tbuckley/cabot-search huggingface dataset:
Abstract 780: Duchenne Muscular Dystrophy Cardiac Exosomes Contribute to the Pathogenesis of Dystrophin-deficient Cardiomyopathy
Authors: Melanie Gartz, Zeeshan Afzal, Jennifer L Strande
Journal: Circulation Research (2019)

Introduction: Cardiomyopathy is a devastating consequence of Duchenne muscular dystrophy (DMD) and its pathogenesis is not well known. Exosomes (exos) are small, secreted vesicles with the ability to exert paracrine effects in target cells by transfer of their molecular cargo. This cargo can be dysregulated in disease and may contribute to pathogenesis. Duchenne muscular dystrophy exos in skeletal muscle promoted pathology, but whether exos are pathological in the DMD heart is unclear. We hypothesize that exposure to DMD cardiac exos promotes pathogenesis and their inhibition will protect against cardiomyocyte injury. To investigate, we used DMD iPSC-derived cardiomyocytes (iCM) and mdx mouse models of DMD. Methods/Results: In vitro, 2 non-affected (N), 2 patient-derived DMD and 1 gene-edited DMD iCMs were exposed to either exos isolated from N- or DMD-iCMs for 48 hr, or to GW4869, an exo inhibitor for 24 hr, followed by 1 hr stress (100 μM H 2 O 2 in 10 mM deoxyglucose in RPMI - glucose) and 4 hr recovery (RPMI + glucose) and stained with either DHE, TMRE and propidium iodide to assess ROS levels, mitochondrial membrane potential (Δψm) and cell death, respectively. Stress increased ROS levels in all 3 DMD-iCMs from 413-1102AU to 955-2008AU, which was diminished with N-exo (346-1061AU) but not DMD-exo (882-1995AU). Stress caused Δψm loss in DMD-iCM from 4049-4082AU to 439-1315AU, and N-exo (1917-2867AU) but not DMD-exo (870-1586AU) were protective. Stress increased cell death in DMD-iCM from 3-10% to 30-45% which was decreased with N-exo (10-21%) but not DMD-exo (26-46%). GW4869 decreased ROS levels from 955-2008AU to 344-528AU , cell death from 30-45% to 6-28% and partially rescued Δψm from 439-1315AU to 1947-3842AU in DMD-iCM. In mdx mice, GW4869 reduced isoproterenol induced cardiac injury ( GW+Iso: 3±2% vs. Veh+Iso: 13±3% ). Conclusions: In vitro , unlike N-exo, DMD-exo exposure failed to protect DMD-iCM from stress. Inhibiting DMD-exo with GW4869 protected DMD-iCM against cell stress and reduced mdx cardiac isoproterenol-induced injury. Together, these data suggest that DMD-exo may dysregulate the DMD cardiomyocyte response to stress thereby contributing to injury. Furthermore, exosome reduction may be a strategy for the treatment of DMD cardiomyopathy .
Unplugging the Pipeline — A Call for Term Limits in Academic Medicine
Authors: Whitney H. Beeler, Christina Mangurian, Reshma Jagsi
Journal: New England Journal of Medicine (2019)

Several explanations have been proposed for the "leaky pipeline" of women and underrepresented minorities in academic medicine. One factor that has yet to garner attention is the lack of term limits for senior leaders, whose numbers remain disproportionately white and male.
Self-reported patient barriers and the impact of digital health coaching on PRO in cancer.
Authors: Matthew Allison, Stephen Burton, Dhiren Patel, Kelly Jean Brassil
Journal: Journal of Clinical Oncology (2019)

