tbuckley/cabot-search huggingface dataset:
Abstract 612: Automated Analysis of Displacement From Intravital Multiphoton Microscopy in Mouse Ventricle
Authors: Nathaniel H Allan-Rahill, David M Small, Michael R Lamont, Salomon Djakpa, Marvarakumari G Jhala, Yvette Zhu, Nozomi Nishimura
Journal: Circulation Research (2019)

Background: Multiphoton microscopy (MPM) has enabled in vivo time-lapse imaging of the heart that shows motion of cells within the tissue with micrometer resolution. We developed automated analysis techniques to quantify cellular motion from in vivo cardiac MPM images throughout the cardiac cycle. Methods: Intravital cardiac MPM of the beating mouse heart was performed on 26 week-old, C57Bl6 mice (n=6). Image volumes (100 μm deep) were acquired at 30 frames per second while recording the electrocardiogram and respiratory pressure. An image volume was reconstructed by assembling lines acquired nearest to a specified point in the cardio-respiratory phase space (Fig. a). Motion was calculated as the three-dimensional transformation required to register the reconstructed images to the image at the most stable cardiac phase. Results: Volumes were reconstructed in 50 intervals across the cardiac phase that show vasculature (intravenous Texas-red dextran, red) and cardiomyocytes (rhodamine 6G, cyan) moving across the field of view (Fig. b). Automated analysis indicated a maximum displacement occurring at 16 % (anterior-posterior), 36 % (base-apex) and 38 % (epi-endocardial) of the cardiac cycle defined by R-wave. Comparison by manual tracking of features across the cardiac cycle at a subset of phases (10 cardiac phases at peak exhalation) validated the automated measurement (Fig. c). Automated motion tracking shows superior performance in the spatial resolution and speed of analysis. Conclusions: We have shown a novel, fast, and accurate technique for characterizing cardiac motion from in vivo cardiac MPM to study the performance of the contractile cells in health and disease.
Chloroquine Derivative Lys05 Overcomes Hypoxia-Induced Chemoresistance in Acute Myeloid Leukemia through Metabolic Disruption
Authors: Matthew Johnson, Kaitlyn Dykstra, Tara Cronin, Linda Lutgen-Dunckley, Brandon L Martens, Monica L. Guzman, Eunice S. Wang
Journal: Blood (2018)
Abstract P476: Determinants Of Atrial Fibrillation Mechanisms Using Metabolomic Profiling
Authors: Padmini Sirish, James overton, Jun Yang, Carol Nader, Bob Kiaii, Uma Srivatsa, Bruce D Hammock, Nipavan Chiamvimonvat
Journal: Circulation Research (2021)

