tbuckley/cabot-search huggingface dataset:
Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus
Authors: Megan E. Breitbach, Ryne C. Ramaker, Kevin Roberts, Robert P. Kimberly, Devin Absher
Journal: Arthritis & Rheumatology (2019)

Objective To determine the stage of B cell development at which a systemic lupus erythematosus ( SLE )–associated DNA methylation signature originates in African American ( AA ) and European American ( EA ) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations. Methods B cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence‐activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE ‐associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls. Results Regression analysis across all B cell stages resulted in identification of 60 CpGs that reached genome‐wide significance for SLE ‐associated methylation differences ( P ≤ 1.07 × 10 −7 ). Interrogation of ethnicity‐specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon ( IFN )–regulated genes and binding of EBF 1 in AA patients (each P &lt; 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic [ ROC ] area under the curve [ AUC ] 0.98), and when applied to CD 19+ pan–B cells (mean ROC AUC 0.95) and CD 4+ pan–T cells (mean ROC AUC 0.97) from the independent validation cohort. Conclusion These results indicate that SLE ‐specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN ‐regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF 1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE ‐associated epigenetic changes.
Real-World Patterns of First-Line Hydroxyurea Treatment Among Patients with Essential Thrombocythemia in US Community Oncology Practices
Authors: Jingbo Yu, Philomena Colucci, Dilan Chamikara Paranagama, Smitha Sivaraman, Pavel Atanasov, Becky Hanna, Jackson Tang, Shreekant V. Parasuraman
Journal: Blood (2017)
Inhibition of E-Selectin (GMI-1271) or E-selectin together with CXCR4 (GMI-1359) re-sensitizes multiple myeloma to therapy
Authors: Barbara Muz, Feda Azab, Mark Fiala, Justin King, Daniel Kohnen, William E. Fogler, Ted Smith, John L. Magnani, Ravi Vij, Abdel Kareem Azab
Journal: Blood Cancer Journal (2019)
Abstract 19303: A Small Molecular Activator of the ER Proteostasis Regulator, ATF6, is Beneficial in the Ischemic Heart
Authors: Erik A Blackwood, Khalid M Azizi, Jungkang Jin, Lars Plate, Ryan J Paxman, Donna J Thuerauf, Luke Wiseman, Jeff Kelly, Chris C Glembotski
Journal: Circulation (2017)

Rationale: Reactive oxygen species generated during myocardial ischemia/reperfusion (I/R) potentiate myocyte death and cardiac dysfunction. Recently, we found a new, previously unappreciated role f...
AB0025 Study of lymphocyte phenotype in rheumatoid arthritis patients
Authors: IR Kolosova, ER Polosukhina, AY Baryshnikov, GV Loukina, YA Sigidin
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To examine the expression of surface markers on lymphocytes in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Peripheral blood samples were obtained from 36 patients with active RA (mean disease duration 8,8 years, mean age 54,8 years) and 18 normal subjects. The patients were treated with NSAIDs, DMARDs and prednisolone. Fluorescent flow cytometry on FACScan (Becfon Dichinson) was used to assess the expression of CD3, CD4, CD5, CD7, CD8, CD11b, CD16, CD18, CD20, CD25, CD26, CD50, CD54, CD56, CD71, CD95, HLA-DR antigens. <h3>Results</h3> The expression of CD16 antigen on peripheral blood lymphocytes was elevated as compared with healthy volunteers (16,5 ± 1,7% vs 11 ± 1,5%, P = 0,03). The percentage of lymphocytes expressing CD95 antigen was higher in patients treated with NSAIDs (n = 24) as compared with controls (32,9 ± 3,6% vs 25,6 ± 2,9%, P = 0,05). The expression of CD 95 antigen correlated with expression of antigens ÑD26 (r = 0,77), CD71 and CD25 (r = 0,6). <h3>Conclusion</h3> Lymphocyte phenotype in RA patients is characterised by the increased expression of CD16.
Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome
Authors: Julia Richter, Andreas Hüttmann, Jan Rekowski, Christine Schmitz, Selina Gärtner, Andreas Rosenwald, Martin-Leo Hansmann, Sylvia Hartmann, Peter Möller, Hans-Heinrich Wacker, Alfred Feller, Christoph Thorns, Stefan Müller, Ulrich Dührsen, Wolfram Klapper
Journal: Blood Cancer Journal (2019)
Association of Severe Hyperoxemia Events and Mortality Among Patients Admitted to a Pediatric Intensive Care Unit
Authors: Sriram Ramgopal, Cameron Dezfulian, Robert W. Hickey, Alicia K. Au, Shekhar Venkataraman, Robert S. B. Clark, Christopher M. Horvat
Journal: JAMA Network Open (2019)

