tbuckley/cabot-search huggingface dataset:
Abstract 178: Development of a New Structural Family of Microbial Choline Trimethylamine Lyase Inhibitors for the Treatment and Prevention of Cardiovascular Disease
Authors: Ashraf S Duzan
Journal: Circulation Research (2019)

Ashraf Duzan, BPharm., MS 1,2 ; Xiaodong Gu, Ph.D. 1,3 ; Adam Roberts, Ph.D. 1,3 ; Jennifier Buffa, MS 1,3 ; James Anderson 1,3 , Valentine Gogonea, Ph.D 1,2,3 Stanley L. Hazen, MD, Ph.D. 1,2,3 . 1 Department of Cellular &amp; Molecular Medicine, 3 Center for Microbiome and Human Health, 4 Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195; 2 Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115 Recent clinical research points to trimethylamine N-oxide (TMAO), a gut microbiota generated metabolite, as a biomarker associated with acute thrombotic event and cardiovascular disease risks, and a direct causative contributor to these adverse phenotypes. Our goal in this project is to develop novel microbial enzyme inhibitors that alter the biosynthetic pathway of TMAO in vivo through the selective potent inhibition of gut microbial choline trimethylamine (TMA) lyase activity, the rate limiting step in TMA and TMAO generation in vivo. TMA generation by gut microbiota is predominantly catalyzed by the gut microbial enzyme pair CutC/D, members of the microbial choline utilization ( cut ) gene cluster. We are using structure activity relationships (SAR) to predict new classes of chemical structures as potential efficient inhibitors. Thus, we are exploring the synthesis of new chemical compounds, non-lethal to the gut microbial community, with high inhibitory potency in multiple in vitro assays employing evolutionarily diverse microbial cutC/D (primary and secondary screens), polymicrobial communities (tertiary screens), and for inhibitors that pass the above screening assays, progression to in vivo studies. We are preparing and assessing inhibitors that can work either through irreversible non-competitive or competitive mechanisms, possess appropriate physico-chemical pharmaceutical properties and have minimal systemic exposure to the host in effort to minimize possibility of side effects. Our leading candidates have excellent enzyme blocking efficiency and display good pharmacokinetic/pharmacodynamics properties.
Abstract 717: CGMP Expanded First Trimester Human Umbilical Cord Perivascular Cells (FTM HUCPVC) Induce Significant Angiogenesis, Myocardial Regeneration and Sustained Functional Recovery Exceeding Older MSC Sources in the Rat Myocardial Infarction (MI) Model
Authors: SzÃ¡raz PÃ©ter, Alexander Johnston, Farwah Iqbal, Banafshe Hoseini, Alexandra Lucato, Poonam Mander, Jun Wu, Ren-Ke Li, Clifford Librach
Journal: Circulation Research (2019)

