tbuckley/cabot-search huggingface dataset:
Abstract 834: Roles of Muscle-specific MicroRNAs During Differentiation of Mouse Embryonic Stem Cells into Cardiac Myocytes
Authors: Tomohide Takaya, Teruhisa Kawamura, Koh Ono, Rieko Takanabe-Mori, Shinji Kaichi, Toru Kita, Hiromichi Wada, Tatsuya Morimoto, Akira Shimatsu, Koji Hasegawa
Journal: Circulation (2007)

Increasing evidence suggests important roles of microRNAs (miRs), short non-coding RNAs that repress translation or cleave RNA transcripts, in various biological processes. Previous studies report that miR-1 and miR-133 are involved in skeletal muscle differentiation, and that miR-143 is required for growth inhibition. However, the role of these miRs during differentiation of embryonic stem (ES) cells into cardiac myocytes is unknown. Mature miR-1, miR-133 and miR-143 were specifically amplified by real-time RT-PCR using miR-unique primers. These three miRs were strongly expressed in the adult mouse heart but very weakly expressed in undifferentiated mouse ES cells. Upon the induction of differentiation, the amount of each miR normalized with that of 5S ribosomal RNA was increased. Among these three miRs, the expression level in the adult heart relative to that in undifferentiated ES cells was highest in miR-1 and lowest in miR-143. To examine the role of these miRs in myocardial differentiation, we overexpressed miR-1, miR-133, or miR-143 in ES cells by lentivirus-mediated gene transfer. Overexpression of miR-1 or miR-133 reduced the expression levels of cardiac-specific genes such as Nkx2.5 and ANF, while overexpression of miR-143 had no effect. The 3′ untranslated region (3′ UTR) of mRNAs for HDAC4 and cyclin-dependent kinase 9 (CDK9), possible targets of miR-1, were subcloned downstream of luciferase cDNA in the luciferase expression vector. The expression of miR-1 in ES cells reduced luciferase activity in the CDK9 –3′UTR construct, but not in the HDAC4 –3′UTR construct. Interestingly, trichostatin A (TSA), an inhibitor of histone deacetylase, markedly decreased the levels of muscle-specific miR-1 but not those of ubiquitously expressed miR-24, induced the amount of CDK9, and specifically enhanced myocardial differentiation. A dominant-negative form of CDK9 inhibited TSA-induced differentiation of ES cells into cardiac myocytes, suggesting a role of CDK9 in myocardial differentiation. These findings demonstrate that miR-1 represses the differentiation of ES cells into cardiac myocytes, in part, by de-stabilizing mRNA of CDK9.
P454The cannabinoid receptor type two is a therapeutic target for muscular dystrophy cardiomyopathy
Authors: A Gowran, E Castiglioni, D Rovina, F Casalnuovo, P Nigro, P Spinelli, R Visone, M Rasponi, A Redaelli, G Pompilio
Journal: Cardiovascular Research (2018)

