tbuckley/cabot-search huggingface dataset:
LONG-TERM SAFETY AND EFFECTIVENESS OF MAVACAMTEN IN SYMPTOMATIC OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY PATIENTS, PIONEER-OPEN LABEL EXTENSION STUDY (PIONEER-OLE)
Authors: Stephen B. Heitner, Daniel Jacoby, Steven J. Lester, Andrew Wang, David Zhang, Amy Sehnert
Journal: Journal of the American College of Cardiology (2019)
THE PROGNOSIS OF WORSENING RENAL FUNCTION AFTER PERCUTANEOUS CORONARY INTERVENTION: FROM SHINANO 5 YEAR REGISTRY
Authors: Yoshiteru Okina, Takashi Miura, Keisuke Senda, Minami Taki, Masanori Kobayashi, Masafumi Kanai, Yukari Ookuma, Takashi Yanagisawa, Naoto Hashizume, Kyuhachi Otagiri, Kyoko Shoin, Noboru Watanabe, Kenichi Karube, Hiroyuki Nakajima, Tatsuya Saigusa, Soichiro Ebisawa, Yusuke Miyashita
Journal: Journal of the American College of Cardiology (2019)
Abstract 572: Role Of Human Cardiac RLC In Modulating The Super-relaxed State Of Myosin: A Cardiomyopathy Perspective
Authors: Na Sa, Ivan Tomasic, Sampath Gollapudi, Ferdinand Evangelista, Kristina Green, Suman Nag
Journal: Circulation Research (2018)

Myosin regulatory light chain (RLC) is a major regulatory subunit of the myosin molecule, the role of which has been well-characterized in non-striated muscle. However, in striated muscle, its purpose is less well defined, and it is only in the past decade that researchers have started unraveling the function of RLC and its phosphorylation in muscle contraction. Mutations in this protein result in ~ 2% of total familial cardiomyopathy, an autosomal dominant disorder, manifested by ventricular and septal hypertrophy and myofibrillar disarray that can lead to sudden cardiac death. In this study, we report the role of human cardiac RLC in forming the super-relaxed state (SRX) of myosin in reconstituted full-length cardiac myosin thick filaments. We show that the presence of RLC fine-tunes the ability of myosin to form the SRX state and that its removal depopulates the SRX state. A similar reduction in SRX population is also achieved by phosphorylating the RLC with MLCK. The second mechanism of RLC-mediated regulation in muscle is thought to be by the binding of either Mg 2+ or Ca 2+ to the N-terminal EF-hand domain. Mg 2+ did not affect myosin SRX population, but increasing Ca 2+ enhanced the population of the myosin SRX state. Preliminary SRX studies on cardiomyopathy-causing RLC mutants R58Q (HCM), K104E (HCM) and D94A (DCM) show that none of the mutants affects the SRX population in the dephosphorylated state of the RLC; however these mutants also do not affect the SRX population when RLC is phosphorylated, unlike the wild-type. Additionally, in micro-scale thermophoresis binding experiments, only the dephosphorylated form of the DCM-causing D94A RLC mutant exhibits weaker binding to the myosin lever arm as compared to WT RLC. Binding of the mutants resembles WT upon phosphorylation. Altogether, these observations demonstrate that either RLC phosphorylation or Ca 2+ binding to RLC can alter the number of accessible myosin heads for contraction and cardiomyopathy-causing RLC mutants can modify this mechanism to varying extents.
