tbuckley/cabot-search huggingface dataset:
Abstract 409: Regulation of Cardiomyocyte Maturation by an RNA Splicing Regulator Rbfox1
Authors: Josh Zixi Lee, Jijun Huang, Christoph Rau, Chen Gao, Ziyue Yang, He Wang, Ivan Pushkarsky, Shan Parikh, Dino Di Carlo, Bjorn Knollmann, Yibin Wang
Journal: Circulation Research (2019)

The maturation of stem cell derived cardiomyocytes (iCMs) is incomplete relative to the fully matured adult myocytes. Lack of maturation represents a major limitation to the applications of iCMs as heart disease models or heart failure therapies. Current attempts to promote iCMs maturation, such as prolonged culture, mechanical stretching and electronic pacing, are often based on empirical methods with poor reproducibility or little mechanistic basis. In order to better understand the molecular mechanisms driving cardiomyocyte maturation, we performed extensive transcriptome analyses in neonatal vs. adult hearts. In addition to metabolic and cell cycle regulatory pathways, Gene Ontology analysis revealed RNA splicing regulation is significantly enriched in the transcriptome reprogramming during postnatal maturation in heart. Specifically, we find a cardiomyocyte enriched RNA splicing factor Rbfox1 is dramatically induced in the perinatal maturating mouse hearts. Ectopic expression of Rbfox1 in neonatal cardiomyocytes markedly promotes the cellular and molecular features of adult cardiomyocyte, including contractility, calcium handling, sarcomere organization, morphology, electrophysiology and gene expression. Most remarkably, expression of RBFox1 in human iPSC derived cardiomyocytes promotes similar maturation process as observed in the neonatal rat myocytes. At mechanistic level, RBFox1 expression in the iCMs enhances transcriptome maturation as indicated by targeted RNA splicing in genes involved in muscle contraction, gene expression, RNA processing and sarcomere organization. In summary, we have uncovered a novel molecular path towards neonatal myocyte maturation in perinatal murine hearts by targeted modulation of cardiomyocyte transcriptome via RNA-splicing. This approach has potential to be employed as a molecular approach to promote human iCMs maturation.
A Clinico-Genotypic Prognostic Index for De Novo Composite Diffuse Large B-Cell Lymphoma Arising from Follicular Lymphoma in the Rituximab Era
Authors: Ryan Mao Heng Lim, Natalie Pei Xin Chan, Lay Poh Khoo, Chee Leong Cheng, Leonard Tan, Eileen Yi Ling Poon, Nagavalli Somasundaram, Mohamad Farid, Tiffany Tang, Miriam Tao, Soon Thye Lim, Jason Yongsheng Chan
Journal: Blood (2018)
Abstract 766: SGLT-Mediated Na <sup>+</sup> Overload Results in Oxidative Stress and Abnormal SR Ca <sup>2+</sup> Release in Diabetic Hearts
Authors: Sathya Velmurugan, Amanda Hoskins, Florin Despa, Sanda Despa
Journal: Circulation Research (2019)

Intracellular Na + concentration ([Na + ] i ) regulates Ca 2+ cycling, oxidative state and electrical stability of the heart. [Na + ] i is linked to glucose uptake through the Na + -glucose cotransporter (SGLT). The SGLT1 isoform is present in the heart and its overexpression causes hypertrophy and left-ventricular dysfunction. Here, we hypothesized that cardiac SGLT activity is increased in type-2 diabetes (T2D), which causes myocyte Na + overload and results in oxidative stress and exacerbated sarcoplasmic reticulum (SR) Ca 2+ leak. To test this hypothesis, we analyzed myocardial tissue from humans with/without T2D and compared rats with late-onset T2D that display diabetic cardiomyopathy similar to that seen in humans (HIP rats) with their non-diabetic littermates (WT). SGLT1 expression was increased in hearts from T2D patients compared to non-diabetic individuals and in hearts from HIP vs . WT rats. SGLT inhibition significantly decreased the uptake of both glucose and Na + in myocytes from HIP rats but not in WT, which indicates that SGLT function is increased in T2D hearts. While SGLT1 upregulation may partially compensate for the reduced insulin-dependent glucose uptake, the ensuing raise in Na + influx resulted in elevated [Na + ] i in HIP myocytes (by 3 mM compared to WT). Higher [Na + ] i causes oxidative stress by activating the mitochondrial Na + /Ca 2+ exchanger (mitoNCX), which lowers mitochondrial [Ca 2+ ] and thus slows down regeneration of the antioxidant NADPH. In agreement with a role for elevated [Na + ] i in causing oxidative stress in T2D hearts, H 2 O 2 production was increased in HIP myocytes vs . WT and mitoNCX inhibition, which uncouples mitochondria from [Na + ] i , significantly reduced H 2 O 2 production in HIP hearts. Oxidative stress enhances the SR Ca 2+ leak directly through oxidation of ryanodine receptors (RyRs) and indirectly via CaMKII activation and consequent RyR phosphorylation. SR Ca 2+ leak was augmented in myocytes from HIP vs . WT rats and mitoNCX inhibition significantly reduced the leak in HIP myocytes, but not in the WT. Thus, our data indicate that SGLT activity is enhanced in myocytes from T2D rats, which increases Na + influx and causes Na + overload. Elevated [Na + ] i contributes to oxidative stress and abnormal SR Ca 2+ leak in diabetic hearts.
Abstract 116: Inhibition of Autosis Attenuates Ischemia/reperfusion Injury in the Heart
Authors: Gihoon NAH, Alvaro Fernandez, Peiyong Zhai, Beth Levine, Junichi Sadoshima
Journal: Circulation Research (2019)

Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. Recent studies provided evidence that excessive autophagy induces cell death with characteristic morphological and biochemical features, termed autosis. However, whether autophagy contributes to death in cardiomyocytes (CMs) is controversial. We here show that inhibition of autosis by targeting Rubicon attenuates ischemia/reperfusion (I/R) injury in the heart. Treatment with TAT-Beclin1 (TB1), a peptide that mobilizes endogenous Beclin 1, increased autophagic flux and induced cell death in CMs, which was inhibited by inhibitors of autophagy but not apoptosis or necrosis. CMs treated with TB1 at high doses showed typical morphological and biochemical features of autosis, namely an increased number of autophagic vacuoles with ballooning of perinuclear spaces and rescue of cell death by downregulation of Na + ,K + -ATPase. To examine whether autosis is activated by I/R in the heart in vivo , mice were subjected to 30 minutes of ischemia followed by 24 hours of reperfusion, and autophagic flux and morphological features of CMs were examined at several time points. Autophagic flux was increased during ischemia and the early phase of reperfusion; however, more autophagosomes started to accumulate 6 hours after reperfusion due to suppression of autophagosome maturation, which was caused by increased Rubicon expression. CMs exhibited typical morphological features of autosis and Na + ,K + -ATPase was significantly upregulated starting 6 hours after reperfusion. Injection of ouabain into cardiac glycoside- sensitive knock-in mice exhibited protection against I/R injury with decreased features of autosis. To normalize autophagic flux during I/R, we generated cardiac-specific Rubicon knockout ( rubi -cKO) mice. rubi -cKO prevented the marked accumulation of autophagosomes and significantly reduced the size of infarct following I/R, with prominent suppression of autosis. These results indicate that autosis is triggered by dysregulated autophagic flux due to upregulation of Rubicon during the late phase of I/R in the heart and that inhibition of autosis protects the heart against I/R injury.
Abstract 865: The E3 Ubiquitin Ligase Parkin Regulates Metabolism From the Nucleus
Authors: Sarah E Shires, Rita H Najor, Leonardo J Leon, Melissa Q Cortez, Åsa B Gustafsson
Journal: Circulation Research (2019)