Background: Lamin A/C is involved in many cellular functions due to its ability to bind chromatin transcription factors and affect their properties.Mutations of LMNA gene encoding lamin A/C affect differentiation capacity of stem cells.However, signaling pathways involved in interaction with lamins in cellular differentiation remain unclear.Notch pathway are major differentiationresponsible pathway.Mandibuloacral dysplasia associated with LMNA R527C mutation causes bone disease.In this study we investigated the role of LMNA R527C mutation in modulating Notch signaling activity in osteogenic differentiation of mesenchymal stem cells.Purpose: To analyze lamin A/C interaction with Notch pathway during osteogenic differentiation.For this we studied the effect of the LMNA point mutation on Notch activity and osteogenic differentiation of mesenchymal stem cells.Methods: Human cardiac stem cells (CSC) were isolated from donor myocardial tissue.We introduced mutant LMNA construct (R527C) into CSC via lentiviral transduction.Notch pathway was activated by introducing Notch-activated domain into CSC using corresponding lentiviral constructs.Activation of Notch was estimated by expression of Notch-responsive genes by qPCR and by activation of luciferase CSL-reporter construct.Differentiation into osteogenic direction was induced by addition of specific inducers into culture media.Differentiation capacity was verified by the expression of specific genes for osteogenic differentiation by qPCR.Effect of LMNA mutation on Notch activation and osteogenic differentiation was analyzed in cells bearing lentiviral LMNA WT or LMNA R527C.Results: We show that point mutation in the LMNA gene leads to a change in the activity of the Notch signaling pathway, and also affects the ability of the stem cells to differentiate.Mutant forms of lamin A (LMNA R527C) have a negative effect on the functioning of the Notch signaling pathways.When Notch signaling pathway is activated, LMNA R527C mutation leads to a decrease the differentiation potential in osteogenic differentiation.Conclusion: Lamin A/C interacts with Notch signaling thereby influencing cellular differentiation and point mutation in LMNA could halt this interaction.
P500Cell shape determines gene expression: cardiomyocyte morphotypic transcriptomes
Authors: S Sagasser, P Haftbaradaran Esfahani, Z Elbeck, X Li, R Knoell
Journal: Cardiovascular Research (2018)

Background: Myocarditis evolving into heart failure belongs to the most common causes for heart transplantation in young adults.While the pathogenesis of myocarditis has been studied for decades, the contribution of the innate immune system remains incompletely understood.Purpose: To study the role of Neutrophil Extracellular Traps (NETs) and the cytokine MK for cardiac inflammation during myocarditis.Methods: Sections of endomyocardial biopsies from patients with myocarditis or from mice after induction of Experimental Autoimmune Myocarditis (EAM) were stained for NETs.Cardiac inflammation was assessed in mice with EAM after blocking NETs or the cytokine midkine (MK).Hoxb8-SCF cell-derived neutrophils generated from mice lacking the MK receptor Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) or control animals were used to study the role of the MK-LRP1 axis during neutrophil recruitment steps in microflow chambers in vitro.NET formation of isolated neutrophils was investigated in the presence of MK.Results: Here, we report for the first time the presence of NETs in cardiac tissue of patients and mice with myocarditis.Inhibition of NET formation in EAM substantially reduced cardiac leukocyte infiltration as well as compensatory cardiac hypertrophy in the acute phase of the disease.Inhibition of the cytokine MK attenuated NET formation as well as leukocyte infiltration, reduced fibrosis and preserved systolic function during EAM.Using Hoxb8-SCF cell-derived neutrophils we demonstrated that LRP1 represents the central receptor triggering MK-induced neutrophil recruitment.Moreover, mice lacking LRP1 on blood cells revealed reduced immune cell adhesion and extravasation, suggesting that MK mediates PMN recruitment and activation via LRP1.Furthermore, MK directly triggered NET formation via LRP1 in primary murine and human as well as Hoxb8-SCF cell-derived neutrophils.Conclusion: In summary, NETosis substantially contributes to the pathogenesis of myocarditis and MK drives cardiac inflammation by mediating NETosis and neutrophil trafficking.Targeting MK as well as NETs represents a novel therapeutic strategy for the treatment of myocarditis.
P89Comparative analysis of the status of the nitric oxide system in the left ventricle of heart in rats with experimental hypertension of different origin
Authors: M I Fedotova, YU M Kolesnyk
Journal: Cardiovascular Research (2018)

