tbuckley/cabot-search huggingface dataset:
Impact of rurality versus neighborhood deprivation on stage at diagnosis and survival: A regional analysis.
Authors: Laura Elizabeth Panattoni, Catherine R. Fedorenko, Qin Sun, Li Li, Karma L. Kreizenbeck, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

158 Background: Evidence that rural residents compared to urban residents are more likely to be diagnosed at later stages and have worse survival outcomes has prompted recent policy initiatives by ASCO to address the rural cancer care gap. However, rural residents are generally poorer, potentially confounding the cause of these disparities. This study examined the impact of rurality, travel time to oncologist (TTO), and neighborhood deprivation (ND) on stage of diagnosis and 3-year survival in a regional setting. Methods: Cancer registry records for patients in Western Washington were linked with claims from regional commercial insurers, Medicare, and Medicaid at time of diagnosis. The study included adult patients with solid tumors diagnosed between 2012-2014. Rurality was sourced from the Rural-Urban Commuting Area Codes (RUCAs): Metro, Metro with Commute, Micropolitan, Small Town/Rural. ND was measured by the census block Area Deprivation Index from 1 (least) to 10 (most) deprived; TTO from Google Maps (minutes). Multinomial logistic regression measured stage at diagnosis (local, regional, distant). Cox survival models were stratified by insurance type. We adjusted all models for age, gender, race, marital status, cancer type and grade, and hierarchical condition categories. Results: The table below lists the effect size of rurality, TTO, and ND on the outcomes where significant (p&lt;0.05). Conclusions: In Washington State, neighborhood deprivation, not rurality, was largely associated with later stage at diagnosis and poorer survival. Regional stakeholders need to carefully examine the local sources of cancer care disparities to effectively target interventions.[Table: see text]
Abstract 754: The Relationship Between Obstructive Sleep Apnea and Coronary Plaque Instability: An Optical Frequency Domain Imaging Study
Authors: Takao Konishi
Journal: Circulation Research (2019)

Background and purpose: Obstructive sleep apnea (OSA) is associated with coronary artery disease (CAD) and with an increased risk of myocardial infarction, stroke or death due to cardiovascular disease. Optical frequency-domain imaging (OFDI) is a useful modality for evaluating the characteristics of atherosclerotic plaque. The purpose of the study was to use OFDI to investigate the association of OSA with coronary plaque characteristics in patients undergoing percutaneous coronary intervention (PCI). Methods: We retrospectively analyzed OFDI data for coronary artery plaques from 15 patients with OSA and 35 non-OSA patients treated between October 2015 and October 2018. Plaque morphology was evaluated for 70 lesions, including 21 from patients with OSA and 49 from non-OSA patients. Results: Compared with the non-OSA group, patients with OSA had significantly higher prevalences of thinned cap fibroatheroma (TCFA) (67% vs. 35%, P=0.014) and microchannels (86% vs. 55%, P=0.014); a significantly higher mean lipid index (1,392±982 vs. 817±699, P=0.021), macrophage grade (8.4±6.4 vs. 4.8±4.5, P=0.030), and maximum number of microchannels (1.5±1.0 vs. 0.7±0.7, P=0.001); and a significantly lower mean minimum fibrous cap thickness (69.4±28.7 vs. 96.1±51.8 μm, P=0.008). Conclusions: This OFDI analysis suggests that OSA is associated with unstable plaque characteristics in patients with CAD. More intensive medical management for stabilization of coronary atherosclerotic plaque is required in patients with OSA.
Abstract 16934: Targeted Cardiac Delivery of miR-29b Mimic via Ultrasound-Mediated Microbubble Cavitation Attenuates Myocardial Fibrosis
Authors: Rafey A Feroze, Jonathan Kopechek, Linda Lavery, Jissy Cyriac, Jianhui Zhu, Xucai Chen, Flordeliza Villanueva
Journal: Circulation (2018)