<h3>Importance</h3> A high Pao<sub>2</sub>, termed hyperoxemia, is postulated to have deleterious health outcomes. To date, the association between hyperoxemia during the ongoing management of critical illness and mortality has been incompletely evaluated in children. <h3>Objective</h3> To examine whether severe hyperoxemia events are associated with mortality among patients admitted to a pediatric intensive care unit (PICU). <h3>Design, Setting, and Participants</h3> A retrospective cohort study was conducted over a 10-year period (January 1, 2009, to December 31, 2018); all 23 719 PICU encounters at a quaternary children’s hospital with a documented arterial blood gas measurement were evaluated. <h3>Exposures</h3> Severe hyperoxemia, defined as Pao<sub>2</sub>level greater than or equal to 300 mm Hg (40 kPa). <h3>Main Outcomes and Measures</h3> The highest Pao<sub>2</sub>values during hospitalization were dichotomized according to the definition of severe hyperoxemia and assessed for association with in-hospital mortality using logistic regression models incorporating a calibrated measure of multiple organ dysfunction, extracorporeal life support, and the total number of arterial blood gas measurements obtained during an encounter. <h3>Results</h3> Of 23 719 PICU encounters during the inclusion period, 6250 patients (13 422 [56.6%] boys; mean [SD] age, 7.5 [6.6] years) had at least 1 measured Pao<sub>2</sub>value. Severe hyperoxemia was independently associated with in-hospital mortality (adjusted odds ratio [aOR], 1.78; 95% CI, 1.36-2.33;<i>P</i> &lt; .001). Increasing odds of in-hospital mortality were observed with 1 (aOR, 1.47; 95% CI, 1.05-2.08;<i>P</i> = .03), 2 (aOR, 2.01; 95% CI, 1.27-3.18;<i>P</i> = .002), and 3 or more (aOR, 2.53; 95% CI, 1.62-3.94;<i>P</i> &lt; .001) severely hyperoxemic Pao<sub>2</sub>values obtained greater than or equal to 3 hours apart from one another compared with encounters without hyperoxemia. A sensitivity analysis examining the hypothetical outcomes of residual confounding indicated that an unmeasured binary confounder with an aOR of 2 would have to be present in 37% of the encounters with severe hyperoxemia and 0% of the remaining cohort to fail to reject the null hypothesis (aOR of severe hyperoxemia, 1.31; 95% CI, 0.99-1.72). <h3>Conclusions and Relevance</h3> Greater numbers of severe hyperoxemia events appeared to be associated with increased mortality in this large, diverse cohort of critically ill children, supporting a possible exposure-response association between severe hyperoxemia and outcome in this population. Although further prospective evaluation appears to be warranted, this study’s findings suggest that guidelines for ongoing management of critically ill children should take into consideration the possible detrimental effects of severe hyperoxemia.
Automatic Neuroimage Processing and Analysis in Stroke—A Systematic Review
Authors: Roger M. Sarmento, Francisco F. Ximenes Vasconcelos, Pedro P. Reboucas Filho, Wanqing Wu, Victor Hugo C. de Albuquerque
Journal: IEEE Reviews in Biomedical Engineering (2019)