Parkin facilitates mitophagy by ubiquitinating depolarized mitochondria to label them for degradation. We have previously shown that Parkin is important for adaptation to myocardial infarction (MI) and that loss of Parkin leads to accumulation of dysfunctional mitochondria. Although Parkin is mainly studied for its role at the mitochondria, it is unclear whether Parkin also functions in other subcellular compartments. Here, we used immunofluorescence and subcellular fractionation to find that a portion of Parkin localizes to the nucleus under basal conditions in vitro and in vivo . Pathogenic Parkin mutants, however, are selectively excluded from the nucleus. To further examine conditions that induce Parkin nuclear enrichment, we subjected HeLa cells stably expressing YFP-Parkin to starvation or hypoxia. During nutrient-deprivation, Parkin rapidly exits the nucleus and accumulates in the cytosol. Conversely, exposure to hypoxia causes Parkin enrichment in the nucleus and depletion from the cytosol. To separate the roles of nuclear versus mitochondrial Parkin, we generated nuclear- and mitochondrial- targeted constructs: NLS-Parkin and Mito-Parkin. RNA-sequencing analysis revealed widespread transcriptional changes in response to targeting Parkin to the nucleus, particularly in metabolic processes. Through a non-biased proteomics screen, we identified the transcription factor estrogen related receptor α (ERRα) as a potential Parkin target. ERRα is highly expressed in the heart and promotes transcription of genes involved in mitochondrial biogenesis and metabolism. We therefore used co-immunoprecipitation and qPCR to determine whether Parkin regulates cellular energetics through ERRα. Indeed, we found that NLS-Parkin interacts with and ubiquitinates ERRα. Additionally, expressing NLS-Parkin increases protein levels of both endogenous and overexpressed ERRα and promotes transcription of ERRα-targets. These data indicate that Parkin-mediated ubiquitination of ERRα leads to its increased stability and activity resulting in increased transcription of genes involved in mitochondrial biogenesis and metabolism. This study provides insight into new ways Parkin may be targeted to enhance energetic function in the heart.
OSU-A9, An Indole-3-Carbinol Derivative, Induces Cytotoxicity In Acute Myeloid Leukemia Through Reactive Oxygen Species-Mediated Apoptosis
Authors: Li-Yuan Bai, Jing-Ru Weng, Chia-Yung Wu, Chang-Fang Chiu, Su-Peng Yeh, Yu-Min Liao
Journal: Blood (2013)
Phase I-II Study of Fludarabine, Cytarabine and Oxaliplatin In Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
Authors: Apostolia Maria Tsimberidou, Michael J Keating, Elihu H. Estey, Elias Jabbour, Patrick Zweidler-McKay, William Plunkett, Hagop M Kantarjian, Gautam Borthakur
Journal: Blood (2011)
Abstract 918: Pre-B-cell Leukemia Homeobox Interacting Protein 1 is a Novel Regulator of Growth Signaling in the Heart
Authors: Kelly M Grimes, Anna Pyo, Jeffery D Molkentin
Journal: Circulation Research (2019)

The cellular mechanisms that allow for cardiomyocyte growth in different directions may yield important information about the development of hypertrophic and dilated cardiomyopathies, diseases which include the widening and lengthening growth of cardiomyocytes, respectively. We have previously found that genetic manipulations of the mitogen-activated protein kinase kinase 1 (MEK1) and extracellular signal-related kinase 1/2 (ERK1/2) signaling pathway cause cardiac hypertrophy and cardiomyocyte widening when the pathway is activated or dilated cardiomyopathy and cardiomyocyte lengthening when it is inhibited. The downstream effectors of the directional growth response controlled by these kinases have yet to be studied. Therefore, an unbiased phosphoproteomic screen was conducted on cardiomyocytes subjected to activation or inhibition of MEK1-ERK1/2 signaling. After validation of the screening hits with western and Phos-tag blots, Pre-B-cell leukemia homeobox interacting protein 1 (PBXIP1) emerged as an interesting target. Although it is known as a microtubule binding protein and regulator of proliferation in cancer cells, its function has never before been studied in the heart. Inhibition of MEK1-ERK1/2 increases phosphorylation of PBXIP1. However, activation of the pathway increases PBXIP1 protein expression, and as such we sought to determine the effects of PBXIP1 overexpression in the heart via adeno-associated virus 9 (AAV9) treatment. At four months of age, mice overexpressing PBXIP1 have significantly larger hearts than controls without a change in cardiac contractility. Intriguingly, histological analysis showed that cardiomyocytes highly infected with PBXIP1 AAV9 are significantly smaller in size compared to uninfected cells. Current studies are manipulating the PBXIP1 phosphorylation sites identified in the phosphoproteomic screen to determine the exact roles they may play in the cardiac growth response.
Former footballers are more likely to die from neurodegenerative disease, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Former professional football (soccer) players are more likely to die from neurodegenerative disease than the general population but less likely to die from other common causes such as lung cancer, a study has found.1

In response, the Football Association (FA) has called for more research to see whether the findings relate to the “modern day professional footballer.”

Researchers from the University of Glasgow compared differences in mortality from neurodegenerative disease between former professional Scottish football players and the general population.

