tbuckley/cabot-search huggingface dataset:
Associations of Circulating Extracellular RNAs With Myocardial Remodeling and Heart Failure
Authors: Ravi V. Shah, Jian Rong, Martin G. Larson, Ashish Yeri, Olivia Ziegler, Kahraman Tanriverdi, Venkatesh Murthy, Xiaojun Liu, Chunyang Xiao, Alexander R. Pico, Tianxiao Huan, Daniel Levy, Gregory D. Lewis, Anthony Rosenzweig, Ramachandran S. Vasan, Saumya Das, Jane E. Freedman
Journal: JAMA Cardiology (2018)

Mortality is high among patients heart failure (HF) who are receiving treatment, and therefore identifying new pathways rooted in preclinical cardiac remodeling phenotypes may afford novel biomarkers and therapeutic avenues. Circulating extracellular RNAs (ex-RNAs) are an emerging class of biomarkers with target-organ epigenetic effects relevant to myocardial biology, although large human investigations remain limited.To measure the association of highly expressed circulating ex-RNAs with left ventricular remodeling and incident HF in a community-based cohort.This is a prospective observational cohort study of individuals who were included in the eighth examination of the Framingham Offspring Cohort (2005-2008). Collected data include measurements of the left ventricle via electrocardiography, determination of circulating ex-RNAs in plasma, and incidence of heart failure. Data analysis was completed from December 2016 to June 2018.A total of 398 circulating ex-RNA molecules in plasma were measured by reverse transcription polymerase chain reaction; disease ontology analysis was also performed.Echocardiographic indices of left ventricular (LV) remodeling and incident heart failure.A total of 2763 participants of the Framingham Heart Study with measured ex-RNAs (mean [SD] age, 66.3 [9.0] years; 1499 [54.3%] female) were included in this study. Of this sample, 2429 to 2432 individuals had echocardiographic measures recorded (depending on the measurement). A total of 2681 individuals had HF status determined, of whom 116 (4.3%) experienced HF (median [interquartile range] follow-up, 7.7 [6.6-8.6] years). We identified 12 ex-RNAs associated with LV mass and at least 1 other echocardiographic phenotype (LV end-diastolic volume or left atrial dimension). Of these 12 ex-RNAs, 3 micro RNAs (miR-17, miR-20a, and miR-106b) were associated with a 15% reduction in long-term incident HF per 2-fold increase in circulating level during the follow-up period, after adjustments for age, sex, established HF risk factors, and prevalent or interim myocardial infarction. These 3 RNAs shared sequence homology and targeted a shared group of messenger RNAs that specified pathways relevant to HF (eg, transforming growth factor-β signaling, growth/cell cycle, and apoptosis), and shared a disease association with hypertension in disease ontology analysis.This study identifies a group of circulating, noncoding RNAs associated with echocardiographic phenotypes, long-term incident HF, and pathways relevant to myocardial remodeling in a large community-based sample. Further investigations into the functional biology of these ex-RNAs are warranted for surveillance for HF prevention.
Choices in Managing Full-Term Pregnancy
Authors: Michael F. Greene
Journal: New England Journal of Medicine (2018)

The distribution of the length of gestation at delivery in the United States has changed dramatically over the past 25 years. The percentage of all deliveries during the 39th or 40th week of gestation has increased, while the dispersion around that peak has narrowed considerably; this change is even more dramatic for singleton pregnancies. In 2015, a total of 60.2% of all singletons were delivered during the 39th or 40th week, 7.1% were delivered at 41 weeks or later, and 0.4% were delivered at 42 weeks or later (a decline from 0.6% in 2007).1 Yet perinatal mortality at 41 weeks . . .
Abstract 13243: Pericardial Fat is a Useful Predictor of Future Cardiovascular Events Independent of High-Risk Coronary Plaques
Authors: Aiko Sakamoto, Masae Uehara, Nobukazu Ishizaka, Jiro Ando, Issei Komuro
Journal: Circulation (2016)