LIPOPROTEIN(A) IS ASSOCIATED WITH ELEVATED MITRAL E/E' RATIO IN JAPANESE NON-HEART FAILURE POPULATION
Authors: Yoshiko Mizuno, Masao Daimon, Kohei Uemura, Hidetaka Ito, Kiriyama Hiroyuki, Yuriko Yoshida, Koki Nakanishi, Hidehiro Kaneko, Daisuke Koide, Nobutake Yamamichi, Issei Komuro
Journal: Journal of the American College of Cardiology (2019)
Distinct Features of Chip-Derived and De Novo MDS
Authors: Yasunobu Nagata, Hideki Makishima, Cassandra M. Hirsch, Hassan Awada, Abhinav Goyal, Teodora Kuzmanovic, Bartlomiej P. Przychodzen, Tetsuichi Yoshizato, Kenichi Yoshida, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Sudipto Mukherjee, Tomas Radivoyevitch, Thomas Laframboise, Aziz Nazha, Mikkael A. Sekeres, Torsten Haferlach, Seishi Ogawa, Jaroslaw P. Maciejewski
Journal: Blood (2018)
Different role of circulating myeloid-derived suppressor cells in patients with multiple myeloma undergoing autologous stem cell transplantation
Authors: Sung-Eun Lee, Ji-Young Lim, Tae Woo Kim, Da-Bin Ryu, Sung Soo Park, Young-Woo Jeon, Jae-Ho Yoon, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Hee-Je Kim, Seok Lee, Seok-Goo Cho, Dong-Wook Kim, Jong Wook Lee, Chang-Ki Min
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The aim of this study is to evaluate the prognostic impact of myeloid-derived suppressor cells (MDSCs) in multiple myeloma (MM) in the context of autologous stem cell transplantation (ASCT). <h3>Methods</h3> Peripheral blood samples were collected for measuring monocytic (M-) MDSCs (CD14<sup>pos</sup>HLA-DR<sup>low/neg</sup>) and early-stage (E-) MDSCs (Lin<sup>neg</sup>HLA-DR<sup>neg</sup>CD33<sup>pos</sup>CD11b<sup>pos</sup>) before and after ASCT. Clinical outcomes following ASCT differed according to the frequency of each MDSC phenotype. <h3>Results</h3> In the pre-ASCT analyses, lower M-MDSCs (&lt;median) but not E-MDSCs were associated with a longer time to progression (TTP), whereas both MDSC phenotypes post-ASCT did not have a role in TTP. Both MDSC phenotypes pre-ASCT but not post-ASCT similarly suppressed in vitro autologous T and natural killer T cell proliferation. Importantly, pre-ASCT M-MDSCs more strongly inhibited the in vitro cytotoxic effect of melphalan compared with pre-ASCT E-MDSCs. Transcriptome analysis of each isolated MDSC subtype showed that expression of osteoclastic differentiation factors, particularly colony-stimulating factor 1 receptor (CSF1R), was significantly increased in M-MDSCs pre-ASCT. Finally, blockade of CSF1R substantially recovered the melphalan-induced cytotoxicity reduced by pre-ASCT M-MDSCs. <h3>Conclusions</h3> Our data demonstrate that pre-ASCT M-MDSCs are correlated with poor clinical outcomes after ASCT through reduced cytotoxicity of melphalan. We propose that targeting CSF1R on these cells may improve the results of ASCT in MM.
CLL Cells with 13q- Are Characterized By High BCL2 Levels and CLL Cells with Trisomy-12 By Increased Activation of STAT3 and NF-κB
Authors: Uri Rozovski, David M. Harris, Ping Li, Zhiming Liu, Preetesh Jain, Alessandra Ferrajoli, Jan A. Burger, Prithviraj Bose, Philip A. Thompson, Nitin Jain, William G. Wierda, Michael J. Keating, Zeev E. Estrov
Journal: Blood (2018)
PRESENCE OF PERIPHERAL ARTERY DISEASE IS ASSOCIATED WITH INCREASED MORTALITY AND MORBIDITY IN PATIENTS ADMITTED WITH ST-ELEVATION MYOCARDIAL INFARCTION: AN INSIGHT FROM MOST RECENT NATIONAL INPATIENT DATABASE (2016)
Authors: Vivek Modi, Dhrubajyoti Bandyopadhyay, Hassan Beydoun, Faris Haddadin, Alba Munoz Estrella, Eyal Herzog
Journal: Journal of the American College of Cardiology (2019)
Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology
Authors: Damon Tumes, Kiyoshi Hirahara, Magdalene Papadopoulos, Kenta Shinoda, Atsushi Onodera, Jin Kumagai, Kwok Ho Yip, Harshita Pant, Kota Kokubo, Masahiro Kiuchi, Ami Aoki, Kazushige Obata-Ninomiya, Koji Tokoyoda, Yusuke Endo, Motoko Y. Kimura, Toshinori Nakayama
