tbuckley/cabot-search huggingface dataset:
Beta-Blockers in COPD — A Controversy Resolved?
Authors: William MacNee
Journal: New England Journal of Medicine (2019)

Cardiovascular disease, which is common in patients with chronic obstructive pulmonary disease (COPD), has a profound effect on morbidity and mortality,1 yet the condition is often unrecognized and as a result is undertreated.2 Systematic reviews have recognized the underuse of beta-blockers in patients with COPD who have coexisting cardiovascular disease because of fear of worsening lung function.3 Beta-blockers have positive effects on morbidity and mortality in patients with heart failure and in those who have had a myocardial infarction.4,5 Most retrospective observational studies have suggested that such positive effects also occur in patients with COPD who have cardiovascular disease.6,7 Along . . .
Abstract 784: Eicosapentaenoic Acid, Unlike Other Omega-3 Fatty Acids, Inhibits Membrane Cholesterol Crystalline Domains Under Conditions of Hyperglycemia
Authors: Samuel C Sherratt, R. P Mason
Journal: Circulation Research (2019)

Prescription eicosapentaenoic acid (EPA) reduced cardiovascular events in the REDUCE-IT study population, including in patients with diabetes. During hyperglycemia, there is abnormal membrane cholesterol aggregation which has been linked to oxidative stress and plaque instability. EPA at a pharmacologic dose may preserve normal cholesterol distribution as compared to other omega-3 fatty acids (FAs), including docosahexaenoic acid (DHA), eicosatriaenoic acid (ETE) and α-linolenic acid (ALA). Membrane vesicles were prepared from dilinoleoylphosphatidylcholine (DLPC) at a cholesterol-to-phospholipid mole ratio of 0.6:1 and treated with the omega-3 FAs under conditions of hyperglycemia (200 mg/dL). Changes in membrane lipid organization and width were measured using small angle X-ray diffraction approaches. Cholesterol domains were identified by the presence of diffraction peaks corresponding to a unit cell periodicity or width of 34 Å. Results showed that only EPA was able to prevent the formation of cholesterol domains and had a membrane structure characterized by a normal width (54 Å) and cholesterol distribution despite hyperglycemia. But samples containing the other FAs had a biphasic membrane structure containing prominent cholesterol crystalline domains. The relative size of the cholesterol domains was greatest in the order of ALA&gt;DHA&gt;ETE. Thus, EPA preserved normal cholesterol distribution under conditions of hyperglycemia in a manner that was not reproduced with other omega-3 FAs. These data indicate differences between these long chain FAs and support a potential benefit for EPA in reducing atherosclerotic disease.
Whole Genome DNA Methylation Analysis of Commpass Identifies Biomarkers of Multiple Myeloma Survival
Authors: Benjamin G Barwick, Daniel Auclair, Alex Blanski, Meghan Kirchhoff, Brianne Docter, Daniel C Rohrer, Jonathan J Keats, Sagar Lonial, Lawrence H. Boise, Paula M Vertino
Journal: Blood (2018)
Abstract 117: A Novel Ubiquitination Dependent Pathway Regulating Myocardial Necroptosis and Ischemic Injury
Authors: Xiaoyun Guo, Haifeng Yin, Yi Chen, Siqi Hong, Hui He, Yachang Zeng, Rachel Steinmetz, Qinghang Liu
Journal: Circulation Research (2019)

