tbuckley/cabot-search huggingface dataset:
Abstract 9655: Risk Factors and Clinical Outcomes Associated with Gastrointestinal Bleeding Among Amyloidosis Patients
Authors: Tayana Rodriguez, Jennifer Ma, Alejandro Sarabia-Gonzalez, Sarah Ream, Luis Alvarado, Alok Dwivedi, Debabrata Mukherjee
Journal: Circulation (2021)

Background: Amyloidosis is the deposition of abnormal localized or systemic extracellular proteins in tissues. Upper and lower gastrointestinal (GI) bleeds are a known complication of amyloidosis. We assess risk factors and outcomes associated with GI bleeding in hospitalized patients with amyloidosis. Methods: This retrospective study used data from the 2015-2018 National Inpatient Sample Database to determine the prevalence of GI bleeding and risk factors associated with GI bleeding in patients with amyloidosis based on ICD-9 codes. Demographics included age, race, and gender. Comorbidities included hypertension, diabetes, heart failure, renal failure and coronary artery disease. Outcomes included death, and length of stay (LOS). The weight adjusted prevalence of GI bleed was estimated using binomial model with 95% confidence interval (CI) and the association was summarized with weighted relative risk (RR) regression analyses. Results: This study included 34,894 records of patients with amyloidosis, of which 1,022 had GI bleed. Amyloidosis patients with GI bleeds were older than patients without GI bleeds (63.86 vs. 60.94 years, p= &lt;.0001 and more likely to be male (51.85 vs. 42.04 p= &lt;.0001) and had more renal failure, diabetes, heart failure, and liver disease. Amyloidosis patients with GI bleed had significantly higher length of stay (2.93 [95% CI 2.75-3.12]) and higher mortality than those without GI bleeding (RR 2.64 [95% CI 2.17 - 3.22], p &lt;0.0001). Conclusion: Among patients with amyloidosis, GI bleeding was more common in males, older individuals, and those with renal failure, diabetes, heart failure, and liver disease. Patients with amyloidosis and GI bleeds had significantly higher mortality with longer LOS than those without GI bleeding. Patients with amyloidosis with GI bleeding should be targeted for aggressive therapies to improve outcomes.
Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair
Authors: Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. MacRae, Utpal Banerjee, Pei-Yu Chiou, Marcus Seldin, Dian Huang, Michael Teitell, Ilya Gertsman, Michael Jung, Steven J. Bensinger, Robert Damoiseaux, Kym Faull, Matteo Pellegrini, Aldons J. Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb
Journal: Journal of Clinical Investigation (2021)

Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
Drug delivery approaches for HuR-targeted therapy for lung cancer
Authors: Rajeswari Raguraman, Santny Shanmugarama, Meghna Mehta, Jo Elle Peterson, Yan D. Zhao, Anupama Munshi, Rajagopal Ramesh
Journal: Advanced Drug Delivery Reviews (2021)

Lung cancer (LC) is often diagnosed at an advanced stage and conventional treatments for disease management have limitations associated with them. Novel therapeutic targets are thus avidly sought for the effective management of LC. RNA binding proteins (RBPs) have been convincingly established as key players in tumorigenesis, and their dysregulation is linked to multiple cancers, including LC. In this context, we review the role of Human antigen R (HuR), an RBP that is overexpressed in LC, and further associated with various aspects of LC tumor growth and response to therapy. Herein, we describe the role of HuR in LC progression and outline the evidences supporting various pharmacologic and biologic approaches for inhibiting HuR expression and function. These approaches, including use of small molecule inhibitors, siRNAs and shRNAs, have demonstrated favorable results in reducing tumor cell growth, invasion and migration, angiogenesis and metastasis. Hence, HuR has significant potential as a key therapeutic target in LC. Use of siRNA-based approaches, however, have certain limitations that prevent their maximal exploitation as cancer therapies. To address this, in the conclusion of this review, we provide a list of nanomedicine-based HuR targeting approaches currently being employed for siRNA and shRNA delivery, and provide a rationale for the immense potential therapeutic benefits offered by nanocarrier-based HuR targeting and its promise for treating patients with LC.
Abstract 13259: IRX5 Transcription Factor Cooperate With TBX5/GATA4/NKX2-5 Complex to Regulate Several Human Cardiomyocyte Functions
Authors: Robin Canac, Bastien Cimarosti, Aurore Girardeau, Virginie Forest, Cynthia Fourgeux, Jeremie Poschmann, Guillaume Lamirault, Patricia Lemarchand, Nathalie Gaborit
Journal: Circulation (2021)