189 Background: Barriers during cancer care include lack of social support, financial concerns, and communication with providers. While navigation has been identified as a way to address these concerns in the clinical context, opportunities exist to identify and address patient-reported barriers through digital health coaching to support patients beyond the clinical care setting. Methods: A retrospective analysis evaluated patient-reported barriers during cancer care for 708 individuals over the course of a digital health coaching program. Barriers were assessed in six domains, each represented by 5-10 questions in a company developed survey. The questions were administered prior to coaching on content aligned to the domains, specifically eating healthy, exercise, financial, access to care and medication adherence. Patients ranked both the presence and severity of the barrier. Patient reported outcomes such as exercise (Godin), health eating (Start the Conversation), financial toxicity (Comprehensive Score for Financial Toxicity (COST)) and physiologic and psychosocial outcomes (Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) 10) were measured and aligned to the barrier domains identified by the participants. Results: The eating healthy domain (2.43) received a significantly higher average score compared to other domains: financial (1.86), exercise (1.71), medication adherence (1.68) and access to care (1.65). Over the 12-week coaching program, physical activity increased by 56%, fatigue was reduced by 32%, financial toxicity was reduced by 8%, the healthy eating score improved by 17% and pain was reduced by 13%, as reflected in the PROMIS GH-10, Godin, STC and COST data. Conclusions: Outcomes suggest that healthy eating is a significant barrier identified by cancer patients during their treatment, followed by financial concerns and exercise, each of which demonstrated improvement over the course of digital health coaching. These results suggest digital health coaching provides a benefit to addressing barriers during cancer treatment and may improve patient reported outcomes, particularly as they relate to wellness behaviors such as healthy eating and exercise.
Treatment Outcomes in Monoclonal Immunoglobulin Deposition Disease (MIDD): A Two Center Experience
Authors: Matthew J. Pianko, Timothy Tiutan, Jessica Flynn, Sean M Devlin, Insara Jaffer-Sathick, Adriana C. Rossi, Steven P. Salvatore, Heather J. Landau, Nikoletta Lendvai, Eric L. Smith, Neha Korde, Sham Mailankody, Alexander M. Lesokhin, Malin Hultcrantz, David J. Chung, Sergio Giralt, Ola Landgren, Hani Hassoun
Journal: Blood (2018)
Human and Nonhuman Primate Lineage-Specific Footprints in the Salivary Proteome
Authors: Supaporn Thamadilok, Kyoung-Soo Choi, Lorenz Ruhl, Fabian Schulte, A Latif Kazim, Markus Hardt, Omer Gokcumen, Stefan Ruhl
Journal: Molecular Biology and Evolution (2019)

Proteins in saliva are needed for preprocessing food in the mouth, maintenance of tooth mineralization, and protection from microbial pathogens. Novel insights into human lineage-specific functions of salivary proteins and clues to their involvement in human disease can be gained through evolutionary studies, as recently shown for salivary amylase AMY1 and salivary agglutinin DMBT1/gp340. However, the entirety of proteins in saliva, the salivary proteome, has not yet been investigated from an evolutionary perspective. Here, we compared the proteomes of human saliva and the saliva of our closest extant evolutionary relatives, chimpanzees and gorillas, using macaques as an outgroup, with the aim to uncover features in saliva protein composition that are unique to each species. We found that humans produce a waterier saliva, containing less than half total protein than great apes and Old World monkeys. For all major salivary proteins in humans, we could identify counterparts in chimpanzee and gorilla saliva. However, we discovered unique protein profiles in saliva of humans that were distinct from those of nonhuman primates. These findings open up the possibility that dietary differences and pathogenic pressures may have shaped a distinct salivary proteome in the human lineage.
Flow-Dependent Functions Of Soluble Or Immobilized Tissue Factor In Mural Thrombus Formation Mediated By Von Willebrand Factor
Authors: Yasunori Matsunari, Masaaki Doi, Hideto Matsui, Kenji Nishio, Hitoshi Furuya, Masahiko Kawaguchi, Mitsuhiko Sugimoto
Journal: Blood (2013)
Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study
Authors: Jan A. Burger, Paul M. Barr, Tadeusz Robak, Carolyn Owen, Paolo Ghia, Alessandra Tedeschi, Osnat Bairey, Peter Hillmen, Steven E. Coutre, Stephen Devereux, Sebastian Grosicki, Helen McCarthy, David Simpson, Fritz Offner, Carol Moreno, Sandra Dai, Indu Lal, James P. Dean, Thomas J. Kipps
Journal: Leukemia (2019)

Abstract RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years ( n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk ( TP53 mutation, 11q deletion, and/or unmutated IGHV ) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
Analysis of Infection-Related Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Recipients with Refractory/Relapse Acute Leukemia
Authors: Ren Lin, Jing Sun, Yujing Mao, Mengxia Zhao, Qifa Liu, Hongsheng Zhou, Fen Huang, Xiaoling Song, Han Li, Qinghui Ma
Journal: Blood (2012)
Assessment of Pharmacy Closures in the United States From 2009 Through 2015
Authors: Jenny S. Guadamuz, G. Caleb Alexander, Shannon N. Zenk, Dima M. Qato
Journal: JAMA Internal Medicine (2019)