Objective: Necroptosis is a new caspase-independent, regulated form of necrosis, which has recently been implicated in ischemic cardiac injury and remodeling. This study aims to determine a novel ubiquitination-dependent mechanism that regulates necroptosis in the heart and the implications of necroptosis signaling in the setting of ischemic injury and remodeling. Methods and Results: Here we identified a novel ubiquitination-dependent mechanism mediated by the E3 ubiquitin ligase TRAF2 (TNF receptor associated factor-2) and the deubiquitinase CYLD (cylindromatosis), which critically regulates myocardial necroptosis and pathological remodeling. TRAF2 and CYLD specifically regulate K63-linked protein ubiquitination, which regulates signal transduction but not proteasomal degradation. Intriguingly, CYLD is up-regulated, but TRAF2 is down-regulated, in the heart after ischemia-reperfusion injury. We found that wild-type TRAF2 inhibits, whereas the ligase inactive mutant TRAF2-ΔRING promotes cardiomyocyte necroptosis. Importantly, acute deletion of TRAF2 in the adult heart in Traf2 fl/fl -MerCreMer mice induces severe dilated cardiomyopathy and lethal heart failure by promoting myocardial necroptosis. Conversely, AAV9-mediated TRAF2 gene transfer significantly attenuates ischemic-reperfusion injury. On the other hand, CYLD overexpression promotes, whereas CYLD deletion inhibits cardiomyocyte necroptosis. In vivo , genetic ablation of CYLD in Cyld-/- mice attenuates ischemic myocardial injury and adverse remodeling by suppressing myocardial necroptosis. Mechanistically, TRAF2 and CYLD opposingly regulate K63-linked polyubiquitination of TAK1 (TGFβ-activated kinase 1), TAK1-RIP1 interaction, and the formation of RIP1-RIP3 necrosome. These results thus identify a ubiquitination-dependent mechanism of necroptosis mediated by TRAF2 and CYLD, providing a new paradigm of necroptosis signaling. Conclusion: The E3 ligase TRAF2 and the deubiquitinase CYLD, as a suppressor and an activator of necroptosis respectively, opposingly regulate myocardial homeostasis, ischemic injury, and remodeling, thus representing promising therapeutic targets for heart disease.
Facile and efficient encapsulation of antimicrobial peptides via crosslinked DNA nanostructures and their application in wound therapy
Authors: Sybil Obuobi, Hilda Kai-Lin Tay, Nhan Dai Thien Tram, Vanitha Selvarajan, Jasmeet Singh Khara, Ying Wang, Pui Lai Rachel Ee
Journal: Journal of Controlled Release (2019)

There is growing interest in the development of nucleic acid nanostructures as smart functional materials for applications in drug delivery. Inspired by the diverse physical interactions that exist in nature, crosslinked DNA nanostructures can serve as attractive affinity binding networks that interact with therapeutic cargos or living cells. Herein we report a strategy that addresses the challenges of topical oligopeptide therapy by exploiting high binding affinity between polyanionic DNA nanostructures and cationic antimicrobial peptides (AMPs) to fabricate hydrogels that release a model antimicrobial L12 peptide in response to pathogenic S. aureus infections. We further demonstrated controlled peptide release profiles via the DNA hydrogels that were biocompatible and delivered superior antimicrobial activity against nuclease-releasing susceptible and methicillin-resistant S. aureus infections. Single application of the L12-loaded DNA hydrogels on porcine explant S. aureus infections revealed potent efficacy after 24h. As a result of the capacity of the crosslinked DNA nanostructures to elicit a strong anti-inflammatory response, in vivo treatment of mice excision wounds translated into faster healing rates. Overall, the crosslinked DNA nanostructures reported in this study offer significant advantage as functional wound dressings and their future adaptation holds equally great promise for the delivery of cationic antimicrobials.
Abstract 813: Downregulation of the Cardiac Sodium Channel Nav1.5 Mediates Obesity-Induced Atrial Fibrillation
Authors: Arvind Sridhar, Mark McCauley, Liang Hong, Ambili Menon, Srikanth Perike, Meihong Zhang, Xun Ai, JiaJie Yan, Seock-Won Youn, Ivson Bezerra da Silva, Marcelo Bonini, Jalees Rehman, Dawood Darbar
Journal: Circulation Research (2019)

Background: Obesity increases atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. Emerging evidence supports reduced cardiac Na + channel (Nav1.5) expression and current ( I Na ) as one potential mechanism. Objective: We used an acquired (diet-induced obese, DIO) obese mouse model to test the hypothesis that obesity increases AF risk by downregulating Nav1.5. Methods: Weight, BP, plasma glucose, and F 2 -isoprostanes were measured in DIO mice and compared to controls. Echocardiography, EP studies, immunohistochemistry, Western blotting, cellular patch clamping and optical mapping studies were performed. Results: DIO (37.5±3.8) mice were heavier than controls ( 24.3 ±4.1;P &lt;0.001). AF burden was 355±383 sec in DIO mice vs. 8.3± 21.4 sec in controls ( P &lt;0.0001). Nav1.5 expression, I Na , atrial action potential duration (APD) and conduction velocity (CV) were reduced, and F 2 -IsoPs were increased. AF burden was reduced in the DIO model after chronic treatment with MitoTEMPO antioxidant, with partial restoration of the APD90, I Na and AP upstroke and reduction in F 2 -IsoPs. Conclusions: Mice with either acquired or genetic susceptibility to obesity are more prone to develop AF. And this is partially mediated by increased oxidative stress leading to downregulation of Nav1.5, shortened atrial APD and reduced atrial conduction velocity suggesting a possible reentrant mechanism of AF.
Aberrant Hedgehog Signaling Represents a Novel Therapeutic Target in B Cell Lymphomas.
Authors: Qiuju Wang, Craig Peacock, Kortney Hensley, Sarah Brennan, Akil Merchant, Evan Jones, Irwin Freed, Richard Ambinder, Karen McGovern, Martin Tremblay, D. Neil Watkins, William Matsui
Journal: Blood (2007)
Survival Outcomes of Young Multiple Myeloma Patients: A Single Center Experience
Authors: Pelin Aytan, Mahmut Yeral, Cigdem Gereklioglu, Aslı Korur, Funda Tanrıkulu, Soner Solmaz, Nurhilal Buyukkurt, Mutlu Kasar, Suheyl Asma, Can Boga, Ilknur Kozanoglu, Hakan Ozdogu
Journal: Blood (2018)
Abstract 335: Titin Truncations in Human Heart Tissue
Authors: Quentin McAfee, Jeff Brandimarto, Joshua Rhoades, Ken Bede, Kenneth Margulies, Zoltan Arany
Journal: Circulation Research (2019)

