tbuckley/cabot-search huggingface dataset:
Prevalence of hospital PCR-confirmed COVID-19 cases in patients with chronic inflammatory and autoimmune rheumatic diseases
Authors: Jose L Pablos, Lydia Abasolo, Jose M Alvaro-Gracia, Francisco J Blanco, Ricardo Blanco, Isabel Castrejón, David Fernandez-Fernandez, Benjamín Fernandez-Gutierrez, María Galindo-Izquierdo, Miguel A Gonzalez-Gay, Sara Manrique-Arija, Natalia Mena Vázquez, Antonio Mera Varela, Miriam Retuerto, Alvaro Seijas-Lopez
Journal: Annals of the Rheumatic Diseases (2020)

Background The susceptibility of patients with rheumatic diseases and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown. Methods We performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with severe acute respiratory syndrome coronavirus 2-positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups. Results Patients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Patients with systemic autoimmune or immune-mediated disease (AI/IMID) showed a significant increase, whereas patients with inflammatory arthritis (IA) or systemic lupus erythematosus did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. Patients with IA on targeted-synthetic or biological disease-modifying antirheumatic drugs (DMARDs), but not those on conventional-synthetic DMARDs, had a greater prevalence despite a similar age distribution. Conclusion Patients with AI/IMID show a variable risk of hospital-diagnosed COVID-19. Interplay of ageing, therapies and disease-specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyse the specific factors involved in COVID-19 susceptibility.
The Impact of COVID-19 on Cardiovascular Training Programs
Authors: Gaby Weissman, James A. Arrighi, Naomi F. Botkin, Julie B. Damp, Friederike K. Keating, Venu Menon, Lisa J. Rose-Jones, Harsimran S. Singh, Victor Soukoulis, Andrew M. Kates
Journal: Journal of the American College of Cardiology (2020)
Morphea-like skin lesions reported in the phase 3 Long-Term Odanacatib Fracture Trial (LOFT) in postmenopausal women with osteoporosis
Authors: Kenneth G. Saag, Tobias J. de Villiers, Peter Alexandersen, Heidi Jacobe, Carrie Kovarik, Victoria P. Werth, Albert Leung, Avani Desai-Merchant, Julie Mattaliano, Deborah Gurner
Journal: Journal of the American Academy of Dermatology (2020)
z‐Wire: A Microscaffold That Supports Guided Tissue Assembly and Intramyocardium Delivery for Cardiac Repair
Authors: Luis Eduardo Portillo‐Esquivel, Vibudha Nanduri, Feng Zhang, Wenbin Liang, Boyang Zhang
Journal: Advanced Healthcare Materials (2020)

Abstract Tissue engineering holds promise to replace damaged tissues for repair of vital organs in the human body. In cardiac repairs specifically, approaches are developed for intramyocardial delivery of cells and the epicardial delivery of tissue‐engineered cardiac patches, providing benefit of cell localization and tissue structure, respectively. However, to improve cell retention and integration, there is a need for the intramyocardial delivery of functional tissues while preserving anisotropic muscle alignment. Here, a biodegradable z‐wire scaffold that supports the scalable gel‐free production of an array of functional cardiac tissues in a 384‐well plate format is developed. The z‐wire scaffold design supports cellular alignment, provides tunable mechanical support, and allows for tissue contraction. When the scaffold is imparted with magnetic properties, individual tissues can be assembled with macroscopic alignment under magnetic guidance. When used in combination with a customized surgical delivery tool, z‐wire tissues can be injected directly into the myocardial wall, with controlled tissue orientation according to the injection path. This modular tissue engineering approach, in combination with the use of smart scaffolds, can expand opportunity in functional tissue delivery.
<i>ESR1</i> Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
Authors: Nicholas C. Turner, Claire Swift, Lucy Kilburn, Charlotte Fribbens, Matthew Beaney, Isaac Garcia-Murillas, Aman U. Budzar, John F.R. Robertson, William Gradishar, Martine Piccart, Gaia Schiavon, Judith M. Bliss, Mitch Dowsett, Stephen R.D. Johnston, Stephen K. Chia
Journal: Clinical Cancer Research (2020)