Background: Pericardial fat is recognized as a risk factor for coronary stenosis. However, it remains unclear whether ectopic fat deposition, such as pericardial fat and intrathoracic fat, is an independent predictor of future cardiovascular events. Methods: We measured pericardial fat volume (PFV) and intrathoracic fat volume (IFV) in 355 patients (203 men; mean age, 68.1 ± 10.6 years) who underwent coronary computed tomography angiography. Among 200 patients who were judged to have obstructive coronary artery disease (CAD), cardiovascular events, defined as death, acute coronary syndrome, cerebral stroke, heart failure, and coronary revascularization, were assessed at 5 years. Results: There was a strong association between PFV and IFV (R=0.707, P&lt;0.001). Body mass index (BMI) was significantly associated with PFV (R=0.538, P&lt;0.001) and IFV (R=0.633, P&lt;0.001). PFV and IFV were significantly larger in patients with high-risk coronary plaque (HRP), including low-density plaque, positive remodeling, and spotty calcification, than in those without (PFV, 106 mL [interquartile range, IR 80-144] vs. 85 mL [IR 61-112], P&lt;0.001; IFV, 110 mL [IR 68-158] vs. 90 mL [IR 55-123], P=0.006). Among patients with obstructive CAD, 38 patients developed a cardiovascular event during 5 years. Patients with PFV of median or greater (≥110 mL) had a significantly higher risk of events than those with PFV below median (P=0.025). Patients with IFV of median or greater (≥118 mL) had a higher risk of events than those with IFV below median (P=0.047). When age, gender, BMI, HRP, PFV, and IFV were included in a Cox regression model, PFV, but not IFV, was a significant predictor of cardiovascular events (hazard ratio 3.02 per 100 mL increase, 95% confidence interval 1.26-7.26, P=0.014). Conclusions: PFV was predictive of cardiovascular events independent of other obesity parameters and HRP, indicating that pericardial fat may have local effects on the development of cardiovascular disease.
Abstract 4153: Commissioning and radiobiological verification of the small animal radiotherapy research platform (SARRP)
Authors: Jonathan L. Kane
Journal: Cancer Research (2018)

Abstract Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. Small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed in small animal cancer models by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. The technological evolution from simple, broad field irradiation configurations, to more sophisticated dose deliveries for preclinical radiobiology experiments has introduced new dosimetry challenges for preclinical small animal cancer research. Because of this, robust QA and dosimetry techniques are a key part of using novel treatment platforms using very small irradiation fields. In this study, we present a dosimetric study of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on the small field dosimetry. Physical dosimetry was assessed using ion chambers and radiochromic film, investigating the impact the beam focus size has on the dose rate output as well as beam characteristics (beam shape and penumbra variations). Two film reading modalities have been used to assess the dose output using the 0.5 mm diameter aperture. This study establishes that FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. Furthermore, all small field dosimetry data generated in this study are equally comparable with our Monte Carlo simulations for both focal spot sizes. Overall, it was observed that the small focal spot, while having a lower dose-rate output was shown to produce a more stable and homogenous beam with minimum penumbra over time when compared to the larger focal spot. These findings suggest that when preclinical stereotactic irradiation fields are used, a practical compromise (time to deliver a desired dose and field homogeneity) needs to be considered when deciding the optimum treatment plan and beam configuration used. Citation Format: Jonathan L. Kane. Commissioning and radiobiological verification of the small animal radiotherapy research platform (SARRP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4153.
Abstract 12939: Platelet Activation is Less Enhanced in Edwards Sapien 3 Valve Compared to Its Precursor Model
Authors: SuzanneFateh-Moghadam, SabrinaVoesch, MeinradGawaz, wolfgangbocksch
Journal: Circulation (2014)