The FIELD study included 7676 former footballers born from 1900 to 1976 and 23 028 matched controls from the general population. Over the 18 year study 1180 former …
Abstract 17270: Prognostic Impact of Ventricular Ectopy During the Recovery Phase of Stress Testing: A Meta-Analysis
Authors: Muhammad T Ayub, Muhammad S Khan, Sagar Ranka, Muhammad Ishaq, Muhammad F Khalid, Luis H Paz, Jose Sleiman, Ezequiel Munoz, Sisir Siddamsetti, Yasmeen Golzar
Journal: Circulation (2018)

Introduction: Ventricular ectopy after exercise, due to parasympathetic activity, predicts an increased risk of death in population-based cohorts. We sought to examine the composite risk of all cause mortality in patients with premature ventricular contractions (PVCs) in the early recovery phase of stress testing. Methods: PubMed, Medline &amp; EMBASE were queried for all English language articles from 1993 to 2017. The primary outcome was incidence of all cause mortality in patients with frequent PVCs during recovery phase (RPV) of stress testing. Frequent PVCs were defined as the presence of seven or more ventricular premature beats/min, frequent ventricular couplets, ventricular bigeminy or trigeminy, or any other form of ventricular tachycardia or ventricular fibrillation. Meta-analysis of the main outcome was performed using a weighted random effects model. Results: A total of four observational studies including 38765 patients were retrieved. Data for 2065 patients with RPV was pooled. A comparative analysis of PVC vs Infrequent/Non-PVC group showed a calculated risk ratio for all cause mortality of 1.8 (95% CI 1.36-2.38; p=0.001). I 2 statistic for heterogeneity testing was 82.8% (Fig.1). Conclusion: Frequent premature ventricular contractions during early recovery phase of stress testing are associated with increased all cause mortality as compared to patients with infrequent or no PVCs.
Treatment Patterns Among Patients with Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ CML) Treated with Imatinib in a Community Setting.
Authors: Kavita R Sail, Lei Chen, James Jackson, Solveig G. Ericson, Sally Haislip, Tamara Ibison, James Gilmore, Mansoor N Saleh
Journal: Blood (2012)
Fewer people are attending NHS health checks, show figures
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The proportion of eligible patients in England attending an NHS health check is at its lowest in six years, new data show.1

In 2017-18 two fifths (41% or 1 108 841) of eligible people attended an NHS health check, down from the high of 46% (974 267) in 2013-14. The absolute number of people attending a health check fell for the second consecutive year in 2017-18, down by more than 52 000 since the peak attendance of 1 161 027 in 2015-16.

The report from NHS Digital looked at numbers of health checks attended in England over …
Identification of Genes Associated with Risk to Aplastic Anemia (AA) Using Array-Based Genotyping.
Authors: Il-Kwon Lee, Hee Nam Kim, Yeo-Kyeoung Kim, Kyeong-Soo Park, Deok-Hwan Yang, Je-Jung Lee, Myung Geun Shin, Chan Choi, Hoon Kook, Tae Ju Hwang, Hyeoung-Joon Kim
Journal: Blood (2007)
Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study
Authors: Peter Collins, Albert Faradji, Massimo Morfini, Monika Maas Enriquez, Eduard Gorina, Lawrence Schwartz, Georg Lemm
Journal: Blood (2008)
Mortality disparities in insured patients with cancer.
Authors: Robert Michael Cooper, Joanie Chung, Joanne E. Schottinger, Reina Haque
Journal: Journal of Clinical Oncology (2019)

150 Background: We examined mortality related to socioeconomic status (SES) in an insured Southern California population diagnosed with cancer and how healthcare settings can affect these differences. Methods: We identified adults diagnosed with the eight most common cancers from 2009-2014 from the California Cancer Registry and followed them through 2017. We calculated person-year mortality rates by SES and healthcare system (integrated healthcare system [IHS] or private insurance [PI]). Adjusted hazard ratios for the association between all-cause mortality and SES were estimated using Cox proportional hazards models accounting for covariates (race/ethnicity, demographics, stage, treatments). Results: The cohort was followed a maximum of 8 years. A total of 164,197 adults were diagnosed with cancers of the breast, prostate, lung, colon, melanoma, uterus, kidney and bladder (N=47,039 in IHS and N=117,158 in PI). In the whole cohort, we found an increased mortality risk between the highest and each of the lower SES quintiles. Specifically, the adjusted mortality risk was 16 to 37% greater in the lower SES groups as compared to the highest. We then examined the mortality in the IHS and PI groups separately. Overall mortality for all cancers combined was slightly lower in the IHS group (74.7/1,000 PY) than in the PI group (87.8/1,000 PY). In multivariable models, mortality risk was 6% to 16% greater in the lower SES groups versus the highest SES in the IHS population, while the risk was 19% to 45% greater in the lower SES groups in the PI population. Conclusions: Even among insured patients, and after multivariable adjustment, we found disparities in mortality in the lower SES groups. However, the magnitude of these differences was lower in patients cared for in IHS than those with PI. Preliminary data suggest that IHS may be well positioned to reduce disparity gaps in cancer outcomes. [Table: see text]
Abstract 524: Activated Fms-like Tyrosine Kinase 3 Receptor Prevents Ventricular Remodeling Induced by Ang Ii Through the Attenuation of Autophagy
Authors: Wenzhuo Ma, Chenying Gao, Zhenghang Zhao
Journal: Circulation Research (2019)