Truncating variants in the gene for titin (TTNtvs) strongly associate with dilated cardiomyopathy (DCM) and peripartum cardiomyopathy (PPCM). How TTNtvs lead to cardiomyopathy is unclear. Both haploinsufficient and dominant negative mechanisms have been proposed. To begin to address this question, we have obtained left ventricular myocardium from explanted hearts from patients with DCM or PPCM undergoing cardiac transplantation, as well as myocardium from non-failing donor hearts. Targeted exome sequencing identified 8 hearts bearing TTNtvs in isoforms expressed in adult heart. Modified gel electrophoresis of extracts from these samples revealed no apparent band at the expected (truncated) molecular weight predicted for each TTNtv, indicating that truncated titin protein is likely absent. In addition, the total amount of titin protein appeared preserved in TTNtv extracts, arguing against haploinsufficiency in these hearts. RNAseq of TTNtv-positive hearts revealed balanced representation of all identified heterozygous variants, i.e. preserved allelic balance, indicating that the alleles encoding TTNtvs are appropriately transcribed, and do not undergo nonsense mediated decay. Together these data support neither haploinsufficiency nor dominant negative mechanisms, and leave open the question of how TTNtvs contribute to the development of DCM and PPCM.
Reply to Gregory J. Nason, Michael A.S. Jewett, and Robert J. Hamilton’s Letter to the Editor re: Adam C. Calaway, Lawrence H. Einhorn, Timothy A. Masterson, Richard S. Foster, Clint Cary. Adverse Surgical Outcomes Associated with Robotic Retroperitoneal Lymph Node Dissection Among Patients with Testicular Cancer. Eur Urol 2019;76:607–609
Authors: Adam C. Calaway, Lawrence H. Einhorn, Timothy A. Masterson, Richard S. Foster, Clint Cary
Journal: European Urology (2019)
Enabling Healthful Aging for All — The National Academy of Medicine Grand Challenge in Healthy Longevity
Authors: Victor J. Dzau, Sharon K. Inouye, John W. Rowe, Elizabeth Finkelman, Tadataka Yamada
Journal: New England Journal of Medicine (2019)

Recognizing that aging presents a defining challenge for this century, the National Academy of Medicine is launching a Healthy Longevity Global Grand Challenge, an international effort directed at improving health, productivity, and quality of life for older people.
A Novel Cell Line, Tnet-2, Derived from "Triple-Negative" Essential Thrombocythemia
Authors: Satoru Aoyama, Toshikage Nagao, Shunichiro Yasuda, Daisuke Watanabe, Hiroki Akiyama, Shinya Ishida, Ayako Nogami, Yoshihiro Umezawa, Ken Watanabe, Masahide Yamamoto, Osamu Miura, Norihiko Kawamata
Journal: Blood (2018)
Abstract 547: Metabolomic and Transcriptomic Profiling of Rat Offspring Exposed to Gestational Diabetes Reveals Altered Cardiac Gene Expression and Metabolism
Authors: Stephanie Kereliuk, Prasoon Agarwal, Laura Cole, Kyle Cheung, Bo Xiang, Mario Fonseca, Grant Hatch, Jonathan McGavock, Vernon Dolinsky
Journal: Circulation Research (2019)