Introduction: The transcription factor (TF) Iroquois homeobox 5 (Irx5) is a key patterning and differentiation regulator. In humans, IRX5 regulates the expression of the main cardiac sodium ion channel gene, SCN5A . However, its global mechanistic role in human cardiomyocytes is still to be fully understood. Hamamy syndrome patients, carrying IRX5 mutations, have defects in various organs including the heart and the limbs. Interestingly, heart and limbs defects are also found in Holt-Oram syndrome patients ( TBX5 mutations), suggesting a functional link between TBX5 and IRX5. Moreover, a cooperation of TBX5 with GATA4 and NKX2-5 in cardiac development and functions has already been shown. Hypothesis: We hypothesized that IRX5 may cooperate with the TF complex TBX5/GATA4/NKX2-5 to regulate key cardiac functions in humans. Methods &amp; Results: First, immunoprecipitations in HEK293 cells showed that IRX5 can bind to TBX5, GATA4 and NKX2-5, individually and together as a complex. Using five truncated forms of IRX5 protein, its homeodomain was identified as being the essential protein region for these interactions. Second, we showed by luciferase assays, that each combination of these TFs impacted differently SCN5A expression: e.g. by itself, NKX2-5 has a strong activator effect (increased activity by 10 fold vs . no TF) that is potentialized by IRX5 (12 fold vs . no TF) but inhibited by TBX5 (8 fold vs . no TF). Third, genes bound by IRX5 (n=2253) were identified by ChIP-Seq on cardiomyocytes derived from induced pluripotent stem cells generated from 2 healthy individuals. Analyzing published ChIP-Seq datasets for TBX5, GATA4 or NKX2-5 in the same cellular model, we identified 2990 genes that were bound by these 3 TFs, and associated with cardiac biological pathways, such as muscle contraction. Among these genes, 848 were also bound by IRX5 and were associated with the function of electrical activity and with the fibrosis signaling, suggesting a specific role for IRX5 in these cardiac processes. Conclusions: Overall, our data show new physical and functional interactions between IRX5 and 3 key cardiac TFs (TBX5, GATA4 and NKX2-5), and suggest an unexpected regulatory role for IRX5 in specific human heart functions.
Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy
Authors: Austin G. Kulasekararaj, Antonio Risitano, Alexander Roeth, Guangsheng He, Jeffrey Pu, Lilyan Wright, Anita Appius, Alexandre Sostelly, Sasha Sreckovic, Sven F Stanzel, Talha Munir, Jun-Ichi Nishimura
Journal: Blood (2021)
Abstract 13190: Evidence of Occult Global and Regional Myocardial Strain Abnormalities in Adolescent Athletes After COVID-19 Infection
Authors: Marc Lee, Kan N Hor, Saurabh Rajpal, John Heyniger, Orlando Simonetti, Andrew H Tran, Lydia Wright, Kaitlin E L'Italien, Deipanjan Nandi, Simon Lee
Journal: Circulation (2021)

Introduction: There is increased scrutiny on cardiac screening of competitive athletes after COVID-19 illness, and cardiac magnetic resonance (CMR) is frequently undertaken. Limited reports with echocardiography-based strain techniques suggest occult abnormalities in collegiate athletes after COVID-19. Cardiac involvement in the adolescent athlete has not been well characterized. The purpose of this study is to describe CMR findings, including strain encoded (SENC) imaging, in adolescent athletes after COVID-19 (C19+AA). Methods: Retrospective review was performed of ambulatory C19+AA patients who underwent CMR (Group A). Healthy athletes (Group B) and nonathlete healthy controls (Group C) underwent CMR with SENC for comparison. Myocardial strain was evaluated by MyoStrain (Myocardial Solutions, Morrisville, NC). LV global (GLS) and regional strain (from modified AHA-16 segment model) were compared between the three groups with abnormal defined as magnitude &lt;17 and statistical significance set at p &lt; 0.05. Results: Group A patients were younger (n = 87, 52% male, age 15.4±1.8 yrs) than Group B (n = 19, 63% male, age 21.3±1.6 yrs) and Group C (n = 9, 52.6% male, age 19.3±1.1 yrs) with no difference in LVEF between the three groups (Group A = 59.1±3.9%, Group B = 60.3±6.2%, Group C = 61.0±4.1%). Despite preserved global function, Group A had significantly lower GLS (-17.6±2.3% vs Group B = -20.8±1.4%, p &lt;0.04 and Group C = -19.1±2.4%, p = 0.02) with no difference between the latter groups (p = 0.07). Higher numbers of abnormal segments were observed in Group A (6.9±3.7, 43.1%) vs Group B (2.4±1.9, p &lt; 0.0001) and Group C (3.7±3.5, p &lt; 0.0001) with no difference between the latter groups (p = 0.1). Conclusions: Global and regional strain abnormalities were common in C19+AA in the setting of normal LVEF. This may represent occult myocardial abnormalities in adolescents after COVID-19. Future longitudinal studies with age matched controls are needed to monitor for progression.
CSIG-11. KINASE-DIRECTED INHIBITION OF PYRIMIDINE BIOSYNTHESIS IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Pranjal Sarma, Kelli N Ennis, Catherine A Behrmann, Collin Wetzel, Biplab Dasgupta, David R Plas
Journal: Neuro-Oncology (2021)