Introduction: Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically, yet, current treatment paradigms have proven largely inadequate. One of the main contributors to the pathophysiology of AF is inflammation. Hence, reduction of inflammation associated atrial remodeling represents a novel therapeutic strategy for the treatment of AF. Oxylipins are derived from arachidonic acid, which is metabolized through three pathways including the cytochrome P450 (CYP450) pathway. The CYP450 products, epoxyeicosatrienoic acids (EETs), are major anti-inflammatory metabolites with several cardioprotective effects. The central hypothesis to be tested is that patients with AF will demonstrate an increase in oxylipin profiles towards inflammatory features compared to patients with normal sinus rhythm (NSR). We further hypothesize that lipid mediators may represent a new therapeutic target for AF. Methods: In the cross sectional study, human atrial appendage specimens and blood from informed and consented patients undergoing coronary artery bypass graft surgery were obtained in accordance with the approved UC Davis IRB protocol. Metabolomic profiling and inflammatory cytokines were assessed from the plasma of patients using LC-MS/MS. The underlying mechanisms of AF were determined using an integrated approach with molecular biology, flow cytometry, and electrophysiology. Results: Metabolomic profiling shows a significant decrease in the EETs/DHETs ratios and EpOMEs/DiHOMEs ratios in the cohort with AF compared to patients in NSR. There was a significant increase in inflammatory cytokine, chemokine levels and oxidative stress in patients with AF compared to patients in NSR. There was a significant increase in nuclear translocation of NF-κB (nNF-κB) from patients with AF compared to NSR using western blot analysis. Assessment of total IκB and phosphorylated-IκB (pIκB) levels showed a decrease in IκB level and an increase in the pIκB levels associated with the activation of NF-κB in AF compared to the NSR cohort. Conclusions: The study provides important insights into metabolomic profiles in patients with AF and reveals the prospect of oxylipins being a novel therapeutic target in the treatment of AF.
Proteomics Analysis Reveals Protein Panels That Are Associated with Prediction to Tyrosine Kinase Inhibitors Response, Bone Marrow Transplant, Survival and Disease Outcome of Chronic Myeloid Leukemia Patients
Authors: Ayodele Alaiya, Mahmoud Aljurf, Zakia Shinwari, Fahad Z. Alsharif, Hazza A. Alzahrani, Syed Osman Ahmed, Tarek Owaidah, Amr Suleiman Hanbali, Marwan Shaheen, Feras Al Fraih, Riad Elfakih, Saud Alhayli, Shahrukh Hashmi, Walid Rasheed, Fahed Almhareb, Naeem A. Chaudhri
Journal: Blood (2018)
Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy, neurological and metabolic disorders
Authors: Hui Deng, Weimin Li
Journal: Acta Pharmaceutica Sinica B (2019)

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors. Although a large number of MAGL inhibitors have been reported, novel inhibitors are still required, particularly reversible ones.
Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling
Authors: Flavian D. Brown, Debattama R. Sen, Martin W. LaFleur, Jernej Godec, Veronika Lukacs-Kornek, Frank A. Schildberg, Hye-Jung Kim, Kathleen B. Yates, Stéphane J. H. Ricoult, Kevin Bi, Justin D. Trombley, Varun N. Kapoor, Illana A. Stanley, Viviana Cremasco, Nika N. Danial, Brendan D. Manning, Arlene H. Sharpe, W. Nicholas Haining, Shannon J. Turley
Journal: Nature Immunology (2019)
NPM-ALK Regulated GSK3β Phosphorylation Results in Mcl-1 and CDC25A Accumulation and Enhanced Oncogenic Potential
Authors: Scott RP McDonnell, Steven R Hwang, Venkatesha Basrur, Kevin P Conlon, Damian Fermin, Elizabeth Wey, Carlos Murga-Zamalloa, Zihua Zeng, Youli Zu, Kojo SJ Elenitoba-Johnson, Megan S Lim
Journal: Blood (2011)
Abstract 141: Identification of a Key Regulator for Activating Bmp Signalling and Promoting Mesodermal Differentiation in Induced Pluripotent Stem Cells
Authors: Yoshikazu Kishino, Shinsuke Yuasa, Keiichi Fukuda
Journal: Circulation Research (2019)

Background: Recently, patient’s own induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) are expected to be cell sources for regenerative therapy. In stem cell differentiation into cardiomyocytes, activation of BMP and Activin signallings in early phase and suppression of Wnt signalling in late phase are important. Although small molecule chemical compounds and recombinant proteins are currently used for differentiation, however, it is better that all recombinant proteins are replaced by chemical compounds, which cost cheaper and improve the efficiency of iPSC-CM differentiation. Several chemical compounds inhibiting Wnt signalling have been reported in previous researches. On the other hand, BMP signalling activator has not been developed because there is little knowledge of factors which strongly modify BMP signalling in various cells. To address this issue, we tried to screen factors activating BMP signalling strongly. Methods and Results: To develop the screening system, we used luciferase assay including BMP-responsive element (BRE) and confirmed that our screening system promptly responds to BMP-4 stimulation. Then, we focused on the molecular target, which has a strong impact on BMP signalling. We screened the possible BMP signal regulators which were reported in previous papers by RNA interference in HEK293T cells. Among many candidate regulators, we found that knockdown of Tripartite motif 33 (TRIM33) , E3 type ubiquitin ligase, significantly and reproducibly enhanced BRE-luciferase assay and induced the expression of Id-1 gene as innate reporter gene of BMP signalling. Next, we investigate whether the suppression of TRIM33 promotes the differentiation of iPSCs into mesodermal cells. We confirmed that TRIM33 knockdown by RNA interference promoted the expression of mesodermal marker Brachyury T and epithelial-mesenchymal transition marker Slug2 in 2-dimensional cardiac differentiation. Conclusions: We successfully detected the factor activating BMP signalling. TRIM33 inhibition enhanced the expression of Id-1 gene and promoted mesodermal differentiation. In the future, chemical compounds targeting TRIM33 may be useful for regenerative medicine as BMP signalling activators.
Safety culture interventions in cancer care: A systematic review.
Authors: Dan Le, Charles Henry Lim, Rouhi Fazelzad, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2019)