This article presents a systematic review of the current computational technologies applied to medical images for the detection, segmentation, and classification of strokes. Besides, analyzing and evaluating the technological advances, the challenges to be overcome and the future trends are discussed. The principal approaches make use of artificial intelligence, digital image processing and analysis, and various other technologies to develop computer-aided diagnosis (CAD) systems to improve the accuracy in the diagnostic process, as well as the interpretation consistency of medical images. However, there are some points that require greater attention such as low sensitivity, optimization of the algorithm, a reduction of false positives, and improvement in the identification and segmentation processes of different sizes and shapes. Also, there is a need to improve the classification steps of different stroke types and subtypes. Furthermore, there is an additional need for further research to improve the current techniques and develop new algorithms to overcome disadvantages identified here. The main focus of this research is to analyze the applied technologies for the development of CAD systems and verify how effective they are for stroke detection, segmentation, and classification. The main contributions of this review are that it analyzes only up-to-date studies, mainly from 2015 to 2018, as well as organizing the various studies in the area according to the research proposal, i.e., detection, segmentation, and classification of the types of stroke and the respective techniques used. Thus, the review has great relevance for future research, since it presents an ample comparison of the most recent works in the area, clearly showing the existing difficulties and the models that have been proposed to overcome such difficulties.
Desire for and use of genetic testing in a population-based sample of breast cancer patients.
Authors: Sarah T. Hawley, Ann S. Hamilton, John Graff, Steven J. Katz, Reshma Jagsi
Journal: Journal of Clinical Oncology (2013)

6615 Background: Prior research suggests that receipt of genetic testing to assess risk of disease in patients or their families is not limited to those who meet high-risk criteria (i.e., diagnosed at young age &amp;/or with strong family history). There is little research from large population-based samples describing patterns and correlates of genetic testing receipt or reasons why patients undergo testing. Methods: We surveyed 2290 women newly diagnosed with breast cancer reported to the Detroit &amp; Los Angeles SEER registries from 6/05-2/07. We merged these data to SEER and re-surveyed them again approximately 4 years later (n=1536). The primary outcomes were patient reports of a strong desire for genetic testing, participation in a discussion about genetic testing, and receipt of genetic testing. We also evaluated patient reports of reasons for getting tested. We compared dependent and independent factors using chi-square tests and used logistic regression to evaluate correlates of each outcome. Results: One third (33.9%) reported a strong desire to be tested, of whom 54% discussed testing with a health professional, &amp; 46% were tested. A strong desire to be tested was associated with younger age (F=32.03, P&lt;0.001), minority race (F=62.5, P&lt;0.001), family history of breast &amp;/or ovarian cancer (F=18.5, P&lt;0.001) and worry about recurrence (OR: 1.8; 95% CI: 1.3-2.6). Overall, 19.3% were tested. Test receipt was significantly associated with younger age (F=26.8, P&lt;0.001), higher education (OR: 1.8; 95% CI:1.13-2.71), and family history (F=25.1, P&lt;0.001). Of those tested, reasons included: physician recommendation (61.8%), wanting more information about one’s own health (51.8%), wanting more information for family (54.2%), and family desire (13.6%). 7.8% of those not tested indicated it was because of the expense. Conclusions: Many women have a strong desire for genetic testing after diagnosis of breast cancer but often do not discuss testing with professionals. Desire for testing was correlated with pertinent clinical factors but also non-clinical factors such as minority race and worry about recurrence. Results suggest the continued need to address patient desire for testing and selection of appropriate patients for testing.
T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia
Authors: Simo Xia, Xiang Liu, Xuetao Cao, Sheng Xu
Journal: Cellular and Molecular Immunology (2019)