Introduction: Cardiac fibrosis contributes to adverse ventricular remodeling in ischemic or hypertensive heart disease, increases heart failure risk, and is associated with loss of microRNA-29b (miR-29b). Plasmid or i.v. injection of miR-29b mimic has proven the concept that restoring miR-29b blunts cardiac fibrosis, but these are inefficient, non-targeted delivery strategies with low clinical translational potential. We hypothesized that ultrasound (US) mediated cavitation of microbubbles (MBs) loaded with miR-29b mimic would inhibit cardiac fibrosis. We first tested effects of US-targeted cavitation of miR29b-MBs (UTMC) on cardiac fibroblasts in vitro , then performed in vivo studies in a mouse model of angiotensin II (ANGII)-induced hypertension/fibrosis. Methods: Cationic lipid MBs were loaded with miR-29b mimic or negative control (NC) miRNA, placed with cultured neonatal cardiac fibroblasts, then treated with 10 sec pulsed US ( f =1.3 MHz, MI 1.6, 4 frames/burst, 4 bursts/second). Cells were harvested at 24 hrs to measure downstream fibrotic mediators. Mice received continuous ANGII infusion via osmotic pump and UTMC with miRNA-loaded MBs at days 0, 3, 7. Serial echo was performed; the heart was harvested on day 10. Results: In cardiac fibroblasts, UTMC treatment with MBs loaded with miR-29b mimic vs NC miRNA caused a 543±51% increase in miR-29b ( p &lt;0.01) and knockdown in transcripts for collagen 1A1 (26±6%, p &lt;0.01), collagen 1A2 (53±8%, p &lt;0.01), collagen III (31±5%, p &lt;0.01), and fibrillin (43±10%, p &lt;0.05) ( n =4/group). ANGII mice treated with UTMC + miR-29b mimic vs. NC miRNA ( n =8-9/group) had downregulated cardiac fibrillin (37±8%, p &lt;0.05); trends of lower collagen IA1, 1A2, and III by RT-PCR; decreased cardiac α-SMA protein by immunoblot ( p &lt;0.05); and preservation of ejection fraction and fractional shortening ( p &lt;0.01). Conclusion: UTMC-mediated delivery of miR-29b mimic blunts pathologic expression of fibrosis markers and is associated with preservation of left ventricular function in ANGII-induced murine cardiac fibrosis. This is the first demonstration of UTMC-delivery of a miRNA mimic for attenuating cardiac fibrosis, and has promising implications for targeted RNA-based approaches for treating cardiac disease.
Response to: ‘In search for the ideal anatomical composition of vascularised human skin equivalents for systemic sclerosis translational research: should we recruit the telocytes?’ by Manetti and Matucci-Cerinic
Authors: Alexandru Emil Matei, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2019)

We would like to thank Dr Manetti and Prof Matucci-Cerinic1 for their stimulating letter on our manuscript.2 The authors discuss strengths and potential limitations of vascularised skin equivalents as a novel in vitro model for systemic sclerosis (SSc).

They raise two key points:

1.  Although the model includes key populations of cells relevant to skin homeostasis and to the pathogenesis of SSc such as fibroblasts, endothelial cells and keratinocytes, other relevant cell populations are not included. Can the model be modified to include less frequent, but also potentially relevant cellular populations?

2.  Do vascularised skin equivalents in their current form address …
Abstract 748: Circulating Extracellular Vesicles as Novel Biomarkers of Cardiovascular Risk in Older Women With Different Sitting Time Patterns
Authors: Ya-Ju Chang, Yesenia Avitia, Suneeta Godbole, John Bellettiere, Cheryl L Rock, Ruth E Patterson, Marta M Jankowska, Jacqueline Kerr, Matthew A Allison, Loki Natarajan, Dorothy D Sears
Journal: Circulation Research (2019)

Background and Hypothesis: Extracellular vesicles (EVs) are membrane-bound particles shed from a variety of cell types. They contain molecular cargo from the parent cell including metabolites, proteins, and nucleic acids. EVs are present in biofluids and could be promising biomarkers for monitoring wellness. Total sedentary time is linearly associated with cardiovascular and coronary heart disease mortality risk among older women, indicating the intensive impact of sedentary behavior on the circulatory system. Endothelial cells (ECs) provide a barrier and maintain circulatory homeostasis in response to physical and biochemical stimuli. We hypothesize that EC-derived EV count and content changes with EC health and that EC-EVs play a role in bridging sedentary lifestyle with cardiovascular disease risk. Materials and Results: Archival parent study data and plasma samples from a combined cohort of 518 women aged ≥55 years and BMI ≥25kg/m 2 enrolled in the Metabolic, Exercise, and Nutrition at UCSD, Reach for Health, and Community of Mine studies were available to examine EV levels and contents associated with sitting time. Physical activity was measured objectively using accelerometers. Women in the lowest quartile of moderate-vigorous physical activity and who had the highest and lowest mean sitting bout duration across quartiles were indicated as Super Sitters and Interrupted Sitters, respectively. For EC-EV characterization, CD144 was shown to be a specific marker of EC-derived EVs and an anti-CD144 antibody specifically recognized EC-derived EVs from human plasma. EV biochemical markers (e.g., Hsp70, LAMP1, and CD63) were detected on the CD144 + EVs. Immune-gold staining identified CD81, CD63, LAMP1, and CD144 on individual EVs with a typical toroidal shape featuring phospholipid-bilayers using transmission electron microscopy. A protection assay showed CD144 + EVs protect miR-126, an EC-enriched miRNA, from RNase degradation. Study of EV levels and contents in plasma from Super Sitter and Interrupted Sitter groups is underway. Conclusion: CD144 + EVs carrying molecular cargo from ECs. Hence, EVs and their cargo (e.g., miRNAs) are valuable for examination as novel biomarkers associated with sedentary behavior-induced cardiovascular risk.
Abstract 19007: Multimodality Blood Flow Imaging in Mice
Authors: Marie A Guerraty, Lindsay C Johnson, Eric Blankemeyer, Tao Wang, David A Mankoff, Scott D Metzler, Daniel J Rader
Journal: Circulation (2017)