Background: Due to a different design of the Cobalt chromium alloy frame and the additional outerskirt to minimize paravalvular leakage one might imagine that the extent of platelet activation (PA) of new Edwards Sapien 3 valve (ESV3) might differ from the Edward Sapien XT valve (ESVXT). Aim of the study: The aim of our study was to compare platelet aggregation (Agg) and platelet activation (PA) of the ESV-XT with the newer ESV-3 in pts undergoing TAVI on dual antiplatelet therapy . Methods: Pts scheduled for TAVI were loaded with 600 mg Clp and 500 mg ASA the day before intervention. Platelet Agg were evaluated in all pts by the Multiplate system (Dynabyte, Munich, Germany) before (T0), directly after intervention (T1) and on T2 (day1), T3 (day2) , T4 (day3) . PA was simultaneously assessed with the use of immunologic markers of PA as CD62P and PAC-1 by flow cytometry. Results: 43 pts (age 81.3 +1.2 years ) with severe aortic stenosis and high surgical risk (log Euroscore 18.1 +1.3 %) underwent successfu...
Abstract 5465: Resveratrol inhibits cell proliferation via crosstalk between integrin αvβ3 and IGF-1R in primary cell cultures of human uterine fibroids
Authors: Yi-Ru Chen, Ya-Jung Shih, Heng-Yuan Tang Tang, Hung-Yun Lin, Paul J. Davis
Journal: Cancer Research (2018)

Abstract A uterine fibroid is the most common benign smooth muscle cell tumor of the myometrium. Resveratrol, a stilbene, has been used as an anti-inflammatory and antitumor agent. We aimed to determine the expression of growth factor molecules for growth inhibition after treatment of resveratrol in the primary cell lines from human uterine fibroid. In terms of growth rate, of the 24 uterine fibroid primary cell culture cells, 5 were mildly sensitive, 13 were medium-, and 6 were sensitive to resveratrol treatment. 19 out of the 24 primary cell lines responded to treatment of resveratrol from middle to sensitive ranges. Resveratrol arrested cell proliferation and also induced apoptosis, indicating that an intact apoptotic pathway was present in these cells by resveratrol. Reduction of integrin αvβ3 expression diminished resveratrol-induced antiproliferative effect in uterine fibroid cells. Resveratrol induced the expression of proapoptotic genes such as COX-2 and p21. On the other hand, the expression of proliferative (antiapoptotic) genes was either inhibited in such as BCL2 and CDKN2 or not changed in Cyclin D1 and PCNA. The expression of mRNA and protein of insulin-like growth factor-I (IGF-I) was inhibited by resveratrol in primary uterine fibroid cells. The proapoptotic proteins such as caspase 3 and caspase 9 were activated after resveratrol treatment and demonstrated that resveratrol induced apoptosis in the resveratrol-sensitive primary cell cultures, which was consistent with studies of the flow cytometry. In addition, resveratrol blocked the expression of integrin αvβ3 and protein. Concurrently, constitutive AKT phosphorylation in uterine fibroid cells was inhibited by resveratrol. Therefore, growth modulation of uterine fibroid cells occurs via mechanisms dependent on crosstalk between integrin αvβ3 and IGF-1R. Our findings suggest that resveratrol can be considered as an alternative therapeutic agent for uterine fibroid. Citation Format: Yi-Ru Chen, Ya-Jung Shih, Heng-Yuan Tang Tang, Hung-Yun Lin, Paul J. Davis. Resveratrol inhibits cell proliferation via crosstalk between integrin αvβ3 and IGF-1R in primary cell cultures of human uterine fibroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5465.
Aortic Arch Curvature and Atherosclerosis Have Overlapping Quantitative Trait Loci in a Cross Between 129S6/SvEvTac and C57BL/6J Apolipoprotein E–Null Mice
Authors: HirofumiTomita, SvetlanaZhilicheva, ShinjaKim, NobuyoMaeda
Journal: Circulation Research (2010)