Abstract The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.
Abstract 395: A Synonymous Coding SNP Alters SCN5A Regulation by miR-24 and Associates With Non-Arrhythmic Death in Heart Failure
Authors: Xiaoming Zhang, Jin-Young Yoon, Michael Morley, Patrick Breheny, Heather Bloom, Samuel Dudley, Patrick Ellinor, Kenneth Margulies, Barry London, Ryan L Boudreau
Journal: Circulation Research (2017)

Mutations disrupting SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and SNPs linked to SCN5A splicing, localization and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. Recently, we generated a transcriptome-wide map of microRNA (miR) binding sites in human heart and evaluated their interface with polymorphisms. Among &gt;500 common SNPs residing within miR target regions, we identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within SCN5A coding sequence. This SNP is known to reproducibly associate with heart rhythm measurements, but is not considered to be “causal”. Here, we show that miR-24 potently suppresses SCN5A and that rs1805126 modulates this regulation. In further exploring the clinical significance of this, we found that rs1805126 minor allele homozygosity associates with decreased cardiac SCN5A expression and increased mortality in heart failure patients. Unexpectedly, this risk was not linked with arrhythmic sudden cardiac death, but rather, with clinical signs of worsening heart failure (e.g. reduced ejection fraction) and myocardial gene expression changes related to bioenergetics, inflammation and extracellular remodeling. Together, these data attribute a molecular mechanism to this firmly-established GWAS SNP and highlight a novel and surprising link between common variations in SCN5A expression and non-arrhythmic death in heart failure.
Health Insurance for Diabetes Prevention Confers Health Benefits and Breaks Even on Cost Within 2 Years
Authors: Mary Beth Weber, K.M. Venkat Narayan
Journal: Diabetes Care (2019)

Diabetes and its predecessor prediabetes are huge and costly problems in the U.S., affecting 24.7 (1) and 84.1 million people (2), respectively. Treatment of prevalent diabetes is a leading contributor of rising U.S. health care costs (3), and the cost of treating prediabetes, diabetes, and gestational diabetes mellitus combined is $404 billion (4). Fortunately, there is strong evidence for prevention, or at least delay, of type 2 diabetes in high-risk individuals, especially those with impaired glucose tolerance (IGT), through lifestyle education programs, interventions that have been shown to be effective, cost-effective, and translatable in real-life settings (5–8). The challenge lies in scaling the implementation of proven programs like the U.S. Diabetes Prevention Program (DPP) at the community level with effective, easy, and low-cost ways to reach at-risk individuals and enroll, engage, and keep them in programs like the National DPP (9).

In their article in this issue of Diabetes Care , Ackermann et al. (10) evaluated the costs and financial implications for commercial health care insurers offering reimbursements for the National DPP available at YMCAs, the YDPP. They report impressive results: the YDPP program had no effects on net health care costs at 2 years, with no difference between the mean per-person health expenditures between YDPP participants and matched control subjects. In addition, the authors report on the efficacy of workplace screening for identifying individuals with prediabetes for YDPP enrollment. They found that worksite screening, using the undescribed protocols set up by the individual worksites, were only able to identify 9.7% of the estimated …
BCL-6 suppresses miR-142-3p/5p expression in SLE CD4+ T cells by modulating histone methylation and acetylation of the miR-142 promoter
Authors: Shu Ding, Qing Zhang, Shuangyan Luo, Lihua Gao, Jinhua Huang, Jianyun Lu, Jing Chen, Qinghai Zeng, Aiyuan Guo, Jinrong Zeng, Qianjin Lu
Journal: Cellular and Molecular Immunology (2019)