This quality improvement study examines trends in pharmacy closures in the United States between 2009 and 2015, as well as pharmacy, community, and market factors that might be associated with such closures.
Delayed Immune Reconstitution After Allogeneic Hematopoietic Cell Transplantation with Yttrium-90 Ibritumomab Tiuxetan-Based Reduced-Intensity Conditioning
Authors: Dominik Schneidawind, Sebastian Jendryssek, Birgit Federmann, Christoph Faul, Wichard Vogel, Lothar Kanz, Wolfgang A Bethge
Journal: Blood (2012)
Spliceosomal Gene LUC7L2 Mutation Causes Missplicing and Alteration Of Gene Expression In Myeloid Neoplasms
Authors: Naoko Hosono, Hideki Makishima, Bartlomiej Przychodzen, Jarnail Singh, Richard A Padgett, Mikkael A. Sekeres, Andres Jerez, Kenichi Yoshida, Yuichi Shiraishi, Satoru Miyano, Masashi Sanada, Seishi Ogawa, Jaroslaw P. Maciejewski
Journal: Blood (2013)
Non-Interventional Retrospective Multicenter Study Evaluating Real Word Idelalisib Use in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin Lymphoma Patients Enrolled in the French Early Access Program
Authors: Loic Ysebaert, Pierre Feugier, Gilles Andre Salles, Eric Durot, Alexis Talbot, Choquet Sylvain, Denise Glorian Kergaravat, Alastair Simpson, Heribert Ramroth, Tarek Abdelhadi, Corinne Haioun, Xavier Troussard
Journal: Blood (2018)
Abstract 891: Phosphorylation of RNA Binding Motif 20 is a Novel Target to Reduce Myocardial Stiffness in Diastolic Dysfunction
Authors: Mingming Sun, Yutong Jin, Chaoqun Zhu, Maimaiti Rexiati, Hanfang Cai, Martin Liss, Michael Gotthardt, Ying Ge, Wei Guo
Journal: Circulation Research (2019)

Introduction: Published work has shown that RNA binding motif 20 (RBM20) can improve ventricular stiffening through altering titin sizes in HFpEF, a syndrome with no effective therapeutic options. Reducing RBM20 activity to treat diastolic dysfunction is promising, but it may cause side effects due to its multiple targets except for titin. RBM20 is one of the serine-arginine (SR) proteins of which the phosphorylation plays a critical role in gene splicing. Here we investigate the phosphorylation status of RBM20 and its potential role in diastolic dysfunction. Methods: Insect cell expression system was utilizedfor RBM20 expression. Purified RBM20 was subjected to the middle-down mass spectrometry (MS) analysis. Identified phosphorylation sites were mutated for in-vitro splicing and dual luciferase splice reporter assay through co-transfection with titin mini-gene. In-vitro kinase and co-IP assays were performed to identify the kinases that phosphorylate RBM20. Since phosphorylation is also important for translocation of RNA binding proteins, the confocal microscope was applied to estimate RBM20 trafficking. Results: Sixteen phosphorylation sites with four of them on SR domain of RBM20 were identified with MS analysis. In-vitro splicing and dual luciferase reporter assays revealed that two phosphorylation sites on SR domain play a major role in titin mini-gene splicing. In-vitro kinase assay indicated that kinases SRPK, CLK, and AKT can all phosphorylate RBM20, and co-IP confirmed the interaction between kinases and RBM20. Co-transfection of these kinases with RBM20 and titin mini-gene revealed that splicing pattern was different from co-transfection of mutated RBM20. Interestingly, two-phosphorylation sites mutation on SR domain facilitated RBM20 trafficking from the nucleus to the cytoplasm and thus, form RNA granules, suggesting the new role of RBM20 phosphorylation in diastolic dysfunction. In-vivo studies with mutation knock-in mouse model will be warranted in near future. Conclusion: These results suggest that RBM20 phosphorylation plays an important role in titin splicing, which is a potential target to treat diastolic dysfunction. RBM20 trafficking could be another new pathway to treat HFpEF.
The Role of HLA-E Polymorphism in Acute Leukemia Patients Receiving a 10/10 HLA Matched Unrelated HSCT
Authors: Chrysanthi Tsamadou, Tao Wang, Daniel Fürst, Stephanie J. Lee, Stephen R. Spellman, Katharina Fleischhauer, Katharine C. Hsu, Sophie Paczesny, Michael R Verneris, Christine Neuchel, Hubert Schrezenmeier, Joannis Mytilineos
Journal: Blood (2018)
Activity of New Heat Shock Protein 90 (hsp90) Inhibitor NVP-AUY922 Against Myeloma Cells Sensitive and Resistant to Conventional Agents.
Authors: Douglas W. McMillin, Joseph Negri, Jake Delmore, Patrick Hayden, Melissa Ooi, Nicholas Mitsiades, Robert Schlossman, Paul G. Richardson, Nikhil C. Munshi, Michael R. Jensen, Cornelia Quadt, Patrick Chène, Joseph Schoepfer, Carlos García-Echeverría, Kenneth C. Anderson, Constantine S. Mitsiades
Journal: Blood (2007)
Abstract 121: Precision Intervention of Cardiac Remodeling Based on Cellular Composition Principles Uncovered by Single-Cell Transcriptomics
Authors: Peng Yu, Zongna Ren, Li Wang
Journal: Circulation Research (2019)