Aim: FMS-like tyrosine kinase 3 (Flt3) is a receptor tyrosine kinase. This study was to determine whether activation Flt3 could regulate autophagy ameliorate AngII-induced heart cardiac remodeling and to elucidate the mechanisms of action. Methods: In vivo cardiac remodeling was induced in male C57BL/6 mice by implanting subcutaneously osmotic minipumps releasing Angiotensin II (Ang II) for 28 days (1100ng/kg/min). Flt3 ligand (FL) was administered intraperitoneally (5μg/mouse/2days). Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. In vitro, hypertrophy was induced by Ang II on adenovirus vector-mediated overexpression Flt3 receptor in H9c2 cells, and NRCMs. Crystal violet staining, flow cytometry and TUNEL were used for in vitro experiments. The levels of signaling proteins were measured using western blotting, while the expression of the relevant genes was analyzed using real-time qRT-PCR. Results: Echocardiography demonstrated that Ang II induced marked damaged heart function, while cardiac Flt3 receptor activation significantly decrease left ventricular internal dimension at end-diastole (LVIDd), left ventricular posterior wall thickness at end-diastole (LVPWd), and increase ejection fraction (EF%) and fractional shortening (FS%). FL-treated mice showed a significant attenuation of cardiac hypertrophy, ratios of heart weight/body weight (HW/BW) and heart weight/tibia length (HW/TL), as well as cardiac fibrosis and apoptosis. Additionally, the autophagic levels in cardiomyocytes of FL-treated mice were distinctly decreased as evidenced by expression of LC3 in immunohistochemical staining and western blotting. In H9c2 cells with adenovirus vector-mediated overexpression of Flt3 and neonatal rat cardiomyocytes, FL treatment significantly decrease the cell size, apoptosis and autophagy induced by Ang II. Additionally, using rapamycin or metformin, respectively canceled FL protective effects. Conclusion: Flt3 activation suppresses Ang II-induced cardiac hypertrophy and apoptosis via AMPK /mTOR/ FOXO3a autophagy signaling pathway. These results provide evidence supporting Flt3 as a novel therapeutic target in cardiac remodeling.
Microbial Contribution to the Human Metabolome: Implications for Health and Disease
Authors: William Van Treuren, Dylan Dodd
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

The human gastrointestinal tract is home to an incredibly dense population of microbes. These microbes employ unique strategies to capture energy in this largely anaerobic environment. In the process of breaking down dietary- and host-derived substrates, the gut microbiota produce a broad range of metabolic products that accumulate to high levels in the gut. Increasingly, studies are revealing that these chemicals impact host biology, either by acting on cells within the gastrointestinal tract or entering circulation and exerting their effects at distal sites within the body. Given the high level of functional diversity in the gut microbiome and the varied diets that we consume, the repertoire of microbiota-derived molecules within our bodies varies dramatically across individuals. Thus, the microbes in our gut and the metabolic end products they produce represent a phenotypic lever that we can potentially control to develop new therapeutics for personalized medicine. Here, we review current understanding of how microbes in the gastrointestinal tract contribute to the molecules within our gut and those that circulate within our bodies. We also highlight examples of how these molecules affect host physiology and discuss potential strategies for controlling their production to promote human health and to treat disease.
Early Death in Multiple Myeloma. Analysis of Patients in Real-World Practice
Authors: Sunil Lakhwani Lakhwani, Miguel T Hernández, Pablo Lorenzo-Barreto, Deborah Cabrera-Brito, Marta Fernández-González, Patricia Machado-Machado, Maribel Díaz-Gómez, Jose Maria Raya Sanchez
Journal: Blood (2018)