247 Background: Creation of a culture of safety in healthcare organizations is fundamentally important to patient safety. However, there is limited guidance on how to effectively promote a culture of safety in healthcare settings including in oncology. We performed a systematic review to identify interventions or strategies to promote safety culture in cancer care. Methods: Medical Subject Headings and text words for “safety culture” and “cancer care” were combined to conduct structured searches in MEDLINE, EMBASE, CDSR, CINAHL, Cochrane CENTRAL, Epub Ahead of Print &amp; In-Process, PsycINFO, Scopus, and Web of Science databases, for peer-reviewed articles published between 1999 and 2017. Articles were included if they described an intervention or strategy to promote safety culture in an oncology setting, and quantitative outcomes were reported. Study quality was assessed using the ROBINS-I risk of bias tool. Results: We screened 21,572 studies, of which 46 underwent full-text review, and 19 met the inclusion criteria. Studies described interventions in radiation oncology (15 articles), medical oncology (3), and general oncology (1) settings in either North America (15) or Europe (4). The most common experimental designs were interrupted time series (10) or before-and-after comparisons (6), and were of either moderate (89%) or severe (11%) risk of bias. Interventions varied but could be broadly categorized as incident learning systems (8), quality improvement programs (7), provider education programs (2), a provider scheduling system (1), and a patient safety champion intervention (1). While 89% of studies reported improvement in safety culture, there was substantial heterogeneity in evaluated outcomes. Most assessed provider outcomes such as number of reported adverse events (11) or Agency for Healthcare Research and Quality Safety Culture survey results (7). Conclusions: Despite a growing evidence base to identify interventions to promote safety culture in cancer care, definitive recommendations were difficult to make due to heterogeneity in study designs and outcomes. Given the importance of safety culture in cancer care, additional high-quality studies and standardization of outcome measures are needed.
Abstract 896: Cardiomyocyte-derived Mir-200c-3p In Exosomes Affects Endothelial Angiogenic Capacity And Impairs Cardiac Function
Authors: Lara M Ottaviani, Rio P Juni, Marida Sansonetti, Vasco Sampaio-Pinto, Julie Halkein, Hamid el Azzouzi, Servé Olieslagers, Diana S Nascimento, Leon J de Windt, Paula A da Costa Martins
Journal: Circulation Research (2019)