Abstract Purpose: ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. Experimental Design: The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. Results: ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69). Conclusions: Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
Risk of infections in patients with myeloproliferative neoplasms—a population-based cohort study of 8363 patients
Authors: Anna Ravn Landtblom, Therese M-L Andersson, Paul W Dickman, Karin E Smedby, Sandra Eloranta, Nurgul Batyrbekova, Jan Samuelsson, Magnus Björkholm, Malin Hultcrantz
Journal: Leukemia (2020)
Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies
Authors: Michael Byrne, William Donnellan, Manish R Patel, Amer M. Zeidan, Mohamad Cherry, Maria R. Baer, Amir T. Fathi, Jason Kaplan, Feng Zhou, Fred Zheng, April M. Barbour, Michael R. Savona
Journal: Blood (2017)
A Patient-Level Model to Estimate Lifetime Health Outcomes of Patients With Type 1 Diabetes
Authors: An Tran-Duy, Josh Knight, Andrew J. Palmer, Dennis Petrie, Tom W.C. Lung, William H. Herman, Björn Eliasson, Ann-Marie Svensson, Philip M. Clarke
Journal: Diabetes Care (2020)

OBJECTIVE To develop a patient-level simulation model for predicting lifetime health outcomes of patients with type 1 diabetes and as a tool for economic evaluation of type 1 diabetes treatment based on data from a large, longitudinal cohort. RESEARCH DESIGN AND METHODS Data for model development were obtained from the Swedish National Diabetes Register. We derived parametric proportional hazards models predicting the absolute risk of diabetes complications and death based on a wide range of clinical variables and history of complications. We used linear regression models to predict risk factor progression. Internal validation was performed, estimates of life expectancies for different age-sex strata were computed, and the impact of key risk factors on life expectancy was assessed. RESULTS The study population consisted of 27,841 patients with type 1 diabetes with a mean duration of follow-up of 7 years. Internal validation showed good agreement between the predicted and observed cumulative incidence of death and 10 complications. Simulated life expectancy was ∼13 years lower than that of the sex- and age-matched general population, and patients with type 1 diabetes could expect to live with one or more complications for ∼40% of their remaining life. Sensitivity analysis showed the importance of preventing renal dysfunction, hypoglycemia, and hyperglycemia as well as lowering HbA1c in reducing the risk of complications and death. CONCLUSIONS Our model was able to simulate risk factor progression and event histories that closely match the observed outcomes and to project events occurring over patients’ lifetimes. The model can serve as a tool to estimate the impact of changing clinical risk factors on health outcomes to inform economic evaluations of interventions in type 1 diabetes.
Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis
Authors: Iago Pinal-Fernandez, Maria Casal-Dominguez, Assia Derfoul, Katherine Pak, Frederick W Miller, Jose César Milisenda, Josep Maria Grau-Junyent, Albert Selva-O'Callaghan, Carme Carrion-Ribas, Julie J Paik, Jemima Albayda, Lisa Christopher-Stine, Thomas E Lloyd, Andrea M Corse, Andrew L Mammen
Journal: Annals of the Rheumatic Diseases (2020)

Objectives Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. Methods RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. Results The support vector machine learning algorithm classified the muscle biopsies with &gt;90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. Conclusions Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.
Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model
Authors: Shashank R. Ganatra, Allison N. Bucşan, Xavier Alvarez, Shyamesh Kumar, Ayan Chatterjee, Melanie Quezada, Abigail Fish, Dhiraj K. Singh, Bindu Singh, Riti Sharan, Tae-Hyung Lee, Uma Shanmugasundaram, Vijayakumar Velu, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal
Journal: Journal of Clinical Investigation (2020)

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4+ T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4+ T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.
Associations of Air Pollution and Noise with Local Brain Structure in a Cohort of Older Adults
Authors: René Nußbaum, Sarah Lucht, Christiane Jockwitz, Susanne Moebus, Miriam Engel, Karl-Heinz Jöckel, Svenja Caspers, Barbara Hoffmann
Journal: Environmental Health Perspectives (2020)