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 349: Sall4 Blocks Cardiac Trans-differentiation but Stimulates Cardiac Stem-like Cell (iPSC) Generation and Improve Post MI Function In Vivo
Authors: Lina Yang, Pratap Pinnamaneni, Hong Gao, Deepthi Sanagasetti, Vivek Singh, Megumi Mathison, Todd Rosengart, Jianchang Yang
Journal: Circulation Research (2018)

Background: Sall4 is an essential component in maintaining embryonic stem cell self-renewal and pluripotency. Given its functional and protein level interaction with cardiac trans-differentiation factors Tbx5/Gata4, as well as its critical role in modulating embryonic cardiac development, we hypothesized that Sall4 may play an important role in cardiac reprogramming. Material/Method: We conducted gain- and loss- of function studies on neonatal and adult cardiac fibroblast from both mouse and rat. We also evaluated Sall4 function on infarcted rat heart. Results: Gata4/Mef2c/Tbx5 (GMT) administration markedly upregulated mRNA expression levels of stem factors including Sall4 , Bmi1 , and p63 , while inhibition of Sall4 largely enhanced GMT- mediated Cardiac troponin T ( cTNT ) induction. Conversely, overexpression of Sall4 plus Gata4/Mef2C in cardiac fibroblast for 7 days induces over 30-fold increase of Oct4 and Nanog by real-time PCR; longer culture induced rapidly-dividing iPSC-like clusters in both neonatal mouse and adult rat cardiac fibroblasts. Further tests showed that these iPSC-like cells were partially positive in alkaline phosphatases staining, capable of forming cardiosphere and differentiating into various cell types. Sall4 delivery also improved post-infarct cardiac function to a level that is comparable with Gata4 in rat. Conclusion: These results suggested that Sall4 is a promising target for cardiac reprogramming even though further characterization in vitro as well as in vivo is needed.
THROMBOSED ACUTE AORTIC DISSECTION WITH SUBINTIMAL ACTIVE BLOOD FLOW: A NEW INSIGHT FROM ANGIOSCOPY
Authors: Satoru Takahashi, Sei Komatsu, Mitsuhiko Takewa, Tomoki Ohara, Chikao Yutani, Kazuhisa Kodama
Journal: Journal of the American College of Cardiology (2019)
Abstract 363: The Brain - Pancreas Axis: An Alzheimer Nanoplaque Study
Authors: Guenter Siegel, Stephanie Hammersen, Angela Becker, Dan Georgescu, Irit Lubitz, Eugeny Ermilov, Martin Malmsten, Ramsey Saunders, Björn Lindman
Journal: Circulation Research (2018)

Background: The central-nervous regulation of blood glucose occurs purely neuroendocrine via the hypothalamus-hypophysis-adrenal cortex system. In this control loop, insulin is the adjustable and glucose the controlled variable. Methods: Ellipsometry, photometric methods and ELISAs were applied. Intracellular membrane potential and tension were recorded from human intracerebral arteries of consciousness areas. Results and discussion: Despite multiply feedback coupled and safeguarded control loops for maintenance of a constant blood glucose level, 4.7% of the world population suffered from diabetes mellitus (T2DM) in 1980 and already 8.5% in 2014. In parallel, the risk for cardiovascular (heart attack, stroke) and Alzheimer diseases (AD) has risen by a factor of four to eight. In ellipsometry measurements with polyanionic heparan sulfate proteoglycan (HS-PG), VLDLapoE4/E4 and IDLapoE4/E4, β-amyloid (1-42) and Ca 2+ -ions, we could show that non-enzymatic glycation of these substances leads to an Alzheimer nanoplaque formation increased by 20-30%. Since the viscoelastic polyelectrolyte HS-PG serves not only as lipoprotein receptor but also as blood flow sensor, we recorded with the same glycation a flow-dependent dilatation reduced by up to 80% in human brain arteries ex vivo (from neurosurgery) which express HS-PG in endothelial and smooth muscle cell membranes. The resulting O 2 -deficiency with certainty entails neuronal cell death. Postprandial, blood glucose levels can appear as were experimentally applied here. Conclusion: Also short-term distinctly increased blood glucose concentrations in apoE4 carriers can explain neuronal cell death like in AD.