Background: The insufficient regenerative capacity of the adult human heart represents a great therapeutic challenge, and treatments that could promote regeneration are urgently needed.The mammalian hearts lose their intrinsic regenerative capacity within the first week of postnatal life.This coincides with a metabolic switch in cardiomyocytes, in which the energy production converts from glycolysis to lipid oxidation.More detailed understanding of the metabolic changes and regulation of cardiomyocyte cell cycle withdrawal is required for the development of regenerative therapies.Purpose: The aim of this work was to elucidate the metabolic changes occurring in the murine heart in the early postnatal period in order to identify potential new drug targets for the development of cardiac regeneration-inducing therapies.Methods: Ventricular tissue samples from C57/Bl6 mouse pups at postnatal days 1, 4, 9 and 23 (P1, P4, P9 and P23, respectively) were analysed using genome-wide RNA sequencing, quantitative shotgun proteomics (LC-MS/MS) and global metabolomics (LC-MS, GCxGC-MS).RNA sequencing was performed from one set of tissue samples (Set 2, n¼3 pooled samples per group, each from 3 hearts) while proteomics and metabolomics analyses were carried out with two separate sets of tissue samples (Sets 1 and 2; individual hearts analysed separately, n¼5-15 for each group in both sets).Differential expression analysis was carried out and changes were considered significant when FDR-corrected p<0.01.For RNA sequencing and metabolomics, a fold change limit of 1.5 was also applied.Fuzzy clustering, gene set enrichment analysis and KEGG pathway analysis were performed to identify correlative changes in RNA, protein and metabolite data.Results: The multiomics analysis identifies a number of metabolic pathways with significant and correlative changes on all levels (mRNA, protein, metabolites) within the early postnatal period.These include previously reported changes in energy metabolism, down-regulation of glycolytic pathways and up-regulation of fatty acid oxidation, as well as metabolic pathways, whose role in cardiac maturation and regeneration has not been reported.Several examples of interesting metabolic pathways that are time-wise associated with the postnatal loss of regenerative capacity of the murine heart will be presented.These may represent attractive therapeutic targets for heart failure.Conclusions: Combining RNA sequencing with proteomics and metabolomics provides a powerful tool for understanding changes in metabolic pathways and for the identification of novel drug targets.The present study provides the first resource of combined transcriptomics, proteomics and metabolomics data from the early postnatal hearts associated with the loss of regenerative potential.
Paving the Way for Improved Treatment of Acute Stroke with Tenecteplase
Authors: Alison E. Baird
Journal: New England Journal of Medicine (2018)

The treatment of acute ischemic stroke is changing rapidly. Three years ago, endovascular thrombectomy was added to thrombolysis with intravenous recombinant tissue plasminogen activator (alteplase) as a cornerstone of treatment of acute stroke. Currently, patients are treated with intravenous alteplase during the first 3 to 4.5 hours after stroke onset, and until recently, those with large-vessel occlusion were eligible to undergo thrombectomy within the first 6 hours. In the past few months, the benefits of thrombectomy have been shown to extend to 16 to 24 hours if there is remaining ischemic but not yet infarcted tissue.1,2 Eligibility to undergo thrombolysis . . .
Protracted Outbreak of <i>Salmonella</i> Newport Infections Linked to Ground Beef: Possible Role of Dairy Cows — 21 States, 2016–2017
Authors: Katherine E. Heiman Marshall, Mackenzie Tewell, Selam Tecle, Molly Leeper, Jennifer Sinatra, Bonnie Kissler, Adrienne Fung, Kerri Brown, Darlene Wagner, Eija Trees, Kelley B. Hise, Vishnu Chaturvedi, Linda K. Schlater, Brenda R. Morningstar-Shaw, Laura Whitlock, Kristin Holt, Karen Becker, Megin Nichols, Ian T. Williams, Michael Jhung, Matthew E. Wise, Laura Gieraltowski
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In January 2017, CDC identified a cluster of Salmonella enterica serotype Newport infections with isolates sharing an indistinguishable pulsed-field gel electrophoresis (PFGE) pattern, JJPX01.0010 (pattern 10), through PulseNet, the national molecular subtyping network for foodborne disease surveillance. This report summarizes the investigation by CDC, state and local health and agriculture departments, and the U.S. Department of Agriculture's Food Safety and Inspection Service (USDA-FSIS) and discusses the possible role of dairy cows as a reservoir for strains of Salmonella that persistently cause human illness. This investigation combined epidemiologic and whole genome sequencing (WGS) data to link the outbreak to contaminated ground beef; dairy cows were hypothesized to be the ultimate source of Salmonella contamination.
Abstract 20503: Trends in Sepsis and In-Hospital Mortality Among Heart Transplant Patients: A United States National Study
Authors: Srikanth Yandrapalli, Deepthi Gandhiraj, Venkat Vuddanda, Lakshmi Asritha Gollapudi, Wilbert S Aronow, Alan L Gass, Chhaya Aggarwal, William H Frishman, Julio A Panza, Gregg M Lanier
Journal: Circulation (2016)