While cardiomyocytes (CMs) have been the main subject of extensive research, the role of other cardiac cell types, such as fibroblasts and endothelial cells (ECs), received considerable less attention in the pathogenesis of heart failure (HF). MiRNAs have recently emerged as mediators of paracrine signaling by being selectively incorporated in exosomes and exchanged between different cell types. The aim of our study is to investigate a potential paracrine miRNA crosstalk between CMs and cardiac ECs and assess the consequences of such miRNA transfer for cardiac vascular remodeling under pathological conditions. We isolated and characterized exosomes from CMs at baseline or after pathological stimulation with phenylephrine and isoproterenol. Although baseline and stressed CMs secrete miRNA-enriched exosomes at similar rates, comparative analysis of extracellular vesicles from both conditions revealed differential miRNA levels, with miR-200c-3p being highly enriched under stress conditions. Direct transfection of ECs with miR-200c-3p precursor molecules or indirect overexpression through transwell co-culture with stimulated CMs leads to diminished angiogenesis reflected by reduced capacity of ECs to proliferate, migrate, and form tubes. This effect was abrogated when we treated CMs with GW4869, an inhibitor of exosomal biogenesis and release. Next, we tested in vivo two doses of specific miR-200c-3p antagomir, Cy3 labelled, to assess specific target of ECs. FACS analysis on cardiac cells derived from the injected mice, confirmed that a low antagomir dose targets ECs whereas, the high dose of antagomir targets all different cardiac cell types. Moreover, when we treated mice subjected transverse aortic constriction (TAC)-induced cardiac pressure overload with miR-200c-3p antagomir, the animals developed a milder hypertrophic phenotype, smaller fibrotic areas, higher amount of capillaries and preserved cardiac ejection fraction, when compared to untreated pressure overloaded mice. Altogether, our results showing exosomal transfer of miR-200c-3p from CMs to ECs indicate the importance of cardiac intercellular communication in the pathophysiology of HF and identify a potential new therapeutic target for intervention strategies.
Abstract 911: New Promoters to Improve the Efficiency of Cardiac Gene Therapies Using 2 Deoxy-ATP
Authors: Kalen Z Robeson, Farid Moussavi-Harami, Jennifer Davis, Michal Regnier
Journal: Circulation Research (2019)

Traditional inotropes work by altering intracellular calcium levels but have many off-target effects. Myosin activators have shown promise for treating the increasing number of heart failure patients today, with one drug in phase three clinical trials. These drugs work by increasing the affinity of myosin for actin. Our lab has demonstrated that the small molecule 2 deoxy-ATP (dATP) can improve both myosin binding to and myosin release from actin. We have also demonstrated the efficacy of a cardiac targeted gene therapy to improve heart function via increasing intracellular dATP levels. This was done by overexpressing ribonucleotide reductase (RNR)—the rate-limiting enzyme in de novo dNTP synthesis. This cardiac therapy, using the cardiac troponin T (cTnT) promoter, was effective in a mouse model but provided variable results in a large animal model due to delivery challenges. Therefore, we are now investigating alternative promoters to deliver dATP to cardiomyocytes and/or other striated muscles. Here we present our investigation of the CK8 promoter for striated muscle specific delivery of RNR. We report that the CK8 promoter was able to produce a greater than fourfold increase in mouse ventricular tissue dATP levels above that seen with the cTnT promoter (2.0 to 8.4 pmol/mg; P&lt;0.01). RNR was also delivered to skeletal muscle with a twofold increase in gastrocnemius dATP levels (0.62 to 1.31 pmol/mg; P&lt;0.01). We have also been investigating cardiac fibroblasts as a route to deliver dATP to cardiomyocytes. We have shown that in vitro fibroblasts can transmit dATP to coupled cardiomyocytes through gap junctions, indicating that overexpressing RNR in cardiac fibroblasts could increase dATP levels in both cell types. Previous research has shown that proliferating fibroblasts have increased levels of dATP, and preliminary results in our lab show that differentiated myofibroblasts have decreased levels of dATP. We therefore hypothesize that increased dATP in cardiac fibroblasts will not only improve contraction in coupled cardiomyocytes but may also inhibit fibroblast transdifferentiation into collagen producing myofibroblasts.
Assisted dying: restricting access to people with fewer than six months to live is discriminatory
Authors: Katherine Sleeman, Iain Chalmers
Journal: BMJ (2019)