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Children exposed to GDM are at an increased risk of developing cardiometabolic diseases later in life, though the mechanisms responsible are unknown. We hypothesize that fetal exposure to GDM induces alterations in cardiomyocyte metabolism and concomitant left ventricular (LV) dysfunction with age. GDM was induced in female rats with a high fat (45% kcal) and sucrose diet prior to mating, throughout pregnancy and lactation. Lean control females received a low fat (10% kcal) diet. Fetal rat ventricular cardiomyocytes (FRVC) were isolated from e20.5 offspring for U-13C glucose metabolic flux analysis and mitochondrial respiration. Serum metabolites and cardiac transcriptome profiles were measured in 3-month old offspring. LV morphology and function was assessed through the life course of the offspring (e18 to 12-months of age) by transthoracic ultrasound. Offspring exposed to GDM exhibited increased LV posterior wall thickness across their life course (fetal to 12-months of age; p&lt;0.05) and impaired LV filling beginning at 6-months of age (p&lt;0.05). U-13C glucose metabolic flux through glycolysis and the citric acid cycle was reduced in FRVC from GDM offspring when treated with isoproterenol, and compared to Lean FRVC. Basal and maximal mitochondrial oxygen consumption was reduced for glucose (35% and 68%) and fatty acid (49% and 52%) substrates in FRVC isolated from GDM offspring (p&lt;0.05). In 3-month old GDM offspring, serum metabolomics revealed elevated levels of beta-hydroxybutyrate (2.4-fold, p&lt;0.05) and reduced levels of several citric acid cycle intermediates, which also corresponded to alterations in gene expression patterns identified by RNASeq transcript analysis. Large-scale profiling revealed GDM induced alterations in the cardiac gene expression profile leading to modified serum metabolite levels in the offspring. These alterations corresponded with mitochondrial dysfunction, impaired cardiomyocyte metabolic flux and contractility, in concert with LV hypertrophy and diastolic dysfunction in the rat offspring. Our findings identify several mechanisms that link early-life GDM exposure to the development of cardiovascular disease later in life.
Methotrexate-Associated Toxicity in Children with Down Syndrome and Acute Lymphoblastic Leukemia during Consolidation Therapy with High Dose Methotrexate According to ALL-BFM Treatment Regimen
Authors: Mirko Kroll, Kirsten Bleckmann, Anja Möricke, Denis Martin Schewe, Martin Stanulla, Martin Zimmermann, Martin Schrappe, Gunnar Cario
Journal: Blood (2018)
Assessing cancer programs' financial resources for rural cancer patients.
Authors: Victoria Marie Petermann, Robin C. Vanderpool, Jan Marie Eberth, Catherine Rohweder, Randall Teal, Lindsay Stradtman, Elizabeth Frost, Erika Trapl, Sarah Koopman Gonzalez, Thuy Vu, Linda Ko, Allison Cole, Paige E. Farris, Jackilen Shannon, Whitney Zahnd, Jessica Lee
Journal: Journal of Clinical Oncology (2019)

165 Background: The National Cancer Institute (NCI) has identified rural cancer control as a research priority. Rural patients may have greater cancer-related financial burdens due to high travel costs, low insurance coverage, and less flexible work schedules. To better understand geographic differences in cancer-related financial toxicity from an organizational perspective, we interviewed staff from a range of cancer treatment settings in counties across the rural-urban continuum. The goal was to qualitatively assess the financial resources available to cancer patients, particularly those residing in rural areas. Methods: Seven research teams within the Cancer Prevention and Research Control Network interviewed personnel providing financial navigation services across four types of cancer care facilities and three urban/rural classifications. Interviews were audio-recorded and transcribed. We identified themes using inductive content analysis. A total of 28 interviews were collected across 7 states and preliminary results have been generated from 20 interviews. Results: Study participants identified transportation and housing costs as primary financial stressors for rural patients. A few personnel from centers in urban counties did not observe clear differences in experiences of financial toxicity between rural and urban patients. No personnel mentioned resources that are long-term or specifically for rural patients. Gas cards and temporary housing are often provided to help rural and urban patients access treatment. Insufficient staffing is a barrier to addressing patients’ financial concerns in rural and urban centers. Urban institutions, particularly NCI-designated facilities, employ more cancer-specific financial navigators than rural institutions. Conclusions: Patients across the rural-urban continuum experience financial hardship, but rural patients may be disproportionately affected by transportation and housing costs. Improving transportation and housing support may improve their ability to access treatment. Financial navigation practices within states vary; thus, patients and cancer centers may benefit from more streamlined approaches to address financial needs for all cancer patients.
Abstract 632: MTOR-Proteasome Imbalance Upon Deletion of Pras40 Inhibits Cardiac Growth but Results in Cardiac Failure
Authors: Eva RIECHERT, Moritz H Kern, Agniezka A Gorska, Christoph Hofmann, Lonny Jürgensen, Kira Gür, Thanh C Ho, Joanna Kirkpatrick, Norman Rahnis, Hugo A Katus, Mirko Völkers
Journal: Circulation Research (2019)