Stress-induced cardiac remodeling forms the foundation of many cardiac diseases, yet little is known about the spatiotemporal interplay amongst cell types underlying the pathological progression of the heart from normal to a diseased state, at single-cell resolution. Here, we analyzed 11,492 single cells, including both cardiomyocytes (CMs) and non-cardiomyocytes (NCMs), at different stages in a mouse model of pressure overload-induced cardiac remodeling, and identified a full list of factors and signaling pathways important for disease progression. Through constructing cell crosstalk maps, we revealed sequential switching in NCM subtype (fibroblasts, macrophages, and endothelial cells) utilization at different stages of cardiac remodeling. Intriguingly, stage-specific pharmacological inhibition of macrophage subtype switch dramatically retarded heart transition from adaptive to a maladaptive state. Consistently, alterations of cardiac remodeling related-genes were highly conserved in human samples. Together, our study not only characterizes the molecular features of different cell types and identifies crucial factors underlying cardiac remodeling, but may also have important implications for stage- and cell type-specific precise intervention in cardiac diseases.
Increasing Incidence and Prevalence of Pathologic Hemoglobinopathies Among Children in Ontario, Canada from 1991-2013
Authors: Ewurabena Simpson, Robert J Klaassen, Pranesh Chakraborty, Beth Potter, Melanie Ann Kirby-Allen, Isaac Odame, Suzan Williams, Uma Athale, Lawrence Jardine, Paul J. Gibson, Mariana Silva, Manuela Merelles-Pulcini, Brooke Bowerman, William Petrcich, Eric I Benchimol
Journal: Blood (2018)
Abstract 413: Adipose-derived Stem Cells With Thymosin Beta 4 Enhanced Neovascularization in Mouse Ischemic Hind Limb Model
Authors: Jong-ho Kim, I-Rang Lim, Hyung Joon Joo, Soon Jun Hong
Journal: Circulation Research (2019)

Adipose-derived stem cells (ASCs) have potential of differentiating into endothelial lineage and are easily obtainable, therefore they are promising candidates for stem cell therapy. Thymosin beta 4 (Tb4) is G-actin sequestering protein that exerts a broad range of functions such as cell migration and angiogenesis. In this study, we investigated the effects of Tb4 on angiogenic and endothelial differentiation potential of ASCs. Exogenous treatment of Tb4 (100 ng/mL) induced a significant increase in endogenous mRNA expression of Tb4, and morphological changes with increased cell length in ASCs. In addition, Tb4-treated ASCs showed significantly higher endothelial differentiation potential than untreated ASCs after the induction of endothelial differentiation for 3 weeks. The expression of endothelial markers such as PDGFRb and CD144 were significantly enhanced by the treatment of Tb4 with the endothelial differentiation induction media compared to untreated ASCs. Indeed, Tb4-treated ASCs expressed higher expression of angiogenic genes including Ang-1, vWF, Tie1, CXCR4, uPAR, FGFR4, IGFR2, and VE-Cadherin than untreated ASCs, both cultured in the endothelial differentiation induction media. Moreover, a scratch wound healing assay revealed that the treatment of Tb4 significantly increased cell migration compared to untreated and Tb4-siRNA transfected ASCs. In the microbead sprouting assay, the treatment of Tb4 significantly augmented the number of sprouts per bead and the length of sprouts compared to untreated and Tb4-siRNA transfected ASCs. Futhermore, transplantation of ASCs with Tb4 induced neovascularization improved the blood flow in mouse ischemic hind limb models, compared to sham, ASC-transplanted, and Tb4-transplanted groups. Taken together, therapeutic application of ASCs with Tb4 could be useful to enhance endothelial differentiation and neovascularization.
Abstract 592: Cardioprotection During Ischemia by Induced Coronary Collateral Growth
Authors: Anurag Jamaiyar, Cody Juguilon, Devan Cumpston, Weiguo Wan, Tao Wang, Zhiyuan Wang, James Gadd, Molly Enrick, Sofia Chinchilla, Caige McCabe, Autumn Y Pu, William Chilian, Liya Yin
Journal: Circulation Research (2019)

