical disease expression of asthma. The IL‐13 response genes, which are upregulated in central airway bronchial epithelial of asthma patients, can be normalized by high‐dose inhaled steroid therapy in severe asthma. However, this is not the case within the peripheral airways. We have sought to further understand IL‐13 in the peripheral airways in severe asthma through bronchoalveolar analysis. Methods Bronchoalveolar lavage samples were collected from 203 asthmatic and healthy volunteers, including 78 with severe asthma. Inflammatory mediators were measured using a multiple cytokine immunoassay platform. This analysis was replicated in a further 59 volunteers, in whom 16S rRNA analysis of BAL samples was undertaken by terminal restriction fragment length polymorphism. Results Severe asthma patients with high BAL IL‐13, despite treatment with high‐dose inhaled corticosteroids, had more severe lung function and significantly higher BAL neutrophil percentages, but not BAL eosinophils than those with normal BAL‐13 concentrations. This finding was replicated in the second cohort, which further associated BAL IL‐13 and neutrophilia with a greater abundance of potentially pathogenic bacteria in the peripheral airways. Conclusion Our findings demonstrate a steroid unresponsive source of IL‐13 that is associated with BAL neutrophilia and bacterial dysbiosis in severe asthma. Our findings highlight the biological complexity of severe asthma and the importance of a greater understanding of the innate and adaptive immune responses in the peripheral airways in this disease.
The role of the computerized tomography scanner in the cross-transmission of carbapenem-resistant Acinetobacter baumannii between hospitalized patients
Authors: Ziv Dadon, Eli Ben-Chetrit, Ofer Benjaminov, Louay Taha, Yonit Wiener-Well, Daniel Belman, Phillip D. Levin
Journal: Clinical Microbiology and Infection (2021)
Abstract 1749: Possible Link between Large Artery Stiffness and Coronary Flow Velocity Reserve
Authors: Makoto Saito, Hideki Okayama, Kazihisa Nishimura, Toyofumi Yoshii, Katsuji Inoue, Go Hiasa, Takumi Sumimoto, Akira Kurata, Jun Suzuki, Akiyoshi Ogimito, Tomoaki Ohtsuka, Jitsuo Higaki
Journal: Circulation (2007)

Background: Population studies have shown that increased large artery stiffness is an independent predictor of cardiovascular events. As the aorta stiffens, the velocity of the pressure wave increa...
Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status
Authors: Esben Agerbo, Betina B. Trabjerg, Anders D. Børglum, Andrew J. Schork, Bjarni J. Vilhjálmsson, Carsten B. Pedersen, Christian Hakulinen, Clara Albiñana, David M. Hougaard, Jakob Grove, John J. McGrath, Jonas Bybjerg-Grauholm, Ole Mors, Oleguer Plana-Ripoll, Thomas Werge, Naomi R. Wray, Preben Bo Mortensen, Katherine L. Musliner
Journal: JAMA Psychiatry (2021)

Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk.To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression.This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs.The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses).Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings.Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders.This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.
Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy
Authors: Ajaz A. Bhat, Sabah Nisar, Selma Maacha, Tatiana Correa Carneiro-Lobo, Sabah Akhtar, Kodappully Sivaraman Siveen, Nissar A. Wani, Arshi Rizwan, Puneet Bagga, Mayank Singh, Ravinder Reddy, Shahab Uddin, Jean-Charles Grivel, Gyan Chand, Michael P. Frenneaux, Mushtaq A. Siddiqi, Davide Bedognetti, Wael El-Rifai, Muzafar A. Macha, Mohammad Haris
Journal: Molecular Cancer (2021)

Abstract Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.
Collapse induration of alveoli is an ultrastructural finding in a COVID-19 patient
Authors: Matthias Ochs, Sara Timm, Sefer Elezkurtaj, David Horst, Jenny Meinhardt, Frank L. Heppner, Steffen Weber-Carstens, Andreas C. Hocke, Martin Witzenrath
Journal: European Respiratory Journal (2021)