Background:  Heart transplant recipients are at increased risk of sepsis owing to long-term immunosuppressive therapy. However, the secular variation of this complication in the United States has not been investigated.   Objective:  To examine trends of hospitalizations associated with sepsis and in-hospital mortality among heart transplant recipients using a US national database.   Methods:  Using the Nationwide Inpatient Sample databases from 2004 through 2012, we identified 119,899 hospitalizations in transplant recipient patients ≥ 18 years of age using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Of these, 6,783 admissions (mean patient age 62±13 years; 22.4% women) were associated with a concomitant diagnosis of sepsis, severe sepsis, or septic shock and were analyzed as a separate cohort.   Results:  Among all hospital admissions in heart transplant patients, the proportion of those complicated by sepsis increased from 3.32% in 2004 to 7.37% in 2012 (P   Conclusion:  In heart transplant patients, hospitalizations with sepsis-related complications increased between 2004 and 2012, while the mortality rate numerically decreased. These hospitalizations represented more than a third of the total in-hospital mortality of these patients. A more aggressive approach to manage sepsis is needed to reduce the overall mortality in heart transplanted patients.
Abstract 20255: New Polymer-Free Everolimus-Eluting Stent Using Nitrogen-Doped Titanium Dioxide Film in a Porcine Coronary Model: Micro-Computed Tomography, Optical Coherence Tomography, and Histopathological Analysis
Authors: Doo Sun Sim, Min Chul Kim, Myung Ho Jeong, Dae Sung Park, Jung Ha Kim, Kyung Seob Lim, In Ho Bae, Piao Zhehao, Hae Young Yang, Je Hoon Lee, Dae Young Hyun, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Jung Chaee Kang
Journal: Circulation (2016)

Background: Titanium dioxide (TiO2) films have been shown to be highly biocompatible and effective as drug-binding matrices for drug-eluting stents (DES). We sought to assess the efficacy of a new ...
P110Effect of MMP-2 on compromised homing of intracoronary delivery of mesenchymal stem cell in a porcine reperfused myocardial infarction: comparison with intramyocardial cell delivery
Authors: A Gugerell, K Zlabinger, D Lukovic, J Winkler, R Hemetsberger, L J Mandic, D Traxler, A Spannbauer, N Pavo, M Gyongyosi
Journal: Cardiovascular Research (2018)