Abstract P5-04-22: Withdrawn
Authors: K Treuner, M Hayes, CA Schnabel, S Heinz
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Treuner K, Hayes M, Schnabel CA, Heinz S. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-22.
Abstract 444: Dusp4 Overexpressed EC Derived Exosomes Promote Angiogenesis: A Novel Therapeutic Strategy For Ischemic Heart Disease
Authors: Julie Dougherty, Mahmood Khan, Mark G Angelos, Chun-an Chen
Journal: Circulation Research (2018)

After an ischemia and reperfusion (I/R) injury to the heart, re-establishing blood flow to the infarct region can salvage myocardium, stimulate angiogenesis and recruit progenitor cells for tissue regeneration. Stimulating angiogenesis through the growth of new microcirculation in the peri-infarct area can help preserve and improve cardiac function following myocardial infarction. In this study, we hypothesize that exosomes derived from DUSP4-overexpressed endothelial cells (ECs) stimulate angiogenesis and improve vascular function. DUSP4-derived exosomes (50 μg/ml) promote angiogenesis by increasing tube formation of endothelial cells (2.74 ± 0.14 versus control exosomes 2.17 ± 0.15 in the total length; p &lt; 0.001). Immunoblotting reveals that DUSP4 overexpression in endothelial cells down-regulates p53 (0.59 ± 0.04 versus 1.0 ± 0.01 of control) expression, which modulates the HIF1α pathway and angiogenesis. Moreover, NO is a critical small molecule involved in regulation of vascular tone, vascular growth, platelet aggregation, and modulation of inflammation. The level of NO generation determined using DAF fluorescence microscopy demonstrated that DUSP4 overexpression augments NO generation. The increase in NO generation also correlates to the increase in eNOS protein (1.23 ± 0.20 versus control) and mRNA (5.84 ± 0.37 versus control) expression. The proteomic analysis of control and DUSP4 derived exosomes showed that DUSP4 overexpression up-regulates several key exosomal proteins including HSP70, HSP90, tubulins, Vimentin, and clathrin. More interestingly, several redox proteins were up-regulated in DUSP4 derived exosomes including glutathione S-transferase P, peroxiredoxin-2, peroxiredoxin-4, and protein disulfide-isomerase. Together, these results demonstrate that exosomes derived from DUSP4 reprogrammed ECs are a valuable therapeutic option for the treatment of ischemic heart disease by promoting angiogenesis.
Abstract 421: High-throughput <i>In vitro</i> Ischemia-reperfusion Model With Real-time Monitoring of Cellular Oxygenation and Reactive Oxygen Species Generation
Authors: Christopher Fleming, Conn Carey, Ralf Ketenhoffen, Mario Schneider, James Hynes
Journal: Circulation Research (2018)

Ischaemia-reperfusion (IR) injury is a feature of multiple diseases including myocardial infarction, renal failure and stroke, occurring when tissue blood supply is restricted and subsequently restored. While reperfusion is essential for tissue survival, it is also associated with significant ROS-mediated damage, triggering inflammatory responses and ultimately cell death. The rational development of targeted therapeutic interventions require both a detailed understanding of the mechanisms underlying reperfusion injury and a convenient means of assessing the efficacy of putative therapeutics. This need has driven the development of a number of in vitro IR models including pharmacological ATP depletion, oil overlays to induce autohypoxia, glucose oxidase addition to cause sample deoxygenation, and N 2 purged hypoxia chambers to induce a slow reduction in dissolved oxygen. The utility of these models has however been limited as they do not facilitate the induction of the rapid, controlled, transient, ischemic shock and reperfusion necessary to replicate IR injury condition in vitro . Critically, neither do they facilitate real-time cellular oxygenation monitoring to allow accurate IR characterisation or parallel measurements of critical IR injury parameters such as ROS and mitochondrial membrane potential (MMP). Here we present a model which addresses these limitations through the combined use of iPS-derived cardiomyocytes (Cor4U), plate reader with integrated atmospheric control facilitating rapid [O 2 ] modulation (ClarioSTAR) and a novel intracellular probe capable of reporting cellular oxygenation in real time (MitoXpress-Intra). Oxygenation monitoring facilitates precise control of an ischemic insult whereby instrument [O 2 ] can be modulated (21% to 0.1% O 2 ) to provide the desired depth and duration of hypoxia. The chamber can then be vented to model rapid reperfusion (1 to 10% in less than 10min), with parallel monitoring of ROS and MMP, facilitating detailed metabolic characterisation of the short-term metabolic implications of reperfusion and the efficacy of model therapeutic intervention.