Introduction: FTM HUCPVC are a novel source of young, immunoprivileged mesenchymal stromal cells (MSC). FTM HUCPVC demonstrate significant homing, angiogenic and tissue remodelling capacities in vitro . We aimed to explore the therapeutic potential of cGMP compliant FTM HUCPVC for myocardial infarction (MI). Methods: FTM HUCPVC and term HUCPVC were expanded in cGMP compliant xeno-free (5% HPL) multilayer cultures (Corning) and Quantum Bioreactor (Terumo). One week post-MI Fox rnu rats (n=6) were intramyocardially injected with 3 million FTM HUCPVC, term HUCPVC, bone marrow MSC (BMSC) or basal media. Cardiac function (echocardiography, pressure/volume catheter and ECG telemetry), infarct scar (Trichrome), ECM remodelling activity (DQ collagenase substrate) vascular density (IB4) and contractile proteins (SarcA) were quantified 4 weeks and 6 months after cell implantation. Myocardial apoptosis (caspase-3) and macrophage infiltration (eNOS, CD68, CD80) were assessed at 5 days after cell treatment. Results: FTM HUCPVC significantly reduced apoptosis at 5 days and infarct size at 4 weeks (5.3±1.1, p&lt;0.05) compared to other treatment groups. Histological analysis showed that the infarcted region of FTM HUCPVC treated hearts displayed significantly higher: M2 macrophage ratio, perivascular gelatinase activity, capillary density (543.4±118.6 vs. 276.5±42.69; p&lt;0.05), abundance of contractile sarcomeric actinin (48.9±6.1 vs. 19.5±7.0; p&lt;0.05), and Ca 2+ pump SERCA (69.9±5.9 vs. 49.8±3.7) over other experimental groups. FTM HUCPVCs induced significant and superior improvements in all measures of contractile function (ESV, EF, dPdt, tau) relative to cell-free media (p&lt;0.001), BMSC (p&lt;0.001) and term HUCPVC (p&lt;0.001). Improvements in inotropy and lusitropy were maintained to 6 months (δ dPdt max 3.8±6.0; δ dPdt min 3.2±8.78) and resulted in near complete abolishment of premature ventricular contractions (&lt;1/min). Conclusion: FTM HUCPVC treatment after MI induces superior structural and functional recovery compared to older MSC sources; characteristics that were maintained during xeno-free upscaling and for up to 6 months post injection. FTM HUCPVC are a promising option as a novel cell therapy for optimal cardiovascular regeneration.
Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy
Authors: Luzalba Sanoja-Flores, Juan Flores-Montero, Noemi Puig, Teresa Contreras-Sanfeliciano, Roberia Pontes, Alba Corral-Mateos, Omar García-Sánchez, María Díez-Campelo, Roberto José Pessoa de Magalhães, Luis García-Martín, José María Alonso-Alonso, Aranzazú García-Mateo, Carlos Aguilar-Franco, Jorge Labrador, Abelardo Barez-García, Angelo Maiolino, Bruno Paiva, Jesús San Miguel, Elaine Sobral da Costa, Marcos González, María Victoria Mateos, Brian Durie, Jacques J. M. van Dongen, Alberto Orfao
Journal: Blood (2019)
A Retrospective Analysis of Outcomes of Diffuse Large B Cell Lymphoma (DLBCL) in the Elder Patients in China
Authors: Peng Liu, Ying Han, Jianliang Yang, Xiaohui He, Changgong Zhang, Shengyu Zhou, Yan Qin, Liqiang Zhou, Song Yongwen, Ming-Zhe Han, Yan Sun, Yuankai Shi
Journal: Blood (2018)
Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)
Authors: Bernd Metzner, Jochen Casper, Koehne Claus-Henning, Andrea Renzelmann, Thomas H. Mueller, Eduard K. Petershofen, Bernd Rosien, Ruth Thole, Andreas Voss, Martin H. Dreyling, Eva Hoster, Wolfram Klapper, Christiane Pott
Journal: Blood (2019)
Abstract 563: Cardiac TIGAR Reduces Myocardial Energetics and Cardiac Functionin the Pressure Overload Heart Failure Model
Authors: Yoshifumi Okawa, Atsushi Hoshino, Tomoya Kitani, Ryoetsu Yamanaka, Daichi Hato, Sakiko Honda, Yohei Fushimura, Ryota Urata, Yoshito Minami, Shyo Hashimoto, Ayumi Matsuki, Shunta Taminishi, Toshiyuki Nishiji, Tomohiro Hino, Nobuichiro Yagi, Eri Iwai-Kanai, Satoaki Matoba
Journal: Circulation Research (2019)

Background: Although metabolic alterations were observed in heart failure (HF), only recently have the mechanisms underlying these changes been identified. Tumor suppressor p53 responds to metabolic changes thorough several mechanisms. One of the p53 targets, TIGAR (TP53-induced glycolysis and apoptosis regulator) reduces glycolysis and suppresses autophagy, which augments ischemic damage, however its role on HF is unclear. Method and Results: In order to investigate TIGAR’s function in HF, we compared myocardial metabolic and functional outcomes between TIGAR deficient (TIGAR–/–) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR–/– mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared to those of TIGAR–/– mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR–/– hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice (TIGARflox/flox/ Tg(Myh6-cre/Esr1) mice). Conclusion: The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR targeted therapy to increase glucose metabolism will be a novel strategy for HF.
Novel intragastric trocar placement by percutaneous endoscopic gastrostomy technique to facilitate pyloromyotomy
Authors: Diogo Turiani Hourneaux de Moura, Hiroyuki Aihara, Ahmad Najdat Bazarbashi, Christopher C. Thompson
Journal: Endoscopy (2019)