Methods: Twenty-eight healthy male Wistar rats were divided into two groups, receiving vehicle (Control; n¼13) or ivabradine (IVA; 10 mg/kg/day; n¼15) in the drinking water for three consecutive weeks.All rats were implanted with radiotelemetry ECG devices and 72-h continuous ECG monitoring was performed in freely moving rats.Heart rate variability indexes in the time and frequency domains were evaluated.Results: As expected, ivabradine significantly decreased resting heart rate (351629 bpm in Control vs. 294631 bpm in IVA; p<0.0001).Chronic ivabradine treatment was associated with increased standard deviation of normal-to-normal intervals (SDNN; 27.366.4ms vs. 17.963.8ms; p<0.0001), root mean square differences of successive R-R intervals (RMSSD; 5.761.4ms vs. 2.760.6 ms; p<0.0001), proportion of successive R-R intervals difference >50 ms (pNN50; 0.2960.09% vs. 0.0760.04%;p<0.0001), as well as with increased total power (44.2617.3ms2 vs. 16.967.1 ms2; p<0.0001), normalized high (HF)-(28.6612.5% vs. 16.365.3%;p<0.01) and low (LF)-frequency (6.161.5% vs. 4.361.9%;p¼0.01) power.LF/HF ratios were not affected by ivabradine (0.260.1 vs. 0.360.1;p¼0.43).Conclusions: In healthy rats, ivabradine administration significantly increased parasympathetic activity, as reflected by the higher RMSSD, pNN50, and HF values in this group.However, the lack of change in the LF/HF ratios points towards simultaneous sympathetic activation.This ivabradineinduced sympatho-vagal coactivation could contribute to the increased propensity to atrial fibrillation reported in ivabradine-treated patients.
Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose
Authors: Siqi Gao, Robert Silasi‐Mansat, Amanda R. Behar, Florea Lupu, Courtney T. Griffin
Journal: Hepatology (2018)

The serine protease plasmin degrades extracellular matrix (ECM) components both directly and indirectly through activation of matrix metalloproteinases. Excessive plasmin activity and subsequent ECM degradation cause hepatic sinusoidal fragility and hemorrhage in developing embryos. We report here that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises hepatic sinusoidal vascular integrity in adult animals. We found that hepatic plasmin activity is up‐regulated significantly at 6 hours after APAP overdose. This plasmin up‐regulation precedes both degradation of the ECM component fibronectin around liver vasculature and bleeding from centrilobular sinusoids. Importantly, administration of the pharmacological plasmin inhibitor tranexamic acid or genetic reduction of plasminogen, the circulating zymogen of plasmin, ameliorates APAP‐induced hepatic fibronectin degradation and sinusoidal bleeding. Conclusion: These studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose. (H epatology 2018; 00:1‐13).
Low dose aflatoxin B1 toxicokinetics and intervention in human volunteers: a pilot study
Authors: George Bailey, John Mata, Graham Bench, William Tracewell, Daniel Sudakin, Clifford Pereira, Mary Garrard, Roderick Dashwood, David Williams, Carole Jubert, Tammie McQuistan, Mike Simonich
Journal: Cancer Research (2007)

1665  We have previously shown that chlorophyll (Chl) and its derivative chlorophyllin (CHL) reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings have been partially extended to humans, where CHL was found to reduce urinary excretion of aflatoxin B1 (AFB1)-DNA repair products in rural Chinese unavoidably exposed to dietary AFB1. However, no AFB1 pharmacokinetic data were gathered by that study, and Chl was not included. To address this a small un-blinded crossover study is under way to establish AFB1 toxicokinetic parameters in human volunteers, and the effects of CHL or Chl co-treatment on those parameters. For protocol 1, fasted subjects received an IRB-approved dose of 14C-AFB1 (31.2 ng, 5 nCi) by gelatin capsule with 100 ml water, followed by normal eating and drinking after hr 2. Blood and total urine samples were collected at specified intervals over 72 hr, and 14C-AFB1 equivalents were determined by accelerator mass spectrometry. The protocol was repeated 3 times for each volunteer. Plasma sample analysis revealed a rapid absorption phase, reaching a Cmax of 0.567 ± 0.095 fg/ml at 1 hr (Tmax) (volunteer 1) and 0.534 ± 0.083 fg/ml at 0.92 ± 0.52 hr (volunteer 2). A two compartment model with first-order input and elimination was fitted to each plasma data set, yielding absorption rate constants for volunteers 1 and 2 of 7.22 ± 4.34 hr-1 and 12.46 ± 7.92 hr-1, mean plasma distribution half-lifes (t1/2 α) of 2.02 ± 0.35 hrs and 4.41 ± 2.79 hrs, terminal half-lifes (t1/2 β) of 68.52 ± 49.27 and 92.04 ± 31.18, and AUC(0-24) of 7.26 ± 2.27 pg hr/L and 7.40 ± 0.46 pg hr/L, resp. Urine eliminated over 0-24 hr contained 28.0 ± 2.2% and 35.0 ± 7.9% of the administered dose for volunteers 1 and 2, resp. Protocols 2 and 3 were similar except capsules also contained 150 mg of Chl purified from spinach, or CHL, resp. Though still in progress, single-trial results suggest CHL delayed AFB1 absorption and reduced Cmax and AUC., whereas Chla reduced absorption, Cmax and AUC. These initial results are providing AFB1 toxicokinetic parameters previously unavailable for humans, and suggest that Chl and CHL may limit the bioavailability of aflatoxin in humans as in animals. (Partially supported by NIH grants ES00210, ES03850, CA90890. The AMS work was performed under the auspices of the U.S. D. O.E. by University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48.)
Loss of PSMA Expression in Non-neuroendocrine Dedifferentiated Acinar Prostate Cancer
Authors: Peter Bronsert, Kathrin Reichel, Juri Ruf
Journal: Clinical Nuclear Medicine (2018)