<b>Electron microscopy reveals collapse induration with alveolar epithelial cell death, basal lamina denudation, collapse and sealing of alveoli in a COVID-19 patient, implicating surfactant dysfunction and alveolar instability in fibrosis initiation</b>https://bit.ly/38yEX2g
Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients
Authors: Sultan Abdul-Jawad, Luca Baù, Thanussuyah Alaguthurai, Irene del Molino del Barrio, Adam G. Laing, Thomas S. Hayday, Leticia Monin, Miguel Muñoz-Ruiz, Louisa McDonald, Isaac Francos Quijorna, Duncan McKenzie, Richard Davis, Anna Lorenc, Julie Nuo En Chan, Sarah Ryan, Eva Bugallo-Blanco, Rozalyn Yorke, Shraddha Kamdar, Matthew Fish, Iva Zlatareva, Pierre Vantourout, Aislinn Jennings, Sarah Gee, Katie Doores, Katharine Bailey, Sophie Hazell, Julien De Naurois, Charlotte Moss, Beth Russell, Aadil A. Khan, Mark Rowley, Reuben Benjamin, Deborah Enting, Doraid Alrifai, Yin Wu, You Zhou, Paul Barber, Tony Ng, James Spicer, Mieke Van Hemelrijck, Mayur Kumar, Jennifer Vidler, Yadanar Lwin, Paul Fields, Sophia N. Karagiannis, Anthony C.C. Coolen, Anne Rigg, Sophie Papa, Adrian C. Hayday, Piers E.M. Patten, Sheeba Irshad
Journal: Cancer Cell (2021)
Higher susceptibility to sunburn is associated with decreased plasma glutamine and increased plasma glutamate levels among US women: An analysis of the Nurses' Health Study I and II
Authors: Keming Yang, Xin Li, Oana A. Zeleznik, A. Heather Eliassen, Clary B. Clish, Eunyoung Cho, Ally-Khan B. Somani, Abrar A. Qureshi, Edward L. Giovannucci, Hongmei Nan
Journal: Journal of the American Academy of Dermatology (2021)
Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol
Authors: Gregory G. Schwartz, Philippe Gabriel Steg, Deepak L. Bhatt, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, J. Wouter Jukema, Yong-Un Kim, Qian H. Li, Garen Manvelian, Robert Pordy, Timothée Sourdille, Harvey D. White, Michael Szarek
Journal: Circulation (2021)

Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score–matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: &lt;25 (n=3357), 25 to 50 (n=3692), or &gt;50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C &lt;25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62–0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64–0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C &gt;50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73–1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels &lt;15 mg/dL. Conclusions: After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels &lt;25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01663402.
Biomarker-Based Risk Prediction of Incident Heart Failure in Pre-Diabetes and Diabetes
Authors: Ambarish Pandey, Muthiah Vaduganathan, Kershaw V Patel, Colby Ayers, Christie M Ballantyne, Mikhail N Kosiborod, Mercedes Carnethon, Christopher DeFilippi, Darren K McGuire, Sadiya S Khan, Melissa C Caughey, James A de Lemos, Brendan M Everett
Journal: JACC Heart Failure (2021)
Exome-wide evaluation of rare coding variants using electronic health records identifies new gene–phenotype associations
Authors: Joseph Park, Anastasia M. Lucas, Xinyuan Zhang, Kumardeep Chaudhary, Judy H. Cho, Girish Nadkarni, Amanda Dobbyn, Geetha Chittoor, Navya S. Josyula, Nathan Katz, Joseph H. Breeyear, Shadi Ahmadmehrabi, Theodore G. Drivas, Venkata R. M. Chavali, Maria Fasolino, Hisashi Sawada, Alan Daugherty, Yanming Li, Chen Zhang, Yuki Bradford, JoEllen Weaver, Anurag Verma, Renae L. Judy, Rachel L. Kember, John D. Overton, Jeffrey G. Reid, Manuel A. R. Ferreira, Alexander H. Li, Aris Baras, Scott A. LeMaire, Ying H. Shen, Ali Naji, Klaus H. Kaestner, Golnaz Vahedi, Todd L. Edwards, Jinbo Chen, Scott M. Damrauer, Anne E. Justice, Ron Do, Marylyn D. Ritchie, Daniel J. Rader
Journal: Nature Medicine (2021)
Modeling human adaptive immune responses with tonsil organoids
Authors: Lisa E. Wagar, Ameen Salahudeen, Christian M. Constantz, Ben S. Wendel, Michael M. Lyons, Vamsee Mallajosyula, Lauren P. Jatt, Julia Z. Adamska, Lisa K. Blum, Neha Gupta, Katherine J. L. Jackson, Fan Yang, Katharina Röltgen, Krishna M. Roskin, Kelly M. Blaine, Kara D. Meister, Iram N. Ahmad, Mario Cortese, Emery G. Dora, Sean N. Tucker, Anne I. Sperling, Aarti Jain, D. Huw Davies, Philip L. Felgner, Gregory B. Hammer, Peter S. Kim, William H. Robinson, Scott D. Boyd, Calvin J. Kuo, Mark M. Davis
Journal: Nature Medicine (2021)
Sofosbuvir/velpatasvir with or without low-dose ribavirin for patients with chronic hepatitis C virus infection and severe renal impairment
Authors: Chen-Hua Liu, Chi-Yi Chen, Wei-Wen Su, Kuo-Chih Tseng, Ching-Chu Lo, Chun-Jen Liu, Jyh-Jou Chen, Cheng-Yuan Peng, Yu-Lueng Shih, Sheng-Shun Yang, Chia-Sheng Huang, Ke-Jhang Huang, Chi-Yang Chang, Ming-Chang Tsai, Wei-Yu Kao, Yo-Jen Fang, Po-Yueh Chen, Pei-Yuan Su, Chih-Wei Tseng, Jow-Jyh Huang, Pei-Lun Lee, Hsueh-Chou Lai, Tsai-Yuan Hsieh, Chung-Hsin Chang, Yi-Jie Huang, Fu-Jen Lee, Chun-Chao Chang, Jia-Horng Kao
Journal: Gut (2021)

Objective Data regarding the real-world effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) with or without low-dose ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI) are limited. We evaluated the performance of SOF/VEL with or without low-dose RBV in HCV-infected patients with chronic kidney disease stage 4 or 5. Design 191 patients with compensated (n=181) and decompensated (n=10) liver diseases receiving SOF/VEL (400/100 mg/day) alone and SOF/VEL with low-dose RBV (200 mg/day) for 12 weeks were retrospectively recruited at 15 academic centres in Taiwan. The effectiveness was determined by sustained virological response at off-treatment week 12 (SVR 12 ) in evaluable (EP) and per-protocol populations (PP). The safety profiles were assessed. Results The SVR 12 rates by EP and PP analyses were 94.8% (95% CI 90.6% to 97.1%) and 100% (95% CI 97.9% to 100%). In patients with compensated liver disease, the SVR 12 rates were 95.0% and 100% by EP and PP analyses. In patients with decompensated liver disease, the SVR 12 rates were 90.0% and 100% by EP and PP analyses. Ten patients who failed to achieve SVR 12 were attributed to non-virological failures. Among the 20 serious adverse events (AEs), none were judged related to SOF/VEL or RBV. The AEs occurring in ≥10% included fatigue (14.7%), headache (14.1%), nausea (12.6%), insomnia (12.0%) and pruritus (10.5%). None had ≥grade 3 total bilirubin or alanine aminotransferase elevations. Conclusion SOF/VEL with or without low-dose RBV is effective and well-tolerated in HCV-infected patients with severe RI.