tbuckley/cabot-search huggingface dataset:
Abstract PO020: Approval for the proliferative marker Ki-67 as an integrated biomarker for endometrial cancer in NRG study GY011
Authors: Megan I. Samuelson, Virginia Filiaci, Kelley Carrick, Anand Rajan KD, William H. Rodgers, Kristina W. Thiel, Linda R. Duska, Kimberly K. Leslie
Journal: Clinical Cancer Research (2021)

Abstract Introduction: NRG Study GY011 is a surgical window trial of medroxy-progesterone acetate (MPA) +/- entinostat (E), a histone deacetylase inhibitor hypothesized to upregulate PR levels through epigenetic modifications. The principal goal of this trial was to determine the impact of treatment on the level as well as the activity of progesterone receptors (PR) in women with endometrial cancer. However, a reliable marker for PR activity was needed, and the most promising choice was Ki-67. To be approved for inclusion in the study as an integrated biomarker, Ki-67 had to first undergo rigorous evaluation by the participating pathologists with oversight by the NIH Biomarker Review Committee. Methods: Fifty patients were enrolled on GY011, and specimen collection was planned by biopsy prior to receiving study drugs and by tissue sample at the time of the hysterectomy. There were 42 pre-drug administration specimens with tumor for analysis and 1 without and 43 hysterectomy specimens with tumor. Ki-67 immunohistochemistry performed on pre and post drug specimens was evaluated by three experienced reviewers (MS, KC and AR) using a qualitative approach, blinded to treatment arm. Pre and post-drug samples for each individual patient were compared and scored as increased, decreased, or unchanged. The Fleiss kappa statistic was chosen as the measure of concordance as it allows for more than two reviewers and more than two categories. Percent agreement and standard weighted kappa statistics were calculated for individual pairs of reviewers. Results: There was very good concordance between reviewers using the qualitative comparison of post to pre-drug Ki-67 staining with Fleiss’ Kappa of 0.91 and weighted Kappa’s ranging between 0.85 and 0.95. Reviewers 1 and 2 had the highest level of concordance. Reviewer agreement ranged from 0.92 to 0.98. The reviewer-specific (marginal) score distributions were similar. Each reviewer scored about 80% (79.5%-82.5%) of pairs as decreasing, with the remainder split similarly between no change (7.5%-10%) and increasing (10%-12.8%). Conclusion: Based upon the high concordance between reviewers, the NIH Biomarker Review Committee approved Ki-67 as an integrated biomarker for GY011, setting the stage for its use as an approved biomarker of therapeutic effectiveness in future endometrial cancer trials. Citation Format: Megan I. Samuelson, Virginia Filiaci, Kelley Carrick, Anand Rajan KD, William H. Rodgers, Kristina W. Thiel, Linda R. Duska, Kimberly K. Leslie. Approval for the proliferative marker Ki-67 as an integrated biomarker for endometrial cancer in NRG study GY011 [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO020.
Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties
Authors: Yiting Tang, Xiangyu Wang, Zhaozheng Li, Zhihui He, Xinyu Yang, Xiaoye Cheng, Yue Peng, Qianqian Xue, Yang Bai, Rui Zhang, Kai Zhao, Fang Liang, Xianzhong Xiao, Ulf Andersson, Haichao Wang, Timothy R. Billiar, Ben Lu
Journal: Immunity (2021)
Coevolutionary and Phylogenetic Analysis of Mimiviral Replication Machinery Suggest the Cellular Origin of Mimiviruses
Authors: Supriya Patil, Kiran Kondabagil
Journal: Molecular Biology and Evolution (2021)