Motility disorders of the stomach, such as gastroparesis, are commonly encountered in clinical practice [1]. The treatment of these disorders remains controversial. Although surgery is usually reserved for patients with chronic and severe symptoms refractory to medical therapy, the true benefit and risk profiles remain unclear [2]. Recently, a new endoscopic technique, termed gastric peroral endoscopy myotomy (G-POEM) has been described. This technique has shown promising results. However, G-POEM is technically challenging and highly dependent on the skill of the endoscopist. To date, several variations of this procedure have been reported [3].
Abstract 578: Brg1 Protects Cardiomyocytes Against Oxidative Damage Through Activation of the Nrf2 Signaling Pathway in Acute Myocardial Infarction
Authors: Ning Hou, Xiaoping Liu, Guanfeng Liang, Jiandong Luo
Journal: Circulation Research (2019)

Background: Brahma-related gene 1 (Brg1), the core ATPase subunit of a large chromatin remodeling complex, plays critical role in the regulation of gene expression during cardiac growth, differentiation. In adults, Brg1 is turned off in cardiomyocytes and reactivated by cardiac stress. How Brg1 in myocardial infarction (MI) is poorly understood. The Keap1-Nrf2-ARE pathway plays an important role in the development of MI. However, by which Nrf2 activation is mediated in MI still remains to be determined. Methods and results: In vivo, adult male C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery for MI model. Our data demonstrated that in peri-infarct zone, the protein of Brg1 was significantly increased 7 days after MI compared with the sham group, accompanied by Nrf2 nuclear translocation, and upregulation of the expressions of NQO1, GSTP1, HO1. We further revealed that with adenoviral intramyocardial injection, the Brg1 overexpression reduced the percentage myocardial infarct, improved cardiac dysfunction, decreased the relative fluorescence intensity of ROS with fluorescent probe DHE in MI mice. Conversely, shRNA-mediated knockdown of Brg1 enlarged the percentage myocardial infarct, exacerbated cardiac dysfunction, increased the relative fluorescence intensity of ROS. More importantly, the Brg1 overexpression significantly induced Nrf2 translocation from cytoplasm to nuclear and upregulated NQO1, GSTP1 and HO1 expressions. Whereas Brg1 knockdown decreased the level of Nrf2 protein in the nucleus, suppressed NQO1,GSTP1 and HO1 expressions. In vitro, Oxygen-Glucose deprivation(OGD) on neonatal cardiomyocytes was established. The effects of Brg1 on OGD and Nrf2 activation were observed with gain- and loss-of-function approaches to regulate Brg1 expression. The results were consistent with in vivo study. Moreover, the down-regulation of Nrf2 by brusatol inhibited the increase of these antioxidative genes induced by Brg1 overexpression. Conclusions: This study indicated that Brg1-induced cardiac protection was partially mediated through transcription activator Nrf2. The Brg1-Nrf2-ARE pathway may represent a novel therapeutic target for preventing cardiac dysfunction in patients with MI.
Chinese medical students and residents' perspectives on medical education for professional role formation: an exploratory cross-sectional study
Authors: Lihong Fan, Russell O Kosik, Angela P Fan, Xudong Zhao, Yunung Hsu, Yuhong Gjiang, Lei Huang, Dan Li, Christopher Lu, Yuanpeng Ren, Baisheng Jiang, Qi Chen
Journal: The Lancet (2019)
GP is struck off after writing reports on holiday sickness for wife’s law firm
Authors: Clare Dyer
Journal: BMJ (2019)

A GP who wrote expert reports on holiday sickness claims for his wife’s law firm has been struck off the UK medical register for failing to declare a conflict of interest and repeatedly diagnosing food poisoning in tourists without sufficient evidence.

A medical practitioners tribunal also found that Zuber Bux, 47, had carried out an unsafe circumcision in the community, of a 15 month old baby with a heart defect. The child was admitted to hospital a few hours after the procedure.

Bux qualified at Liverpool in 1994 and worked as a GP in the area. Since 2016 he has done locum and out-of-hours work, but before that he was a practice partner.