The reduced expression of miR-142-3p/5p in CD4+ T cells of SLE patients caused T cell hyperactivity and B cell hyperstimulation. This study aimed to investigate the mechanisms of regulating miR-142-3p/5p expression in SLE CD4+ T cells. The BCL-6 expression was significantly increased in SLE CD4+ T cells compared with normal controls, and the BCL-6 expression was inversely correlated with miR-142-3p/5p expression. BCL-6 suppresses the expression of miR-142-3p/5p by increasing H3K27me3 level and reducing H3K9/K14ac levels in SLE CD4+ T cells. BCL-6 regulates histone modifications in miR-142 promoter by recruiting EZH2 and HDAC5. Furthermore, we observed significantly decreased CD40L, ICOS, and IL-21 expression levels in SLE CD4+ T cells with BCL-6 interference, and obviously reduced autoantibody IgG production in autologous B cells co-cultured with BCL-6 inhibited SLE CD4+ T cells. Our study found that increased BCL-6 up-regulates H3K27me3 and down-regulates H3K9/14ac at miR-142 promoter in SLE CD4+ T cells. These factors induce a declination in miR-142-3p/5p expression, consequently resulting in CD4+ T cell hyperactivity.
Thromboembolic Risk After Atriopulmonary, Lateral Tunnel, and Extracardiac Conduit Fontan Surgery
Authors: Catherine Deshaies, Robert M. Hamilton, Azadeh Shohoudi, Helen Trottier, Nancy Poirier, Jamil Aboulhosn, Craig S. Broberg, Scott Cohen, Stephen Cook, Annie Dore, Susan M. Fernandes, Anne Fournier, Joseph Kay, Blandine Mondésert, François-Pierre Mongeon, Alexander R. Opotowsky, Anna Proietti, Jennifer Ting, Ali Zaidi, Paul Khairy
Journal: Journal of the American College of Cardiology (2019)
Said the glucose sensor to the insulin pump: can glycemic control be improved in hospitalized ESRD patients with diabetes mellitus?
Authors: Mark E. Williams
Journal: Kidney International (2019)

Although control of chronic glycemia in the population with diabetes and end-stage renal disease (ESRD) has been extensively studied in recent years, the unique problems of short-term glycemic management in acutely ill patients undergoing dialysis have received little attention. Bally et al. evaluated the role of a "closed-loop" (glucose sensor/algorithm tablet device/insulin pump) system in a cohort of hospitalized patients with type 2 diabetes receiving hemodialysis. Compared with usual care, the intervention group had superior glycemic control without increased hypoglycemic events. Additional studies are warranted.
Rapid Response to Pembrolizumab in a Critically Ill Mechanically Ventilated Patient with New Diagnosis of NSCLC
Authors: Erin M. McLoughlin, James M. Larner, Michael P. Bergman, Edward B. Stelow, Kevin Brady, Alia C. Lynch, Ralph S. Abraham, Ryan D. Gentzler
Journal: Journal of Thoracic Oncology (2019)
Monitoring Adherence to Inhaled Medications
Authors: Ginelle A. Bryant, Eliza A. Dy-Boarman, Lynn E. Kassel
Journal: JAMA (2019)

To the Editor Drs Hew and Reddel1 highlighted the importance of adherence to inhaled controller medications in the treatment of chronic respiratory conditions. Some of their claims regarding adherence monitoring systems for inhalers lacked a balanced perspective.
Addressing the Rising Prices of Disease-Modifying Therapies for Multiple Sclerosis
Authors: Daniel M. Hartung, Dennis Bourdette
Journal: JAMA Neurology (2019)

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Studying Cancer Evolution and Therapeutic Responses in Different Organs: The Pros and Cons of a Broad Focus
Authors: Catherine Pham-Danis, James DeGregori
Journal: Cancer Research (2019)

Cellular adaptation brought upon by insults such as old age and therapeutic exposure is a complex phenomenon in which cells undergo adaptive phenotypic changes. Our lab has focused on understanding the mechanisms underlying adaptation during the evolution of cancer, from the early stages of development to the ability of cancer cells to escape therapeutic challenges. Our studies span hematopoietic and lung systems. Herein, we discuss the advantages and disadvantages involved in studying two vastly different organ systems. Through the use of these organ/cancer model systems, we hope to develop interventions to limit oncogenic adaptation leading to cancer development and to prevent adaptation of cancers following treatment leading to cancer relapse.