Abstract Mimivirus is one of the most complex and largest viruses known. The origin and evolution of Mimivirus and other giant viruses have been a subject of intense study in the last two decades. The two prevailing hypotheses on the origin of Mimivirus and other viruses are the reduction hypothesis, which posits that viruses emerged from modern unicellular organisms; whereas the virus-first hypothesis proposes viruses as relics of precellular forms of life. In this study, to gain insights into the origin of Mimivirus, we have carried out extensive phylogenetic, correlation, and multidimensional scaling analyses of the putative proteins involved in the replication of its 1.2-Mb large genome. Correlation analysis and multidimensional scaling methods were validated using bacteriophage, bacteria, archaea, and eukaryotic replication proteins before applying to Mimivirus. We show that a large fraction of mimiviral replication proteins, including polymerase B, clamp, and clamp loaders are of eukaryotic origin and are coevolving. Although phylogenetic analysis places some components along the lineages of phage and bacteria, we show that all the replication-related genes have been homogenized and are under purifying selection. Collectively our analysis supports the idea that Mimivirus originated from a complex cellular ancestor. We hypothesize that Mimivirus has largely retained complex replication machinery reminiscent of its progenitor while losing most of the other genes related to processes such as metabolism and translation.
Childhood Asthma and Mitochondrial Biomarkers for Exposure-Related Outcomes (CAMERO) study: Time-related Changes in Mitochondrial DNA Copy Number
Authors: Jessica Oh, Janelle Rivera, Jacqueline Jezioro, Lydia Lichtiger, Kyung Jung, Matthew Perzanowski, Elizabeth Matsui, Rachel Miller
Journal: Journal of Allergy and Clinical Immunology (2021)
Association Between Caregiver Strain and Self-Care Among Caregivers With Diabetes
Authors: Alexandra King, Joanna Bryan Ringel, Monika M. Safford, Catherine Riffin, Ronald Adelman, David L. Roth, Madeline R. Sterling
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Caregiver strain has been shown to be associated with adverse effects on caregivers' health, particularly among those with cardiovascular disease. Less is known about the association of caregiver strain with health behaviors among caregivers with diabetes, a disease that requires a high degree of self-care. <h3>Objective</h3> To examine the association between caregiver strain and diabetes self-care among caregivers with diabetes. <h3>Design, Setting, and Participants</h3> This cohort study was conducted between July 13, 2018, and June 25, 2020, using data on 795 US caregivers aged 45 years or older with self-reported diabetes from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which comprised 30 239 Black and White adults 45 years or older throughout the US enrolled from January 2003 to October 2007. <h3>Exposures</h3> Caregiver strain, assessed by self-report in response to the question,<i>"</i>How much of a mental or emotional strain is it to provide this care?<i>"</i>Response options were no strain, some strain, or a lot of (high) strain. <h3>Main Outcomes and Measures</h3> Diabetes self-care, which was assessed across 4 domains (Mediterranean diet adherence, physical activity, smoking status, and medication adherence), and a composite self-care score summing performance across these domains. The association between caregiver strain and diabetes self-care was examined with multivariable Poisson regression adjusting for demographic, clinical, physical and mental functioning, and caregiving covariates. <h3>Results</h3> Among the 795 caregivers with diabetes included in the study, the mean (SD) age was 63.7 (8.6) years, 469 (59.0%) were women, and 452 (56.9%) were Black individuals. Overall, 146 caregivers (18.4%) reported high caregiver strain. In unadjusted models, high caregiver strain was associated with less physical activity (prevalence ratio [PR], 0.66; 95% CI, 0.45-0.97), low medication adherence (PR, 0.80; 95% CI, 0.68-0.94), and worse self-care (PR, 0.65; 95% CI, 0.44-0.98). In adjusted models, the association between some and high caregiving strain with low medication adherence remained significant (adjusted PR: some strain, 0.88 [95% CI, 0.78-0.99]; high strain, 0.83 [95% CI, 0.69-0.99]). <h3>Conclusions and Relevance</h3> In this cohort study of US adult caregivers with diabetes, a high level of strain was associated with low medication adherence. Increased awareness of the prevalence of caregiver strain and potential ramifications on caregivers' self-care appears to be warranted among health care professionals and caregivers.
EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia
Authors: Philipp M. Roessner, Laura Llaó Cid, Ekaterina Lupar, Tobias Roider, Marie Bordas, Christoph Schifflers, Lavinia Arseni, Ann-Christin Gaupel, Fabian Kilpert, Marit Krötschel, Sebastian J. Arnold, Leopold Sellner, Dolors Colomer, Stephan Stilgenbauer, Sascha Dietrich, Peter Lichter, Ana Izcue, Martina Seiffert
Journal: Leukemia (2021)

The transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2-/- mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.
Hypoxia-induced Nur77 activates PI3K/Akt signaling <i>via</i> suppression of Dicer/let-7i-5p to induce epithelial-to-mesenchymal transition
Authors: Zeyu Shi, Sally K Y To, Shuaishuai Zhang, Shan Deng, Margarita Artemenko, Minda Zhang, Juan Tang, Jin-Zhang Zeng, Alice S T Wong
Journal: Theranostics (2021)