Rationale: Apolipoprotein E-null mice with a 129S6/SvEvTac strain background (129-apoE) develop atherosclerotic plaques faster in the aortic arch but slower in the aortic root than those with a C57BL/6J background (B6-apoE). The shape of the aortic arch also differs in the 2 strains. Objective: Because circulating plasma factors are the same at both locations, we tested the hypothesis that genetic factors affecting vascular geometry also affect the location and extent of atherosclerotic plaque development. Methods and Results: Tests on the F2 progeny from a cross between 129-apoE-null and B6-apoE-null mice showed that the extent of atherosclerosis in the aortic arch is significantly correlated in males, but not in females, with the shape of arch curvature (r=0.34, P<0.0001) and weakly with the arch diameter (r=0.20, P=0.02). Quantitative trait locus (QTL) analysis identified 2 significant peaks for aortic arch lesion size on chromosome 1 (105 Mb, LOD=5.0, and 163 Mb, LOD=6.8), and a suggestive QTL on chro...
BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation
Authors: Krystin Deason, Ty Dale Troutman, Aakanksha Jain, Dilip K. Challa, Rajakumar Mandraju, Travis Brewer, E. Sally Ward, Chandrashekhar Pasare
Journal: The Journal of Experimental Medicine (2018)

The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.
Abstract 14033: Development of a Drug-induced Spiral Wave Re-entrant Tachycardia Model in Human Induced Pluripotent Stem Cell-derived Mini-3D Cardiac Tissue Sheets
Authors: Masahide Kawatou, Hidetoshi Masumoto, Hiroyuki Fukushima, Gaku Morinaga, Kenji Minakata, Tadashi Ikeda, Ryuzo Sakata, Takashi Ashihara, Yuko Sekino, Jun K Yamashita
Journal: Circulation (2016)

Backgrounds: Life-threatening arrhythmias are critical issues in clinical health care. The development of human induced pluripotent stem cell (hiPSC)-derived arrhythmia models is advantageous for s...
EGF Receptor–Dependent YAP Activation Is Important for Renal Recovery from AKI
Authors: Jianchun Chen, Huaizhou You, Yan Li, You Xu, Qian He, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2018)