Introduction: Coronary microvascular disease (CMVD), sometimes called Ischemia and No Obstructive Coronary Artery Disease, is associated with significant cardiac morbidity and mortality. Mechanisti...
The Role of Exposed Phosphatidylserine on Microparticles and Blood Cells in Coagulant Activity in Acute Kidney Injury Patients on Continuous Renal Replacement Therapy
Authors: Hui Liang, Li Hou, Tao Li, Yan Zhang, Baorong LI, Yingmiao Liu, Cong Zhang, Yan Kou, Lili Zou, Yuqing Guan, Xiaojing Chen, Jialan Shi, Rujuan Xie
Journal: Blood (2018)
Abstract 811: The Role of Mitochondrial Stress and the Late Sodium Current in Ibrutinib-Mediated Atrial Fibrillation
Authors: Ambili Menon, Brandon Chalzan, Liang Hong, Arvind sridhar, Meihong Zhang, Dawood Darbar
Journal: Circulation Research (2019)

Background: Ibrutinib (a Bruton’s tyrosine kinase inhibitor, BTKI) is rapidly becoming the treatment of choice for many B-cell malignancies, but its proarrhythmic effects may limit its widespread use. GWAS have consistently identified an AF risk locus on chromosome (chr) 4q25, and the nearest gene Pitx2c has been implicated in AF development as evidenced by increased AF in Pitx2c +/- mice which serve as an experimental model for clinical AF. Objective: To assess the role of the late cardiac Na current (I Na,L ) and oxidative stress in mediating increased susceptibility to AF in Pitx2c +/- mice which are genetically prone to developing AF as well as in atrial human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to ibrutinib. Method: Pitx2c +/- mice were administered ibrutinib (30mg/kg/day IP) for 14 days while atrial hiPSC-CMs were exposed to ibrutinib for 48 hrs. Results: There was a graded increase in AF episodes and burden with the number of days the Pitx2c +/- mice were exposed to ibrutinib versus controls ( Fig. 1A ). The action potential duration at 90% repolarization and the I Na-L were markedly prolonged ( Fig. 1B-C ). Furthermore, we observed a significant increase in mitochondrial fragmentation ( Fig. 1D-E ) and superoxide production ( Fig. 1F-G ) in ibrutinib treated atrial hiPSC-CMs versus controls. Conclusion: We showed in Pitx2c +/- mice and atrial hiPSC-CMs that ibrutinib-mediated AF may in part be related to enhanced I Na-L and mitochondrial dysfunction leading to increased oxidative stress. Patients undergoing ibrutinib treatment may benefit from novel therapies which target mitochondrial dysfunction or the late cardiac sodium current.
MLL-PTD Causes Hypomorph Condition of CBF Complex (RUNX1/CBFβ) and Predisposes the Abnormal Hematopoietic Stem and Progenitor Cells (HSPCs) to Clonal Expansion
Authors: Yue Zhang, Xiaomei Yan, Goro Sashida, Xinghui Zhao, Yalan Rao, Susumu Goyama, Susan P. Whitman, Nicholas Zorko, Kelsie M. Bernot, David Witte, Qian-fei Wang, Daniel G. Tenen, Zhijian Xiao, Guido Marcucci, James C. Mulloy, Michael A Caligiuri, Gang Huang
Journal: Blood (2011)
Abstract 485: STING(ing) the Heart: How DNA Damage and Inflammation Orchestrate Cardiac Remodeling and Heart Failure
Authors: Mohammad H Al-Khalaf, Gauri Akolkar, Peter P Liu
Journal: Circulation Research (2019)