Background: Colorectal cancer (CRC) and the associated metastatic lesions are reported to be hypoxic. Hypoxia is a common feature in the tumor microenvironment and a potent stimulant of CRC. We have identified a regulatory role of Nur77 on Akt activation to enhance β-catenin signaling essential for CRC progression under hypoxic conditions. Methods: The functional role of Nur77 in hypoxia-induced EMT was examined by scattering assays to monitor the morphologies of CRC cell lines under 1% O2. Sphere formation assays were performed to investigate whether Nur77 induced cancer stem cell-like properties in hypoxic CRC cells. The expression of various epithelial-to-mesenchymal transition (EMT) and stemness markers was analyzed by qPCR and Western blotting. Finally, Nur77 function and signaling in vivo was ascertained in subcutaneous tumor xenograft or liver metastasis model in nude mice using CRC cells stably transfected with appropriate constructs. Results: Herein, we show, for the first time, that Nur77 is a novel regulator of microRNA biogenesis that may underlie its significant tumor-promoting activities in CRC cells under hypoxia. Mechanistically, Nur77 interacted with the tumor suppressor protein p63, leading to the inhibition of p63-dependent transcription of Dicer, an important miRNA processor and subsequent decrease in the biogenesis of let-7i-5p which targeted the 3'UTR of p110α mRNA and regulated its stability. Knockdown of Nur77 or overexpression of let-7i-5p inhibited the tumor metastasis in vivo. Conclusion: Our data uncovered a novel mechanistic link connecting Nur77, Akt, and invasive properties of CRC in the hypoxic microenvironment.
Efficacy of adjunctive nebulized colistin in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial pneumonia: a multi-centre observational study
Authors: Jia-Yih Feng, Chung-Kan Peng, Chau-Chyun Sheu, Yu-Chao Lin, Ming-Cheng Chan, Sheng-Huei Wang, Chia-Min Chen, Yi-Cheng Shen, Zhe-Rong Zheng, Yi-Tsung Lin, Kuang-Yao Yang
Journal: Clinical Microbiology and Infection (2021)
Abstract 16124: Implantable Cardioverter Defibrillators in Patients With Hereditary Transthyretin Cardiac Amyloidosis
Authors: Sreeram Yalamanchili, Matthew T Brown, Evan A Blank, Melissa A Lyle, Kunal N Bhatt
Journal: Circulation (2020)

Introduction: Implantable cardioverter defibrillator (ICD) implantation in patients with cardiac amyloidosis is controversial, with no clear guidelines for clinical decision-making.. The role of ICD implantation in hereditary Transthyretin Amyloid Cardiomyopathy (hATTR-CM) is unclear. We sought to establish the burden of ventricular arrhythmias and the outcomes of ICD implantation in a single center cohort of hATTR-CM patients. Methods: A total of 69 patients with a confirmed diagnosis of hATTR-CM from genetic testing, and technetium pyrophosphate (PYP) scanning, or endomyocardial biopsy underwent retrospective chart review for demographic, clinical, and arrhythmia data. Results: Seventy-four percent of the cohort was male, with a mean age at diagnosis of 68 (SD=18 years). Sixty-five patients (94.2%) patients were African-American; all of whom carried the Valine 122 Isoleucine mutation. Most had systolic heart failure (New York Heart Association Staging II [18, 26%] and III [40, 58.8%]); 37 (54%) patients had an LVEF ≤ 35%. Thirty-six (52.2%) patients had documented episodes of non-sustained ventricular tachycardia (NSVT), three (4.3%) with ventricular tachycardia (VT), and one (1.5%) with ventricular fibrillation (VF). A total of 15 (21.7%) patients had ICDs placed for prevention of sudden cardiac death in the setting of low LVEF (EF &lt;35%). All recorded VT/VF episodes occurred in three patients with ICDs. Of these patients, one experienced two episodes of VT each successfully abated by antitachycardia pacing (ATP), another experienced a single episode of VT abated by ATP, while the final experienced VF with successful 36J shock as well as two episodes of VT each successfully treated with 36J shocks. No inappropriate ICD shocks were delivered, however, there were two instances of ATP for inappropriately detected atrial arrhythmias. Conclusions: In a cohort of patients with hATTR-CM, we observed a high incidence of NSVT, yet only 41% of patients with severe systolic heart failure had ICDs implanted. A high rate of successful defibrillation and no inappropriate ICD shocks were noted, suggesting that ICDs should be strongly considered, and may be underutilized, in patients with systolic heart failure and/or arrhythmias in the setting of hATTR-CM.
Transgenic expression of secreted/active IL-33 results in type 2 immune responses and eosinophilic esophagitis
Authors: Alfred Doyle, Mia Masuda, Huijun Luo, Rish Pai, Takao Kobayashi, Koji Iijima, Matthew Rank, Hirohito Kita
Journal: Journal of Allergy and Clinical Immunology (2021)
Association Between County-Level Change in Economic Prosperity and Change in Cardiovascular Mortality Among Middle-aged US Adults
Authors: Sameed Ahmed M. Khatana, Atheendar S. Venkataramani, Ashwin S. Nathan, Elias J. Dayoub, Lauren A. Eberly, Dhruv S. Kazi, Robert W. Yeh, Nandita Mitra, S. V. Subramanian, Peter W. Groeneveld
Journal: JAMA (2021)