Abstract Targeting pyrimidine biosynthesis has been a mainstay of chemotherapy in oncology, including frontline treatment of pancreatic, breast, and colorectal carcinomas. In glioblastoma, the targeting pyrimidine biosynthesis is a promising emerging approach for counteracting the effects of PTEN-deficiency in glioblastoma. PTEN loss triggers the activation of mTORC1, which in turn phosphorylates and activates the ribosomal protein kinases S6K1 and S6K2. We have previously shown that combination treatment of inhibitors targeting S6K1 and the TYRO3-AXL-MERTK receptor tyrosine kinases (TAM-RTKs) triggers cytotoxic responses in PTEN-deficient glioblastoma cells. Here we show brain-penetrant inactivation of S6K1 and TAM-RTKs using the S6K1 inhibitor LY-2584702 and the TAM-RTK inhibitor BMS-777607, which reduced glioblastoma tumor growth. Pharmacogenetic analysis of signal transduction indicated a key role for S6K2 in sustaining survival signaling in PTEN-deficient glioblastoma cells. Steady-state metabolomics revealed that combined inactivation of S6K1 and TAM-RTKs resulted in decreased nucleotide biosynthesis, and flux analysis indicated reduced flux of glucose to pyrimidines. Altogether the results indicate a kinase-directed therapeutic strategy for targeting S6K1 and TAM-RTKs to reduce pyrimidine biosynthesis and glioblastoma tumor growth.
Abstract 12923: Lack of Concordance Between Parameters Defining Cardiogenic Shock in Patients With ST Elevation Myocardial Infarction
Authors: Triston Eastman, Mirna Ragheb, Mullein Thorleifson, Brett Hiebert, Kunal Minhas, Malek Kass, Amir Ravandi, Ashish Shah
Journal: Circulation (2021)