Patients with poorly developed coronary collateral networks have a poorer prognosis after a cardiovascular event than those with well-developed collaterals. The outcome of patients with metabolic syndrome (MetS) was worse than the patient without MetS. Interestingly, coronary collateral growth is impaired in MetS. We hypothesize that coronary collaterals are critical for the cardiac protection in ischemic heart diseases (IHD) and induction of coronary collateral growth (CCG) might ameliorate the outcome of patients with MetS. We study the cardiac protection by coronary collaterals in IHD and the underlying mechanism of impaired CCG in the MetSin a mouse model of CCG. A pneumatic snare was implanted and situated around the LAD. After the mice recovery from the surgery, periodic inflation of the snare occludes the LAD; thus, producing repetitive ischemia (RI). Cardiac function was measure with echocardiography. CCG was measured by myocardial blood flow with contrast echocardiography and by collateral numbers with micro-CT or by vascular density with fluorescence scope. Our preliminary results showed that with occlusion of the LAD, there was no blood flow in the ischemic area. However, after stimulation of CCG by RI, the blood flow the ischemic area was compensated by the grown coronary collaterals and cardiac function was reserved during ischemia. Diabetic mice failed to grow coronary collaterals after RI stimulation and there was no cardiac protection from coronary collaterals during ischemia. Moreover, we studied the roles of growth differentiation factor 11 (GDF11) and miR21 in the regulation of CCG and cardiac protection in IHD. GDF11 was downregulated and miR21 was upregulated in the hearts of Zucker Obese Fatty (ZOF) rats during CCG. We used the Gdf 11 knockout mice and miR 21 knockout mice to study the underlying mechanism. GDF11 is highly expressed in myocardial blood vessels, which suggested the role of GDF11 in vascular growth. Impaired CCG of mice on high fat and high sugar was restored by miR-21 knockout. These data suggest that miR-21 is involved in the impairment of CCG in MetS.
Impact of High Donor-Derived CD4+ CCR7+ T Cell Count on Incidence of Grade II-IV Acute Graft-Versus-Host Disease Following Haploidentical Hematopoietic Cell Transplantation
Authors: Pauline Varlet, Tamim Alsuliman, Jacques Trauet, Julie Demaret, Myriam Labalette, Ibrahim Yakoub-Agha
Journal: Blood (2018)
A staff leadership model in an NCI-designated comprehensive cancer center: Quality begins with the team.
Authors: Juee Kotwal, Matthew J. Loscalzo, Karen L. Clark, William Dale, Natalie Schnaitmann
Journal: Journal of Clinical Oncology (2019)

73 Background: Patients with cancer face a range of complex biopsychosocial needs and challenges. To manage the complex needs of such “high-risk, high-cost” patients, an integrated interdisciplinary team approach is crucial. Although team members are highly skilled, cancer settings are emotionally charged environments which may create high levels of distress in providers. In 2007, the Department of Supportive Care Medicine (DSCM) at City of Hope (COH) developed the nation’s first Staff Leadership Model (SLM) to enhance relationships among team members which has been demonstrated to improve both the quality of patient care and safety. Within this model, the focus was on creating a high-performance team where team members are as valued as patients and families. Methods: DSCM implemented methods centered on maximizing team engagement by creating trusting relationships, detoxifying conflicts, depersonalizing feedback, and taking personal accountability. Cultural change was achieved by implementing the following interventions: communication skills to manage conflict, frequent team check-ins to identify areas of growth, non-management staff assuming responsibility for meetings and annual retreats and a “buddy” system to orient new team members. Results: Gallup scores increased from 4.46 in 2015 to 4.62 in 2017 (much higher than COH overall). Transition to Press Ganey in 2018 resulted in 2nd highest engagement score across COH departments (4.42 compared to COH overall 4.16). Conclusions: Results suggest support for the relationship between the SLM and the high quality of team relationships as reflected by the consistent increase in engagement scores. The department philosophy focuses on consciously, systematically and strategically activating the best of each team member in an environment of courageous, compassionate and relentless honesty.