<h3>Importance</h3> After a decline in cardiovascular mortality for nonelderly US adults, recent stagnation has occurred alongside rising income inequality. Whether this is associated with underlying economic trends is unclear. <h3>Objective</h3> To assess the association between changes in economic prosperity and trends in cardiovascular mortality in middle-aged US adults. <h3>Design, Setting, and Participants</h3> Retrospective analysis of the association between change in 7 markers of economic prosperity in 3123 US counties and county-level cardiovascular mortality among 40- to 64-year-old adults (102 660 852 individuals in 2010). <h3>Exposures</h3> Mean rank for change in 7 markers of economic prosperity between 2 time periods (baseline: 2007-2011 and follow-up: 2012-2016). A higher mean rank indicates a greater relative increase or lower relative decrease in prosperity (range, 5 to 92; mean [SD], 50 [14]). <h3>Main Outcomes and Measures</h3> Mean annual percentage change (APC) in age-adjusted cardiovascular mortality rates. Generalized linear mixed-effects models were used to estimate the additional APC associated with a change in prosperity. <h3>Results</h3> Among 102 660 852 residents aged 40 to 64 years living in these counties in 2010 (51% women), 979 228 cardiovascular deaths occurred between 2010 and 2017. Age-adjusted cardiovascular mortality rates did not change significantly between 2010 and 2017 in counties in the lowest tertile for change in economic prosperity (mean [SD], 114.1 [47.9] to 116.1 [52.7] deaths per 100 000 individuals; APC, 0.2% [95% CI, −0.3% to 0.7%]). Mortality decreased significantly in the intermediate tertile (mean [SD], 104.7 [38.8] to 101.9 [41.5] deaths per 100 000 individuals; APC, −0.4% [95% CI, −0.8% to −0.1%]) and highest tertile for change in prosperity (100.0 [37.9] to 95.1 [39.1] deaths per 100 000 individuals; APC, −0.5% [95% CI, −0.9% to −0.1%]). After accounting for baseline prosperity and demographic and health care–related variables, a 10-point higher mean rank for change in economic prosperity was associated with 0.4% (95% CI, 0.2% to 0.6%) additional decrease in mortality per year. <h3>Conclusions and Relevance</h3> In this retrospective study of US county-level mortality data from 2010 to 2017, a relative increase in county-level economic prosperity was significantly associated with a small relative decrease in cardiovascular mortality among middle-aged adults. Individual-level inferences are limited by the ecological nature of the study.
Abstract 12344: Use of mHealth Tools by Community Health Workers (CHWs) in a Pragmatic Cluster Randomized Trial Improves Access, Coverage, and Treatment of Uninsured People With High Cardiovascular Disease (CVD) Risk in Two Provinces in Argentina
Authors: Andrea Beratarrechea, Shafika Abrahams-Gessel, Vilma Irazola, Laura Gutierrez, Daniela Moyano, Adolfo Rubinstein, Thomas Gaziano
Journal: Circulation (2018)

Introduction: Despite accounting for 33% of Argentina’s deaths, referral and management of persons at high risk for cardiovascular disease (CVD) remains low at government primary care clinics (PCCs...
Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling
Authors: Lisa E. Dorn, William Lawrence, Jennifer M. Petrosino, Xianyao Xu, Thomas J. Hund, Bryan A. Whitson, Matthew S. Stratton, Paul M. L. Janssen, Peter J. Mohler, Anders Schlosser, Grith L. Sorensen, Federica Accornero
Journal: Circulation Research (2021)