Background: We aimed to investigate the role of DNA breaks in inducing inflammation leading to adverse remodeling, premature senescence, and cardiac dysfunction leading to onset of heart failure. Methods: in vivo : Heart-focused IR (using XRad225Cx from PXi) on adult Sprague Dawley rats; 4-5 per group; dose: 0, 15, 30, 45 Gy (endpoint 12 weeks post-IR). Serial echocardiogram and blood collection, P/V at endpoint; whole heart harvest analysis. in vitro : Primary cardiomyocytes from adult rats; human derived cardiac AC16 cell line; UVB ionizing radiation; protein extraction, western probing; gene expression analysis; immunofluorescence staining and microscopy. Results: DNA damage response, as illustrated by XRCC1 protein expression, is upregulated in multiple heart injury/failure models (TAC, MI, aging) and differ depending on cell stage and/or age ( in vitro proliferative vs differentiated AC16 cells). Using in vitro UVB radiation, exposure alters cardiomyocyte morphology, illustrated by α-actinin immunostaining, and activates innate inflammation and senescence, as illustrated by westerns and immunostaining of cGAS, STING, p16 and other relevant proteins. We demonstrate using heart-focused ionizing radiation a novel technique to induce aging related DNA damage and onset of diastolic heart dysfunction. Serial ECG show significant increase in E/A ratios at 8- and 12-week post irradiation of 30 and 45 Gy (E/A&gt;2.0). We show P/V analysis supporting ECG data (~50% decrease in dPdt min, 2-fold increase in Tau, and significant [p&lt;0.01] increase in End diastolic pressure, and no change in End systolic pressure). Using an inhibitor targeting cytosolic DNA sensor cGAS, we show attenuation of cardiac remodeling and expression of senescence. Conclusions: We elucidate the molecular pathway originating from the onset of DNA damage accumulation, leading to activation of specialized innate immunity proteins that ultimately upregulate inflammation and senescence. Here we uncover and connect key interactions between multiple pathways converging towards heart failure, and provide evidence for a novel therapeutic drug targeting cardiac aging.
PBI-1402: A New Candidate for the Treatment of Anemia.
Authors: Lyne Gagnon, Jean Barabé, Mouna Lagraoui, Brigitte Grouix, Nathalie Julien, Michel Asselin, Dannyck Gaudreau, François Sarra-Bournet, Boulos Zacharie, Christopher Penney, Pierre Laurin, Marie-Josée Morin, Gorazd Krosl, Denis-Claude Roy
Journal: Blood (2006)
Importance of Detection of Intracellular Myeloperoxidase, CD13, CD79a, CD22, CD3 and Terminal Deoxynucleotidyl Transferase By Flow Cytometry Diagnosis of Acute Leukemias
Authors: Aldair Sousa Paiva, Hugo Diogenes De Oliveira Paiva, Geraldo Barroso Cavalcanti, Frank Bahia, Rodrigo Villar Freitas, Lenilton Silva Silveira, Lorena KF Silva, Roberto C Vasconcelos, Dany GKC Silva, Victor lima Soares, Erica Aires Gil, Geisa Januario, Maria Fernandes, Alessandra Suelen Jardim
Journal: Blood (2018)
Targeted IV Vs Oral Busulfan in Very Young Children with Thalassemia Major Undergoing Matched Allogeneic Haematopoietic Stem Cell Transplantation
Authors: Poonkuzhali Balasubramanian, Biju George, Rajesh Nagarajan, Uday Prakash Kulkarni, Ezhil Pavai Mohanan, Eunice Sindhuvi Edison, Kavitha M Lakshmi, Yasir Jeelani Samoon, Anup Devasia, Fouzia N., Anu Korula, Aby Abraham, Vikram Mathews, Alok Srivastava
Journal: Blood (2018)
Abstract 870: Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction and Associated Adverse Remodeling
Authors: Teja Devarakonda, Erik Kohlbrenner, Adolfo G Mauro, Chad Cain, Anindita Das, Roger J Hajjar, Fadi N Salloum
Journal: Circulation Research (2019)