Introduction: In stark contrast to a ~3-5% in-hospital mortality in all comer ST Elevation Myocardial Infarction (STEMI) patients, ~40-50% of STEMI patients complicated by cardiogenic shock (CS) die during their index-hospital admission. None of the pharmaco-mechanical circulatory support therapies have demonstrated survival benefit in CS, likely due to our inability to objectively define and identify CS in the “pre-shock” state. As per the current guidelines, CS is defined as either (1) systolic blood pressure (SBP) ≤ 90mmHg, (2) cardiac-index (CI) &lt;1.8 L/min/m 2 or &lt;2.2 L/min/m 2 with inotropic/vasopressor support in presence of pulmonary capillary wedge pressure ≥15 mmHg, and/or (3) lactate &gt;2 mmol/L. These parameters are used interchangeably. however, data comparing these parameters is lacking. Objective: (1) To identify the incidence of CS using the above three parameters, and (2) assess the concordance between these parameters in STEMI patients . Methods: CI (total body impedance method), SBP and lactate were measured pre- and post-primary percutaneous coronary intervention (PPCI) in consecutive STEMI patients. Results: Sixty-eight STEMI patients (32% female) with a mean age of 65.8 years were recruited. Based upon lactate, CI and SBP the incidence of CS pre-PPCI was 47%, 26% and 17% (Panel-A). Poor concordance was seen between all three parameters. SBP and CI (R 0.466, R 2 0.220; Panel-B), CI and lactate (R -0.228, R 2 0.052; Panel-C), as well as SBP and lactate (R -0.314, R 2 0.098; Panel-D) criteria predominantly identified different patient cohorts, with minimal overlap; demonstrating that these parameters cannot be used interchangeably. Conclusion: Our study is the first to describe poor congruity between the current parameters defining CS. Such limitations raise the need of objectively defining CS so that these high-risk patients can be identified early in the course of CS (pre-CS state), where timely interventions are likely to improve the outcomes.
Alpha (B.1.1.7) and Delta (B.1.617.2 – AY.40) SARS-CoV-2 variants present strong neutralization decay at M4 post-vaccination and a faster replication rates than D614G (B.1) lineage
Authors: Samuel Lebourgeois, Reyene Menidjel, Houssem Redha Chenane, Valentine Marie Ferré, Gilles Collin, Florence Damond, Romain Coppée, Yazdan Yazdanpanah, Jean-François Timsit, Nadhira Houhou-Fidouh, Diane Descamps, Charlotte Charpentier, Benoit Visseaux
Journal: Journal of Infection (2021)
Abstract 14169: Implications of Elevated Troponin on Time-to-Surgery in Non-ST Elevation Myocardial Infarction (NIHR Health Informatics Collaborative: Trop-CABG Study)
Authors: Shubhra Sinha, Umberto Benedetto, Abdulrahim Mulla, Ben Glampson, Vasileios F. Panoulas, Sanjay Gautama, Jim Davies, Dimitri Papadimitriou, Kerrie Woods, Paul Elliott, Harry Hemmingway, Bryan Williams, Folkert W Asselbergs, Narbeh Melikian, George Krasopoulos, Rana Sayeed, Olaf Wendler, Kamran Baig, Andrew Chukwuemeka, gianni angelini, Jonathan Sterne, Tom Johnson, Ajay M Shah, Divaka Perera, Riyaz Patel, Rajesh Kharbanda, Keith M Channon, Jamil Mayet, Amit Kaura
Journal: Circulation (2021)

Background: The optimal timing of coronary artery bypass grafting(CABG) in patients with non-ST elevation myocardial infarction (NSTEMI) and the utility of pre-operative troponin levels in decision-making remains unclear. We investigated (a)the association between peak pre-operative troponin and survival post-CABG in a large cohort of NSTEMI patients and (b)the interaction between troponin and time-to-surgery. Methods: Our cohort consisted of 1746 NSTEMI patients(mean age 69±11 years, 21% female) with recorded troponins that had CABG at five United Kingdom centers between 2010 and 2017. Time-segmented Cox regression was used to investigate the interaction of peak troponin and time-to-surgery on early(within 30 days) and late(beyond 30 days) survival. Results: Average interval from peak troponin to surgery was 9±15 days, with 1466(84.0%) patients having CABG during the same admission. Sixty patients died within 30-days and another 211 died after a mean follow-up of 4±2years(30-day survival 0.97±0.004 and 5-year survival 0.83±0.01). Peak troponin was a strong predictor of early survival(adjusted P=0.002) with a significant interaction with time-to-surgery(P interaction=0.007). For peak troponin levels &lt;100 times the upper limit of normal, there was no improvement in early survival with longer time-to-surgery. However, in patients with higher troponins, early survival increased progressively with a longer time-to-surgery, till day 10. Peak troponin did not influence survival beyond 30 days(adjusted P=0.64). Conclusions: Peak troponin in NSTEMI patients undergoing CABG was a significant predictor of early mortality, strongly influenced the time-to-surgery and may prove to be a clinically useful biomarker in the management of these patients.
Assessment of Mental Health of High School Students 1 Semester After COVID-19–Associated Remote Schooling Measures Were Lifted in Austria in 2021
Authors: Elke Humer, Rachel Dale, Paul L. Plener, Thomas Probst, Christoph Pieh
Journal: JAMA Network Open (2021)