Much of the public debate around the legalisation of assisted dying remains binary: yes or no. But this is a dangerous oversimplification. Assisted dying laws exist along a continuum, argue <b>Katherine Sleeman</b> and <b>Iain Chalmers</b>
MiRNA Profiles in Acute Lymphoblastic Leukemia: Rather a Characteristic for the Leukemia Subtype Than a Reflection of Its Differentiation Status.
Authors: Diana Schotte, Mathilde J.C. Broekhuis, Mieke W.J.C. Jansen, Rob Pieters, Chang-Zheng Chen, Monique L. Den Boer
Journal: Blood (2007)
Abstract 904: Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy
Authors: Michael J Greenberg, Sarah R Clippinger, Paige E Cloonan, Melanie Ernst, Tom Stump, Lina Greenberg
Journal: Circulation Research (2019)

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, one of the outstanding challenges in the field has been connecting mutation-induced changes in molecular function with the phenotype seen in cardiomyocytes. Many of the DCM mutation-induced changes in contractility at the molecular scale are subtle, begging the question of what other factors could link molecular-scale changes in contractile proteins with the cellular phenotype. We hypothesized that disease-causing mutations of sarcomeric proteins would likely affect not only contraction, but also how cardiomyocytes sense and respond to changes in their mechanical environment associated with aging and disease. To test this hypothesis, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, deltaK210. We determined the molecular mechanism of deltaK210 using biochemical and biophysical tools, and then we used computational modeling to predict that the mutation should reduce the force per sarcomere in cells. In mutant human stem cell derived cardiomyocytes, we found that deltaK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate impaired mechanosensing as an under-appreciated mechanism in the pathogenesis and progression of dilated cardiomyopathies. These results also have important implications for our understanding of multiple heart diseases and the design of precision therapeutics.
Association of Maternal Lactation With Diabetes and Hypertension
Authors: Rabel Misbah Rameez, Divyajot Sadana, Simrat Kaur, Taha Ahmed, Jay Patel, Muhammad Shahzeb Khan, Sarah Misbah, Marian T. Simonson, Haris Riaz, Haitham M. Ahmed
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Lactation has been shown to be associated with lower rates of diabetes and hypertension in mothers. However, the strength of association has varied between studies, and sample sizes are relatively small. <h3>Objective</h3> To conduct a systematic review and meta-analysis to determine whether lactation is associated with a lower risk of diabetes and hypertension. <h3>Data Sources</h3> Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, and CINAHL databases were searched from inception to July 2018 with manual search of the references. <h3>Study Selection</h3> Studies of adult women that specified duration of breastfeeding for at least 12 months, evaluated primary hypertension and diabetes as outcomes, were full-text articles in English, and reported statistical outcomes as odds ratios were included. <h3>Data Extraction and Synthesis</h3> Study characteristics were independently extracted using a standard spreadsheet template and the data were pooled using the random-effects model. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline for reporting was followed. <h3>Main Outcomes and Measures</h3> Diabetes and hypertension. <h3>Results</h3> The search yielded 1558 articles, from which a total of 6 studies met inclusion criteria for association between breastfeeding and diabetes and/or hypertension. The 4 studies included in the meta-analysis for the association between lactation and diabetes had a total of 206 204 participants, and the 5 studies included in the meta-analysis for the association between lactation and hypertension had a total of 255 271 participants. Breastfeeding for more than 12 months was associated with a relative risk reduction of 30% for diabetes (pooled odds ratio, 0.70 [95% CI, 0.62-0.78];<i>P</i> &lt; .001) and a relative risk reduction of 13% for hypertension (pooled odds ratio, 0.87 [95% CI, 0.78-0.97];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> This study suggests that education about the benefits of breastfeeding for prevention of diabetes and hypertension in women is a low-risk intervention that can be easily included in daily practice and may have a positive impact on cardiovascular outcomes in mothers.
Infectious Complications Following Venetoclax-Proteasome Inhibitor Based Regimens in Relapsed Myeloma: A Single Center Retrospective Analysis
Authors: Christopher Tor Sauter, Luca L Bernabei, Adam Waxman, Adam D. Cohen, Alfred L. Garfall, Dan T. Vogl, Sara Whittington,, Colleen Harker Erb, Patricia Mangan, Mary Sanchez, Edward A. Stadtmauer
Journal: Blood (2019)