Background: Relaxin signaling confers cardioprotection against acute myocardial infarction (MI) and mitigates adverse cardiac remodeling. We investigated the role of relaxin receptor (RXFP1) overexpression via cardiotropic AAV9 vectors in attenuating MI-associated adverse remodeling. Methods and Results: Murine RXFP1 cDNA with CMV promoter was introduced into AAV cis plasmids for generation of AAV9-RXFP1 viral vectors. 1.0 x 10 11 viral genomes in 100μL saline were administered i.v. to 8-week-old CD1 male mice. Four weeks later, overexpression was confirmed via qPCR of RXFP1 mRNA in whole cardiac tissue lysates ( Fig A ) and primary cardiomyocytes ( Fig B ) versus control. Overexpressing (AAV9-RXFP1) mice were subjected to MI (30 minutes of coronary artery ligation followed by reperfusion for 24h or 7d). Immunohistochemical staining of cardiac sections 7d post-MI shows increased RXFP1 expression in AAV9-RXFP1 mice, as shown in Fig C . Infarct size was reduced at 24h post-MI (TTC staining, Fig D ) and fractional shortening (M mode echo) was preserved at 24h and 7d post-MI in AAV9-RXFP1 mice ( Fig E ); endocardial strain rate assessment (speckle tracking analysis) showed preserved function in the affected ventricular segments of AAV9-RXFP1 mice 7d post-MI ( Fig F ). Picrosirius staining showed reduced LV fibrosis at 7d post-MI in AAV9-RXFP1 mice ( Fig G ). Conclusion: Administration of AAV9-RXFP1 successfully upregulates RXFP1 in cardiac tissue and primary cardiomyocytes, reduces infarct size and fibrosis, and preserves cardiac function post MI. Targeting cardiac RXFP1 via gene therapy could be a novel strategy to prevent MI-related adverse remodeling.
Abstract 932: Translated Alternative Isoforms Coincide With Disordered Sequences in the Cardiac Proteome
Authors: Edward Lau, Yu Han, Damon Williams, Maggie PY Lam
Journal: Circulation Research (2019)

Introduction: Alternative splicing is widely implicated in cardiac development and diseases, but few isoform transcripts have ever been empirically observed as translated proteins. We aim to understand how alternative splicing diversifies proteome function. Method: We show an RNA-seq guided proteomics approach, comprising a custom pipeline of sequence read alignment, splice junction determination, and in silico filtering and translation to identify alternative isoforms across multiple cell types and anatomical regions of the human heart. We further applied the method to a time course study of human iPSC differentiation into cardiomyocytes, collecting isotope-tagged quantification data on a Q-Exactive HF mass spectrometer to examine isoform expression patterns during myocyte differentiation. We cataloged the translated non-canonical isoforms in the heart, and characterized sequence features upon which the empirically observed alternative sequences impinge. Result: We identified 1,216 distinct non-canonical isoform sequences at 1% FDR, including 143 sequences from 107 genes not found in the comprehensive databases TrEMBL and RefSeq. We observed tissue-specific and differentiation stage-specific differences in isoform expression patterns. The data show a proteome-wide enrichment of translated alternative isoforms sequences at intrinsically disordered regions of proteins with implication on isoform function. We observed examples where protein PTMs may be modulated by the exclusion of modification sites via splicing including a novel isoform we found in MYBPC3 which coincides with PKA-mediated phosphorylation implicated in diastolic function regulation in animal models. Conclusion: This is the first study to combine experimental RNA-seq and proteomics to investigate how splicing impacts the human cardiac proteome. The approach may avail understanding of the functional outcome of splicing and its role in disease mechanisms.
Abstract 247: Phagocytosis-mediated Activation of Smad3 in Macrophages Mediates Anti-inflammatory Transition and Protects From Adverse Post-infarction Remodeling
Authors: Bijun Chen, Shuaibo Huang, Ya Su, Jonathan Graff, Nikolaos G Frangogiannis
Journal: Circulation Research (2019)

Macrophages are essential regulators in tissue injury, repair and fibrosis. Although activation of TGF-β signaling cascades critically modulates macrophage phenotype in vitro, the in vivo role of macrophage TGF-β signaling in homeostasis and disease is unknown. Our study examined the role of macrophage-specific TGF-β/Smad3 signaling in a mouse model of myocardial infarction (MI). TGF-βs markedly activated Smad3 in isolated macrophages, without affecting Smad-independent pathways. Infarct macrophages, but not neutrophils exhibited Smad3 activation. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β1 release. Myeloid cell-specific Smad3 knockout mice (MyS3KO) had no baseline defects, but exhibited increased late mortality and accentuated remodeling following MI. Adverse outcome in MyS3KO mice after MI was associated with perturbations in phagocytic activity, with defective transition of macrophages to an anti-inflammatory phenotype and with scar expansion. Milk-fat globule EGF factor-8 (Mfge8) partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Perturbed anti-inflammatory transition of Smad3 null macrophages was associated with marked attenuation of phagocytosis-mediated PPAR induction. We demonstrate that Smad3 is activated in phagocytic macrophages, critically regulates their function and mediates anti-inflammatory transition, and protects the infarcted heart from adverse remodeling.