Background Increasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI. Methods We used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap , Taz , or both occurring specifically in RPTCs) that were subjected to bilateral IRI. Results YAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression. Conclusions This study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.
Right Ventricular Function, Right Ventricular–Pulmonary Artery Coupling, and Heart Failure Risk in 4 US Communities
Authors: Kotaro Nochioka, Gabriela Querejeta Roca, Brian Claggett, Tor Biering-Sørensen, Kunihiro Matsushita, Chung-Lieh Hung, Scott D. Solomon, Dalane Kitzman, Amil M. Shah
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Limited data exist on the prevalence and prognostic importance of right ventricular (RV) dysfunction for heart failure (HF) in the general population. <h3>Objective</h3> To assess the prevalence of RV dysfunction and its association with HF and mortality in a community-based elderly cohort. <h3>Design, Setting, and Participants</h3> Cross-sectional and time-to-event analysis of participants in the Atherosclerosis Risks in the Community (ARIC), a multicenter, population-based cohort study at the fifth study visit from 2011 to 2013, with a median follow-up of 4.1 years. This study included 1004 elderly participants in the ARIC study attending the fifth study visit who underwent both 3-dimensional and 2-dimensional RV echocardiography. Three-dimensional echocardiography data were analyzed between September 15, 2015, and July 24, 2016. <h3>Exposures</h3> Right ventricular ejection fraction (RVEF), RV–pulmonary artery (PA) coupling defined by the RVEF/PA systolic pressure (PASP) ratio, and RV longitudinal strain by 3-dimensional echocardiography. <h3>Main Outcomes and Measures</h3> For cross-sectional analysis, the prevalence of RV dysfunction across ACCF/AHA HF stages (0; A, at elevated risk for HF but without structural heart disease or clinical HF; B, structural heart disease but without clinical HF; and C, prevalent HF). For time-to-event analysis, a composite of incident HF hospitalization or all-cause death among participants free of HF at visit 5. <h3>Results</h3> Of the 1004 participants, mean (SD) age was 76 (5) years, 385 were men (38%), and 121 were black (12%). Mean (SD) RVEF was 53% (8%). Right ventricular EF, RVEF/PASP, and RV longitudinal strain were each progressively lower across advancing HF stages. Using reference limits from stage 0 participants, RVEF was abnormal in 103 asymptomatic persons with stage A HF (15%) and 27 with stage B HF (24%). Among participants free of HF at baseline, lower RVEF and worse RV-PA coupling (ie, lower RVEF/PASP ratio) both were associated with incident HF or death independent of LVEF and N-terminal pro b-type natriuretic peptide (hazard ratio, 1.20; 95% CI, 1.02-1.42 per 5% decrease in RVEF;<i>P</i> = .03; hazard ratio, 1.65, 95% CI, 1.15-2.37 per 0.5 unit decrease in RVEF/PASP ratio;<i>P</i> = .007). <h3>Conclusions and Relevance</h3> Right ventricular function and RV-PA coupling declined progressively across American College of Cardiology Foundation/American Heart Association HF stages. Among persons free of HF, lower RVEF was associated with incident HF or death independent of LVEF or N-terminal pro b-type natriuretic peptide.
Abstract 6: Restoration of Impaired Diastolic Function in Hypertrophic Cardiomyopathy Induced Pluripotent Stem Cell-derived Cardiomyocytes by Re-balancing the Calcium Homeostasis
Authors: Haodi Wu, Huaxiao Yang, Joe Zhang, Chi Keung Lam, June-Wha Rhee, Timon Seeger, Karim Sallam, Ning Ma, Joseph Wu
Journal: Circulation Research (2017)

Background: Diastolic dysfunction is commonly seen in hypertrophic cardiomyopathy (HCM). However, the cellular mechanism is not fully understood, and no effective treatment so far has been developed. We hypothesize here that HCM patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can recapitulate the cellular mechanism, and provide us a platform for mechanistic study and for drug screening of diastolic dysfunctions in HCM. Methods and Results: We generated beating iPSC-CMs from healthy individuals and HCM patients carrying familial mutations (MYH7 R663H (n=2 lines) and MYBPC3 R943ter (n=2 lines)). Sarcomere shortening measurement in patterned iPSC-CMs with live cell confocal imaging showed significantly prolonged diastolic phase and slower relaxation velocity in HCM iPSC-CMs compared to WT cells. To elucidate the cellular mechanism, Fura-2 AM ratiometric calcium imaging showed marked elevation of resting calcium level and increased abnormal calcium handlings in HCM iPSC-CMs, which were exaggerated by β-adrenergic activation with isoproterenol. By applying calcium transient and contractile force simultaneous recording, we defined a “risk index of diastolic dysfunction” (measured as transient-contraction gain factor), which was significantly increased in HCM iPSC-CMs. Thus, both elevated basal calcium level and increased calcium sensitivity of myofilament contribute to the abnormal diastolic function in HCM iPSC-CMs. Gene expression profiling of HCM and WT iPSC-CMs indicated that increased calcium channels may underlie the increased basal calcium concentration in HCM cells. Indeed, partially blocking the calcium influx by calcium blockers reset the basal calcium level, attenuated calcium mishandling, and restored the diastolic function in HCM iPSC-CMs. Moreover, re-balancing calcium homeostasis significantly improved long-term survival rate of HCM iPSC-CMs at both basal level and under β-adrenergic stress. Conclusion: The iPSC-CM models carrying patient-specific HCM mutations recapitulated diastolic dysfunction on single cell level. Future studies using these platform may reveal additional novel cellular mechanisms and therapeutic targets of diastolic dysfunction in HCM disease.