THE PREDICTIVE VALUE OF LEFT ATRIAL FUNCTION BY SPECKLE TRACKING ECHOCARDIOGRAPHY FOR PAROXYSMAL ATRIAL FIBRILLATION RECURRENCE AFTER RADIOFREQUENCY CATHETER ABLATION
Authors: Tuantuan Tan, Bo Hu, Jin-Ling Chen, Rui-Qiang Guo, Qing Zhou
Journal: Journal of the American College of Cardiology (2019)
Comparative Accuracy of Diagnosis by Collective Intelligence of Multiple Physicians vs Individual Physicians
Authors: Michael L. Barnett, Dhruv Boddupalli, Shantanu Nundy, David W. Bates
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The traditional approach of diagnosis by individual physicians has a high rate of misdiagnosis. Pooling multiple physicians' diagnoses (collective intelligence) is a promising approach to reducing misdiagnoses, but its accuracy in clinical cases is unknown to date. <h3>Objective</h3> To assess how the diagnostic accuracy of groups of physicians and trainees compares with the diagnostic accuracy of individual physicians. <h3>Design, Setting, and Participants</h3> Cross-sectional study using data from the Human Diagnosis Project (Human Dx), a multicountry data set of ranked differential diagnoses by individual physicians, graduate trainees, and medical students (users) solving user-submitted, structured clinical cases. From May 7, 2014, to October 5, 2016, groups of 2 to 9 randomly selected physicians solved individual cases. Data analysis was performed from March 16, 2017, to July 30, 2018. <h3>Main Outcomes and Measures</h3> The primary outcome was diagnostic accuracy, assessed as a correct diagnosis in the top 3 ranked diagnoses for an individual; for groups, the top 3 diagnoses were a collective differential generated using a weighted combination of user diagnoses with a variety of approaches. A version of the McNemar test was used to account for clustering across repeated solvers to compare diagnostic accuracy. <h3>Results</h3> Of the 2069 users solving 1572 cases from the Human Dx data set, 1228 (59.4%) were residents or fellows, 431 (20.8%) were attending physicians, and 410 (19.8%) were medical students. Collective intelligence was associated with increasing diagnostic accuracy, from 62.5% (95% CI, 60.1%-64.9%) for individual physicians up to 85.6% (95% CI, 83.9%-87.4%) for groups of 9 (23.0% difference; 95% CI, 14.9%-31.2%;<i>P</i> &lt; .001). The range of improvement varied by the specifications used for combining groups' diagnoses, but groups consistently outperformed individuals regardless of approach. Absolute improvement in accuracy from individuals to groups of 9 varied by presenting symptom from an increase of 17.3% (95% CI, 6.4%-28.2%;<i>P</i> = .002) for abdominal pain to 29.8% (95% CI, 3.7%-55.8%;<i>P</i> = .02) for fever. Groups from 2 users (77.7% accuracy; 95% CI, 70.1%-84.6%) to 9 users (85.5% accuracy; 95% CI, 75.1%-95.9%) outperformed individual specialists in their subspecialty (66.3% accuracy; 95% CI, 59.1%-73.5%;<i>P</i> &lt; .001 vs groups of 2 and 9). <h3>Conclusions and Relevance</h3> A collective intelligence approach was associated with higher diagnostic accuracy compared with individuals, including individual specialists whose expertise matched the case diagnosis, across a range of medical cases. Given the few proven strategies to address misdiagnosis, this technique merits further study in clinical settings.