The introduction of tracers targeting the prostate-specific membrane antigen (PSMA) has revolutionized PET imaging of acinar prostate adenocarcinoma. In general, an increasing PSMA expression is assumed with increasing dedifferentiation. Whereas loss of PSMA expression has been reported in case of neuroendocrine dedifferentiation, we present a patient with acinar prostate adenocarcinoma with a loss of PSMA expression after chemotherapy on PET/CT and in histological and immunohistochemical analyses. All tissue samples indicated the retention of acinar features but no expression of neuroendocrine markers (NSE, synaptophysin, chromogranin, and CD56), corresponding to nonelevated serum NSE.
Atrial Fibrillation Burden: Moving Beyond Atrial Fibrillation as a Binary Entity: A Scientific Statement From the American Heart Association
Authors: Lin Y. Chen, Mina K. Chung, Larry A. Allen, Michael Ezekowitz, Karen L. Furie, Pamela McCabe, Peter A. Noseworthy, Marco V. Perez, Mintu P. Turakhia
Journal: Circulation (2018)

Our understanding of the risk factors and complications of atrial fibrillation (AF) is based mostly on studies that have evaluated AF in a binary fashion (present or absent) and have not investigated AF burden. This scientific statement discusses the published literature and knowledge gaps related to methods of defining and measuring AF burden, the relationship of AF burden to cardiovascular and neurological outcomes, and the effect of lifestyle and risk factor modification on AF burden. Many studies examine outcomes by AF burden classified by AF type (paroxysmal versus nonparoxysmal); however, quantitatively, AF burden can be defined by longest duration, number of AF episodes during a monitoring period, and the proportion of time an individual is in AF during a monitoring period (expressed as a percentage). Current guidelines make identical recommendations for anticoagulation regardless of AF pattern or burden; however, a review of recent evidence suggests that higher AF burden is associated with higher risk of stroke. It is unclear whether the risk increases continuously or whether a threshold exists; if a threshold exists, it has not been defined. Higher burden of AF is also associated with higher prevalence and incidence of heart failure and higher risk of mortality, but not necessarily lower quality of life. A structured and comprehensive risk factor management program targeting risk factors, weight loss, and maintenance of a healthy weight appears to be effective in reducing AF burden. Despite this growing understanding of AF burden, research is needed into validation of definitions and measures of AF burden, determination of the threshold of AF burden that results in an increased risk of stroke that warrants anticoagulation, and discovery of the mechanisms underlying the weak temporal correlations of AF and stroke. Moreover, developments in monitoring technologies will likely change the landscape of long-term AF monitoring and could allow better definition of the significance of changes in AF burden over time.