He began to produce medicolegal reports for his wife’s firm in 2008 on road accident cases. He stopped this in 2011 after the …
Retrospective Analysis of 149 Unselected Patients with Mantle Cell Lymphoma Confirms Prognostic Relevance of Mantle Cell Lymphoma International Prognostic Index: Single Center Experience
Authors: Guldane Cengiz Seval, Bahar Ulas, Onur Tascı, Fulya Ozel, Buğu Bulat, Isinsu Kuzu, Sinem Civriz Bozdag, Selami Kocak Toprak, Meltem Kurt Yuksel, Pervin Topcuoglu, Muhit Özcan, Meral Beksac, Osman Ilhan, Gunhan Gurman, Onder Arslan
Journal: Blood (2018)
Abstract 875: Cardiomyocyte Derived DDT Protects Against Myocardial Infarction Induced Heart Failure
Authors: Yina Ma, Xiaoyue Hu, Xiaohong Wu, Daniel Pfau, Lin Leng, Kenneth Bedi, Kenneth Margulies, Richard Bucala, Lawrence Young
Journal: Circulation Research (2019)

Background: D-dopachrome tautomerase (DDT), the only homolog of macrophage migration inhibitory factor (MIF), is a cytokine highly expressed in cardiomyocytes and has autocrine-paracrine effects, signaling through the CD74 receptor. Endogenous DDT and MIF prevent ischemia-reperfusion injury in mice. In this study, we investigated whether endogenous cardiomyocyte DDT protects against myocardial remodeling and heart failure after myocardial infarction. Methods: Cardiomyocyte-specific DDT knockout (cKO) and littermate control (CON) mice underwent myocardial infarction (MI) or sham surgery. Serial echocardiography was performed at baseline, 1 day before permanent coronary ligation and 1 day, 1 week, and 4 weeks after MI or sham surgery. Hearts were analyzed at 3 days after MI or sham surgery for histology and molecular studies. Results: No baseline differences in left ventricular (LV) function were observed in cKO and CON mice at baseline or after sham surgery. The initial infarction sizes were comparable at 1 day after coronary ligation in cKO and CON. Compared to CON, cKO mice developed more rapid LV dilatation, and decreased LV ejection fraction (EF) and stroke volume (SV) as early as 1 week after MI. At 4 weeks after MI, LVEF was 33% lower and SV lower by 43% in cKO vs. CON (n=4-5/group, all P&lt;0.01). Hemodynamic analysis showed that LV end diastolic pressure in the cKO mice was 38% higher in cKO vs. CON after 4 weeks MI (p=0.052). Immunoblots showed diminished phosphorylation of AMPK and downstream ACC in the cKO mice 3 days after MI. Immunohistochemistry staining with CD3 and F4/80 staining showed increased T cells and macrophage cells in the cKO mice 3 days after MI (p&lt;0.05). We further assessed the regulation of cardiac DDT expression in chronic human heart failure. In hearts explanted from patients with advanced heart failure during transplantation for ischemic cardiomyopathy (n=8), DDT mRNA and protein expression were also reduced by 40% and 58% compared to controls (P&lt;0.01). Conclusion: Cardiomyocyte-derived DDT prevents adverse cardiac remodeling after MI, potentially through AMPK signaling and anti-inflammatory effects. Down-regulation of cardiac DDT may contribute to pathogenesis of advanced heart failure.
Will Emergency Holds Reduce Opioid Overdose Deaths?
Authors: Elizabeth A. Samuels, Otis U. Warren, Corey S. Davis, Paul P. Christopher
Journal: New England Journal of Medicine (2019)

Some state lawmakers are contemplating enacting laws that permit certain patients with severe substance use disorder to be involuntarily detained for short-term observation and, in some cases, treatment. Such laws raise ethical, legal, medical, and practical questions.
Abstract 562: Comprehensive Arteriovenous Metabolomics in the Human Heart
Authors: Danielle S Murashige, Cholsoon Jang, Michael D Neinast, John W Elrod, Daniel P Kelly, Joshua D Rabinowitz, David S Frankel, Zoltan P Arany
Journal: Circulation Research (2019)