Background: Despite the importance of understanding associations of air pollution and noise exposure with loss of neurocognitive performance, studies investigating these exposures and local brain structure are limited. Objective: We estimated associations of residential air pollution and noise exposures with neurocognitive test performance and the local gyrification index (lGI), a marker for local brain atrophy, among older adults. Methods: For n=615 participants from the population-based 1000BRAINS study, based on the German Heinz Nixdorf Recall study, we assessed residential exposures to particulate matter (PM10, PM2.5, PM2.5abs), accumulation mode particle number (PNAM), and nitrogen oxides (NOx, NO2), using land-use regression and chemistry transport models. Weighted 24-h and nighttime noise were modeled according to the European noise directive. We evaluated associations of air pollution and noise exposure at the participants' 2006–2008 residential addresses with neurocognitive test performance and region-specific lGI values (n=590) from magnetic resonance imaging, both assessed in 2011–2015, using linear regression and adjusting for demographic and personal characteristics. Results: Air pollution and noise were associated with language and short-term/working memory and with local atrophy of the fronto–parietal network (FPN), a functional resting-state network associated with these cognitive processes. For example, per 2-μg/m3 PM10, local brain atrophy was more pronounced in the posterior brain regions of the FPN, with a −0.02 [95% confidence interval (CI): −0.04, 0.00] lower lGI. In contrast, in the anterior regions of the FPN, weighted 24-h and nighttime noise were associated with less local brain atrophy [e.g., 0.02 (95% CI: 0.00, 0.04) for 10 dB(A) 24-h noise]. Conclusions: Air pollution and noise exposures were associated in opposite directions with markers of local atrophy of the FPN in the right brain hemisphere in older adults, suggesting that both chronic air pollution and noise exposure may influence the physiological aging process of the brain. https://doi.org/10.1289/EHP5859
An ultralow dose of the NADPH oxidase inhibitor diphenyleneiodonium (DPI) is an economical and effective therapeutic agent for the treatment of colitis-associated colorectal cancer
Authors: Yue Kuai, Hao Liu, Dongyu Liu, Yunlong Liu, Ye Sun, Jiansheng Xie, Jiachun Sun, Yong Fang, Hongming Pan, Weidong Han
Journal: Theranostics (2020)

Long-term inflammatory stimulation is considered one of the most important causes of colorectal cancer.Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, can inhibit a variety of inflammatory responses.However, the systemic toxicity of DPI limits its clinical application.Whether DPI can inhibit colitis-associated colorectal cancer (CAC) at ultralow concentrations remains unknown.Methods: CAC was induced by azoxymethane (AOM) injection followed by treatment with dextran sulfate sodium (DSS), and DPI was intraperitoneally injected (i.p.) in the first cycle for 21 days.Colon tissue was collected and analyzed by western blotting.Immune cell infiltration and macrophage polarization were examined by immunohistochemistry, immunofluorescence, or real-time polymerase-chain reaction (PCR).Reactive oxygen species (ROS) production was measured by flow cytometry.Results: Ultralow dose DPI significantly ameliorated the DSS-induced colitis and attenuated the colon tumorigenesis in the mouse model of AOM/ DSS-induced CAC.Mechanistically, an ultralow dose of DPI inhibited the production of pro-inflammatory cytokines, (tumor necrosis factor (TNF)-α and interleukin (IL)-6), reduced the macrophage infiltration and classical polarization, and induced the ROS generation.These effects were found to be related to the inhibition of the phosphorylation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF -κB). Conclusion:The present study revealed that an ultralow dose of DPI, with no significant systemic toxicity involved, may be an effective way to prevent the occurrence and development of CAC.
MYBPC3 Mutations Cause Hypertrophic Cardiomyopathy by Dysregulating Myosin: Implications for Therapy
Authors: C N Toepfer, H Wakimoto, A C Garfinkel, B McDonough, D Liao, J Jiang, A Tai, J Gorham, I G Lund, M Lun, T L Lynch, S Sadayappan, C S Redwood, H Watkins, J Seidman, C Seidman
Journal: Circulation Research (2018)
Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options
Authors: Wolfgang Löscher, Heidrun Potschka, Sanjay M. Sisodiya, Annamaria Vezzani
Journal: Pharmacological Reviews (2020)

Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. <h3>Significance Statement</h3> Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.
Immune profiling of pediatric solid tumors
Authors: Rachael L. Terry, Deborah Meyran, David S. Ziegler, Michelle Haber, Paul G. Ekert, Joseph A. Trapani, Paul J. Neeson
Journal: Journal of Clinical Investigation (2020)

Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably.
Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction
Authors: Lin Liu, Chenyun Ding, Tingting Fu, Zhenhua Feng, Ji-Eun Lee, Liwei Xiao, Zhisheng Xu, Yujing Yin, Qiqi Guo, Zongchao Sun, Wanping Sun, Yan Mao, Likun Yang, Zheng Zhou, Danxia Zhou, Leilei Xu, Zezhang Zhu, Yong Qiu, Kai Ge, Zhenji Gan
Journal: Journal of Clinical Investigation (2020)

Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.