INITIATION OF SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS VERSUS OTHER GLUCOSE LOWERING DRUGS AND RISK OF HOSPITALIZATION FOR HEART FAILURE AND DEATH IN PATIENTS WITH TYPE 2 DIABETES WITH REDUCED AND PRESERVED LEFT VENTRICULAR EJECTION FRACTION
Authors: Carolyn S.P. Lam, Avraham Karasik, Matthew Cavender, Shun Kohsaka, Anna Norhammar, Marcus Thuresson, Hungta Chen, Eric Wittbrodt, Peter Fenici, Mikhail Kosiborod
Journal: Journal of the American College of Cardiology (2019)
Emergence of a Chimeric Globin Pseudogene and Increased Hemoglobin Oxygen Affinity Underlie the Evolution of Aquatic Specializations in Sirenia
Authors: Anthony V Signore, Johanna L A Paijmans, Michael Hofreiter, Angela Fago, Roy E Weber, Mark S Springer, Kevin L Campbell
Journal: Molecular Biology and Evolution (2019)

As limits on O2 availability during submergence impose severe constraints on aerobic respiration, the oxygen binding globin proteins of marine mammals are expected to have evolved under strong evolutionary pressures during their land-to-sea transition. Here, we address this question for the order Sirenia by retrieving, annotating, and performing detailed selection analyses on the globin repertoire of the extinct Steller's sea cow (Hydrodamalis gigas), dugong (Dugong dugon), and Florida manatee (Trichechus manatus latirostris) in relation to their closest living terrestrial relatives (elephants and hyraxes). These analyses indicate most loci experienced elevated nucleotide substitution rates during their transition to a fully aquatic lifestyle. While most of these genes evolved under neutrality or strong purifying selection, the rate of nonsynonymous/synonymous replacements increased in two genes (Hbz-T1 and Hba-T1) that encode the α-type chains of hemoglobin (Hb) during each stage of life. Notably, the relaxed evolution of Hba-T1 is temporally coupled with the emergence of a chimeric pseudogene (Hba-T2/Hbq-ps) that contributed to the tandemly linked Hba-T1 of stem sirenians via interparalog gene conversion. Functional tests on recombinant Hb proteins from extant and ancestral sirenians further revealed that the molecular remodeling of Hba-T1 coincided with increased Hb-O2 affinity in early sirenians. Available evidence suggests that this trait evolved to maximize O2 extraction from finite lung stores and suppress tissue O2 offloading, thereby facilitating the low metabolic intensities of extant sirenians. In contrast, the derived reduction in Hb-O2 affinity in (sub)Arctic Steller's sea cows is consistent with fueling increased thermogenesis by these once colossal marine herbivores.
Abstract OT2-01-01: Not presented
Authors: B Yang, J Wu
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Yang B, Wu J. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-01-01.
THE IMPACT OF SEVERITY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE ON TRANSCATHETER AORTIC VALVE REPLACEMENT: FROM THE SAPIEN 3 REGISTRY
Authors: Tomo Ando, Danny Dvir, Tamim Nazif, Alexandros Briasoulis, Ajay Kirtane, Rebecca Hahn, David Cohen, Luis Afonso, Hisato Takagi, Aaron Crowley, Maria Alu, Martin Leon, Susheel Kodali
Journal: Journal of the American College of Cardiology (2019)
Abstract 17420: Impact of Pulmonary Embolism Response Team on Outcomes of Patients With Intermediate or High Risk Pulmonary Emboli
Authors: Pulkit Chaudhury, Shruti Gadre, John R Bartholomew
Journal: Circulation (2017)

Introduction: Pulmonary embolism response team (PERT) is a multidisciplinary unit designed to deliver rapid, evidence-based and individualized care to critically ill patients with acute pulmonary e...