Introduction: Despite broad interest in the role of metabolism in the pathogenesis of heart failure, a definitive account of fuel use by the beating human heart in situ is lacking. We therefore determined the uptake and release of over 270 metabolites by simultaneous sampling of arterial, coronary sinus, and femoral venous blood in 100 patients. Methods: We enrolled 100 patients (60% male, 12% diabetic, age = 63.6 +/- 13.5 years, BMI = 29.75 +/- 6.1, EF = 57.14 +/- 6.48) undergoing ablation of atrial fibrillation. We used liquid chromatography-mass spectrometry to quantify over 270 metabolites in plasma from coronary sinus, femoral vein, and arterial blood. We also measured O 2 and CO 2 concentration, as well as atrial pressure. Results: We detected uptake or release of 77 metabolites by the heart and 136 metabolites across the leg (p &lt;0.05 after Benjamini-Hochberg correction). We determined the cardiac extraction of all major fuel sources, including 29 fatty acids, 11 amino acids, lactate, acetoacetate, and 3-hydroxybutyrate. Several patterns emerge: first, while the leg extracts glucose (FV/A = 0.95, q = 4.7x10-14) and releases lactate (FV/A = 1.11, q = 2.87x10-14), the heart extracts lactate (CS/A = 0.95, q = 3.77x10-9) and neither extracts nor secretes glucose. Second, while the leg releases nearly all fatty acid and amino acid species, the heart consumes most fatty acids and certain non-essential amino acids. Third, extraction of unsaturated acylcarnitines correlates with left atrial pressure (p&lt;0.01). Finally, we find a significant positive correlation between myocardial O2 consumption and extraction of ketones (p &lt; 0.01), but not other major cardiac fuels. Conclusion: We present the most comprehensive study to date of metabolite use and secretion by the human heart. We find the heart to be an avid consumer of fatty acids and ketone bodies, but less so of glucose and essential amino acids. Consumption of ketones increases with O2 consumption, suggesting that ketones may be a preferential fuel source under high work loads. Extraction of certain acylcarnitines increases with left atrial pressure, indicating metabolic reprogramming under high filling pressures. In summary, we provide the first comprehensive model of fuel use by the beating human heart in situ.
First Treatment for Lung Disease Related to Scleroderma
Authors: Feyza Sancar
Journal: JAMA (2019)

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Abstract 482: Modeling PKP2 Mutation Associated Arrhythmogenic Cardiomyopathy With CRISPR-edited iPSC-derived Cardiomyocytes in Engineered Cardiac Tissues
Authors: Kehan Zhang, Samuel Tomp, Jourdan K Ewoldt, Christopher N Toepfer, Anant Chopra, Christine E Seidman, Jonathan G Seidman, Christopher S Chen
Journal: Circulation Research (2019)

Arrhythmogenic cardiomyopathy (ACM), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a leading cause of sudden death among young adults. Over half of ACM cases are associated with inherited desmosome gene mutations, most commonly in the gene PKP2 which encodes plakophilin-2. One of the obstacles to better understanding ACM pathogenesis is the lack of appropriate models which encompass the early stages of disease development; this imposes significant constraints on the advancement of clinical therapies. The recent advent of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) has enabled the development of models for studying human cardiac cell biology and pathology. In this work, we combine hiPSC-CMs, CRISPR/Cas9 genome editing, and engineered cardiac tissue platforms to develop human in vitro systems for investigating the molecular mechanisms of ACM pathogenesis. Isogenic control and mutant cell lines of hiPSC-CMs harboring ACM-associated PKP2 mutations were generated using CRISPR/Cas9 technology. Specifically, the PKP2tv cell line has an early truncation in plakophilin-2 that mimics PKP2 c.235C&gt;T found in multiple family lineages. The effects of the PKP2tv mutation on cardiac tissue contractility were characterized using a 3D cardiac micro-tissue (CMT) platform. CMTs composed of PKP2tv cardiomyocytes were shown to have significantly decreased contractile forces compared to the control, which recapitulates the reduced ventricular systolic function seen in ACM patients. This result demonstrated the feasibility of using the hiPSC-derived tissue-engineering model to recapitulate ACM disease phenotype and allow for future investigation into the disease mechanisms.