a Time 1 indicates the period from February 3 to 28, 2021, 1 semester after almost exclusively remote schooling.b Time 2 indicates the period from June 19 to July 2, 2021, after 1 semester of school reopenings.c The total number of participants for time 1 and time 2 includes individuals whose gender identity or gender expression does not conform to socially defined male or female gender norms (n = 4 at time 1 and n = 8 at time 2).
Abstract 12433: Distinct Immune and Mesenchymal Populations Identified by Single Cell RNA Sequencing Contribute to Chronic Thromboembolic Pulmonary Hypertension
Authors: Gayathri Viswanathan, Helene Kirshner, Nour Nazo, Asvin M Ganapathi, Ian Cumming, John Haney, Susana Almeida Peters, David Corcoran, Yen-Rei Yu, Sudarshan Rajagopal
Journal: Circulation (2021)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequelae of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arterial system. This results in vascular obstruction, small vessel arteriopathy and pulmonary hypertension. Previous studies have attempted to identify cells that contribute to CTEPH thrombus but have been limited by the use of specific cell markers or phenotypic modulation after cell growth in culture. Here we have used single cell RNA sequencing (scRNAseq) of samples of CTEPH thrombus removed at the time of pulmonary thromboendarterectomy (PTE) surgery to identify clusters of macrophages, T cells, smooth muscle cells and endothelial cells in CTEPH thrombus. We identified that multiple macrophage subclusters, many of which have an inflammatory phenotype. T cells were a heterogeneous population consisting of CD4+ and CD8+ T cells that are predicted to be inflammatory and also promote vascular remodeling. In the smooth muscle cell cluster, a subcluster of myofibroblasts are predicted to arise from smooth muscle cells based on pseudotime analysis. Notably, cultured endothelial, smooth muscle and myofibroblast cells isolated from CTEPH thrombus have distinct phenotypes from control cells. For example, endothelial cells had reduced angiogenic potential, were proliferative and anti-apoptotic. Lastly, gene expression data identified protease-activated receptor 1 (PAR1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH. Together, these studies suggest a model in which chronic inflammation drives vascular remodeling and mesenchymal senescence in CTEPH pathogenesis and suggest new approaches for targeting this disease.
Abstract 14210: Impaired Mitophagy and Reduced Parkin Expression in Human Pulmonary Arterial Smooth Muscle Cells (PASMCs) in Pulmonary Arterial Hypertension (PAH)
Authors: Rakhshinda Rehman, Shamsudheen Karuthedath Vellarikkal, Paul B Dieffenbach, Hilaire C Lam, Charilaos Filippakis, Laura E Fredenburgh
Journal: Circulation (2021)

Introduction: Mitophagy is the key mitochondrial quality control process of selective removal of damaged mitochondria which is necessary for maintaining cellular homeostasis. While studies have demonstrated that abnormalities in mitochondrial metabolism drive a hyperproliferative phenotype of pulmonary vasculature in PAH, there is limited understanding of mitophagy dysregulation in PAH. Recent studies have shown that hypoxia induced Parkin/Pink1-mediated mitophagy promotes vascular remodeling, however another report suggests that loss of Pink1 and reduced mitophagy in hypoxia promotes PASMC proliferation. The role and mechanisms of altered mitochondrial dynamics/mitophagy dysregulation in driving pulmonary vascular remodeling in PAH remain incompletely understood. Hypothesis: We hypothesized that impaired mitophagy and reduced Parkin expression may drive the apoptosis-resistant, hyperproliferative phenotype in PAH PASMCs. Methods: Mitophagy was assessed in human PASMCs from control donors and PAH patients stably expressing mtKeima protein and in lungs from hypoxia-exposed mtKeima transgenic mice. Parkin expression was assessed by Western blotting and immunocytochemistry. Immunofluorescence staining for Parkin was performed in lungs from mice exposed to chronic hypoxia. Human PASMCs from control donors were transfected with siControl and siParkin and assessed for proliferation and apoptosis by Ki67 and Annexin V/PI flow cytometry and PCNA expression. Results: PASMCs from PAH patients showed reduced KeimaRed vs. KeimaGreen ratio compared to control donors indicating reduced mitophagy i.e. further confirmed by decreased Parkin in PAH PASMCs. Parkin deficient PASMCs demonstrated more Ki67 and less Annexin V/PI positive cells and increased PCNA. Interestingly, lungs from hypoxia-exposed mtKeima transgenic mice showed increased KeimaRed vs. KeimaGreen ratio and increased Parkin in lungs of hypoxia-exposed mice. Conclusions: PAH PASMCs demonstrate impaired mitophagy and reduced Parkin expression; Parkin deficiency promotes proliferation and inhibits apoptosis in PASMCs. Our findings suggest that Parkin may regulate remodeling phenotypes in PASMCs and thus may represent a potential therapeutic target in PAH.