Rationale: Cardiac hypertrophy, a major risk factor for heart failure, occurs when cardiomyocytes remodel in response to complex signaling induced by injury or cell stress. Although cardiomyocytes are the ultimate effectors of cardiac hypertrophy, nonmyocyte populations play a large yet understudied role in determining how cardiomyocytes respond to stress. Objective: To identify novel paracrine regulators of cardiomyocyte hypertrophic remodeling. Methods and Results: We have identified a novel role for a nonmyocyte-derived and TGFβ1 (transforming growth factor β1)–induced extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) in the pathophysiology of cardiac remodeling. We have determined that nonmyocyte cells are the primary sources of MFAP4 in the heart in response to TGFβ1 stimulation. Furthermore, we have demonstrated a crucial role of MFAP4 in the cardiac adaptation to stress. Global knockout of MFAP4 led to increased cardiac hypertrophy and worsened cardiac function following chronic pressure overload. Also, one week of angiotensin-mediated neurohumoral stimulation was sufficient to exacerbate cardiomyocyte hypertrophy in MFAP4 null mice. In contrast, administration of exogenous MFAP4 to isolated cardiomyocytes blunted their phenylephrine-induced hypertrophic growth through an integrin-dependent mechanism. Finally, MFAP4 deficiency leads to dysregulated integration of G protein-coupled receptor and integrin signaling in the heart. Conclusions: Altogether, our results demonstrate a critical paracrine role of MFAP4 in the development of cardiac hypertrophy and could inform future treatment options for patients with heart failure.
Dupilumab Improves Health-Related Quality of Life (HRQoL) and Reduces Symptom Burden in Patients with Eosinophilic Esophagitis (EoE): Results From Part A of a Randomized, Placebo-Controlled Three-Part Phase 3 Study
Authors: Evan Dellon, Marc Rothenberg, Ikuo Hirano, Mirna Chehade, Albert J. Bredenoord, Jonathan Spergel, Qiong Zhao, Bethany Beazley, Isabelle Guillemin, Leda Mannent, Elizabeth Laws, Nikhil Amin, Brad Shumel, Jennifer Maloney, Siddhesh Kamat
Journal: Journal of Allergy and Clinical Immunology (2021)
Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease
Authors: Yun Zhang, Lichong Shen, Katja Dreißigacker, Honglin Zhu, Thuong Trinh-Minh, Xianyi Meng, Cuong Tran-Manh, Clara Dees, Alexandru-Emil Matei, Chih-Wei Chen, Markus Ditschkowski, Stefan Krauss, Julia Winkler, Daniel Wolff, Mirjana Ziemer, Andreas Beilhack, Sigrid Karrer, Wolfgang Herr, Andreas Mackensen, Georg Schett, Bernd M. Spriewald, Jörg H. W. Distler
Journal: Blood (2021)
Tenosynovitis has a high sensitivity for early ACPA-positive and ACPA-negative RA: a large cross-sectional MRI study
Authors: Xanthe Marijn Edmée Matthijssen, Fenne Wouters, Navkiran Sidhu, Ellis Niemantsverdriet, Annette van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2021)

Clinically evident tenosynovitis can be seen in established rheumatoid arthritis (RA). Imaging research has recently shown that tenosynovitis at small joints occurs in early RA, contributes to typical RA symptoms (including joint swelling) and is infrequent in healthy controls. Imaging-detectable tenosynovitis is often not recognisable at joint examination, hence its prevalence can therefore be underestimated. We hypothesised that if MRI-detectable tenosynovitis is a true RA feature, the sensitivity for RA is high, in both anti-citrullinated protein antibodies (ACPA)-positive and ACPA-negative RA, and lower in other diseases that are associated with enthesitis (such as spondyloarthritis (SpA) and psoriatic arthritis (PsA)). So far, no large MRI study addressed these questions.Consecutive patients with early arthritis (n=1211) from one healthcare region underwent contrast-enhanced 1.5T MRI of hand and foot at diagnosis. MRIs were scored for synovitis and tenosynovitis by two readers blinded for clinical data. All included patients with ACPA-positive RA (n=250), ACPA-negative RA (n=282), PsA (n=88), peripheral SpA (n=24), reactive arthritis (n=30) and self-limiting undifferentiated arthritis (UA; n=76) were studied. Sensitivity was calculated.The sensitivity of tenosynovitis in RA was 85%; 88% for ACPA-positive RA and 82% for and ACPA-negative RA (p=0.19). The sensitivity for RA was significantly higher than for PsA (65%; p=0.001), SpA (53%; p<0.001), reactive arthritis (36%; p<0.001) and self-limiting UA (42%; p<0.001). The observed sensitivity of MRI synovitis was 91% in RA and ranged from 83% to 54% in other groups.MRI-detected tenosynovitis has a high sensitivity for early ACPA-positive and ACPA-negative RA. This supports that both juxta-articular (tenosynovitis) and intra-articular synovial involvement is characteristic of RA.