Background: The mammalian target of Rapamycin complex 1 (mTORC1) increases cell size by initiating translation as well as by inhibiting catabolic functions such as proteolysis or autophagy. We have previously proposed Proline-rich Akt substrate 1 (Pras40) as a cardioprotective endogenous inhibitor of mTOR-dependent protein synthesis during pathologic growth. Pras40 is released from mTORC1 during growth, but other interactions are largely unknown. In a proteomic screen we have now found a novel interaction of Pras40 with the 26S proteasome during hypertrophy. We hypothesize that Pras40 directly links the mTOR-dependent protein synthesis network and the proteasomal degradation machinery to balance both processes. Methods and Results: To determine the growth-dependent Pras40-interactome, we identified binding partners by proximity-dependent biotin labeling using APEX2 and subsequent mass-spec. Interestingly, aside from interactions with the mTOR-dependent translation machinery, we find Pras40 binding to subunits of the 26S proteasome only during growth. To test consequences of Pras40 deletion on cardiac function in vivo , we generated cardiomycyte-specific knock-out mice, that we subjected to pathologic hypertrophy (TAC). Conversely to Pras40 overexpression, we find growth significantly blunted in KO animals, function reduced and fibrosis elevated. mTORC1 signaling as well as autophagy and proteasomal function are severely disturbed in KO animals. Mechanistically, chymotrypsin-like 26S proteasome activity is blunted in KO hearts as well as isolated cardiomyocytes from KO animals, whereas overexpression shows reciprocal effects in myocytes. Disturbed proteasomal function in KO mice leads to severe alterations in metabolic functions highlighting the importance of both intact mTORC1 signaling and proper proteasomal maintenance during cardiac stress. Conclusion: In this study we find a novel mechanism how mTOR and proteasomal function are linked in the diseased heart. We provide evidence that Pras40 links anabolic protein synthesis and catabolic proteolysis in the heart: At rest, Pras40 binds and inhibits mTOR, but when released during pathologic growth, Pras40 directly interacts with the 26S proteasome and modulates its activity.
Abstract 938: BET Bromodomain Protein 4 (BRD4) Governance of Cardiovascular Disease Stress-related Cardiomyocyte Remodeling
Authors: Soo Young Kim, Francisco Altamirano, Gabriele G. Schiattarella, Nan Jiang, Herman I. May, Xiang Luo, Hongliang Li, Shwu-Yuan Wu, Cheng-Ming Chiang, Sergio Lavandero, Thomas G. Gillette, Joseph A. Hill
Journal: Circulation Research (2019)

During the past decade, epigenetic control of cardiac remodeling has attracted attention as a major mechanism contributing to heart failure. The BET family of bromodomain proteins (BRD) functions as “readers” of acetylated chromatin. Pharmacological inhibition of BRD proteins prevents cardiac hypertrophy and heart failure in preclinical models, yet mechanistic studies elucidating the biology of BRD proteins in the heart are lacking. Here, we investigated the role(s) of BRD4 in cardiac physiology and pathophysiology. By engineering a cardiomyocyte-specific BRD4 knockout mouse, we discovered that loss of BRD4 triggered progressive decline in ventricular contractile function, culminating in dilated cardiomyopathy in both post-natal and adult hearts. To identify early transcriptomic changes in BRD4-ablated heart, we conducted a global transcriptome analysis in KO hearts prior to the onset of ventricular dysfunction. RNA sequencing analysis of BRD4 KO hearts revealed disruption of genes essential to mitochondrial energy production and homeostasis, as well as key cardiac sarcomeric components. Computational analysis identified key transcription factors involved in BRD4-mediated gene regulation, including MEF2 complex, ERR1, SRF, and Nkx2.5. By studying isolated cardiomyocytes maintained in primary culture, we confirmed that disruption of the candidate TF complexes by BRD4 ablation altered mitochondrial morphology and provoked progressive contractile dysfunction. In aggregate, we describe for the first time a critical role of BRD4 in regulating key cardiomyocyte gene networks, in particular genes involved in mitochondrial homeostasis and contractility, to maintain cardiac function. Moreover, our data suggest that BRD4 is a novel regulator of epigenetic events in dilated cardiomyopathy. Elucidating these novel roles of BRD4 in cardiomyocyte remodeling will provide critical insights into the epigenetic control of stress-related cardiac events with potential clinical relevance.
Association of Cardiovascular Disease With Premature Mortality in the United States
Authors: Yingxi Chen, Neal D. Freedman, Paul S. Albert, Rachel R. Huxley, Meredith S. Shiels, Diana R. Withrow, Susan Spillane, Tiffany M. Powell-Wiley, Amy Berrington de González
Journal: JAMA Cardiology (2019)

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups.