tbuckley/cabot-search huggingface dataset:
Abstract 16292: Selective Platelet Protease-Activated-Receptor (PAR)1 and PAR4 Mediated Thrombin Desensitisation in the Elderly is Correlated With Inflammation and Chronic Thrombin Receptor Stimulation
Authors: Sonali R Gnanenthiran, Gabrielle Pennings, Caroline Reddel, Heather Campbell, Justin Hamilton, Vivien Chen, Leonard Kritharides
Journal: Circulation (2020)

Introduction: Platelet activation, by adenosine diphosphate (ADP) via P2Y 12 receptors and thrombin via PAR1 and PAR4, is a key therapeutic target in cardiovascular disease (CVD). The efficacy of antiplatelet agents diminishes in the elderly, but it is unknown whether these pathways change with aging. Hypothesis: Platelet activation pathways change with aging. Methods: Platelet activity was evaluated in young (20-30yrs), middle-aged (40-55yrs) and elderly (≥70yrs) healthy volunteers (n=174). Whole blood aggregometry and flow cytometry (P-selectin: α-granule release; CD63: dense granule release; PAC1 binding: activated GPIIb/IIIa) were performed under basal conditions and post ex vivo stimulation with ADP, thrombin, PAR1 agonist or PAR4 agonist. EC 50 and E max values were derived for each agonist. Receptor cleavage and quantification (P2Y 12 ; PAR1; PAR4; GPIbα) were assessed with flow cytometry. Thrombin generation (D-Dimer) and inflammation (interleukin [IL]-1β; tumour necrosis factor [TNF]-α) were assessed via ELISA. Results: The elderly had higher basal platelet activation markers (P-selectin, CD63, activated GPIIb/IIIa) than the young, with higher basal activity correlating with increasing IL-1β. P2Y 12 receptor density was higher in the elderly and associated with greater ADP-induced platelet aggregation and activation. Elderly subjects had less platelet activation in response to thrombin (higher EC 50 ), demonstrating hyporeactivity to selective stimulation of PAR1 or PAR4, more basal PAR1/PAR4 cleavage, and less inducible PAR1/PAR4 cleavage. This was associated with reduced thrombin binding receptor GPIbα and reduced secondary ADP contribution to thrombin-mediated activation. D-Dimer and TNF-α levels were elevated in the elderly, and inversely correlated with platelet thrombin sensitivity, implying a role of desensitization from chronic thrombin receptor stimulation. Conclusion: Aging is associated with increased basal platelet activation and hyperreactivity to ADP, but selective desensitization to thrombin. The latter appears mediated by chronic thrombin receptor stimulation and inflammation. Age-specific antiplatelet strategies may require selective targeting of these pathways to treat CVD in the elderly.
Clonal Architecture of <i>EGFR</i> Mutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study (NCT03059641)
Authors: Xinghao Ai, Jiuwei Cui, Jiexia Zhang, Rongrong Chen, Wen Lin, Congying Xie, Anwen Liu, Junping Zhang, Weihua Yang, Xiaohua Hu, Xiaohua Hu, Qiong Zhao, Chuangzhou Rao, Yuan-Sheng Zang, Ruiling Ning, Pansong Li, Lianpeng Chang, Xin Yi, Shun Lu
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Patients and Methods: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.
Abstract 14365: Identification of MicroRNAs and Their Target Genes in Microvascular Disease in Diabetes
Authors: Lei Gao, Atsumi Tsuji Hosokawa, Jody Tori O Cabrera, Tong Zhou, Ayako Makino
Journal: Circulation (2020)

Cardiovascular disease is the leading cause of death in patients with diabetes. Among coronary vascular defects, obstructive coronary artery disease (CAD) is the primary cause of cardiac mortality. However, there is growing evidence that patients with coronary microvascular disease (CMD, also known as non-obstructive coronary disease) also experience chest pain and occasional heart attack. Furthermore, recent studies show that diabetes is the risk factor of CMD. However, the molecular mechanisms by which diabetes develops CMD is not fully understood. MicroRNAs (miRNAs) are a non-coding small RNA that regulates gene expression at the post-transcriptional level, and the change of miRNA profile is implicated in many diseases. In this study, we identified the core miRNAs which are involved in the development of coronary endothelial dysfunction in diabetes. We used an inducible type 2 diabetic (T2D) mouse model generated by high-fat diet and a single injection of low-dose streptozotocin. Our T2D mice did not show detectable atherosclerotic plaque, but developed CMD evidenced by reduced coronary flow velocity reserve. We conducted a miRNA array using mouse coronary endothelial cells (MCECs) isolated from diabetic and control mice, and selected seven miRNAs based on the result. Next, real-time PCR assays were carried out with seven miRNAs and found that miR210 and miR342-5p were downregulated, and miR378 was upregulated in MCECs of diabetic mice compared to the control. To identify the target genes of miR342-5p and miR378, we inhibited miR342-5p or overexpressed miR378 in MCECs. After testing 93 genes that are involved in endothelial functions, we found that inhibition of miR342-5p decreased the levels of Atp2a3 , Opa1 , Sod3 , and Vegfb , whereas miR378 overexpression significantly decreased Aggf1, HK1, Mapk3, Pak1, Panx1, Stim1, Stim2, Vcam1, and Vegfb and increased Casp2 and Gja1 . Western blotting data revealed that the expression levels of Affg1, Opa1, and Pak1 were significantly decreased in the MCECs from diabetic mice compared to the control. In summary, these data suggest that miR342-5p and miR378 could be a potential therapeutic target for CMD in diabetic patients, and Affg1 Opa1 and Pak1 are the downstream mRNAs of miR342-5p or miR378.
Abstract 15034: Exposure to Secondhand Smoke is Associated With Increased Left Ventricular Mass
Authors: Travis M Skipina, Bharathi Upadhya, Elsayed Z Soliman
Journal: Circulation (2020)

Background: Exposure to secondhand smoke (SHS), or passive smoking, has been associated with chronic hypertension. However, little is known about the relationship between SHS and left ventricular (LV) hypertrophy, the most common complication of hypertension and a manifestation of cardiac end-organ damage. Hypothesis: SHS exposure is independently associated with LV mass. Methods: This analysis included 4,982 non-smoker participants (age 60.8±13.6 years, 57.8% women, 77.7% whites) from the Third National Health and Nutrition Examination (NHANES-III). Non-smoking was defined by self-report and serum cotinine ≤ 10 ng/dL, a biomarker for tobacco exposure. SHS was defined as serum cotinine level &gt;1 ng/dL. LV mass was estimated using an electrocardiographic model developed and applied in NHANES-III then validated in the Cardiovascular Health Study. Multivariable linear regression was used to examine the cross-sectional association between SHS exposure (vs. no exposure) with estimated LV mass. In similar models, we also examined the associations of LV mass across quartiles of serum cotinine (reference group, 1 st quartile) and in subgroups stratified by race, sex, and hypertension status. Results: About 9.8% (n=489) of the participants were exposed to SHS. Exposure to SHS was associated with an estimated 2.9 gram increase in LV mass, with a dose-response relationship between higher serum cotinine and LV mass ( Table ). These results were consistent in men and women (interaction p-value= 0.31), whites and non-whites (interaction p-value= 0.21), and those with and without hypertension (interaction p-value= 0.88) Conclusion: In a racially diverse sample of non-smokers, SHS is associated with increased LV mass with a dose-response relationship between level of exposure and LV mass. These findings underscore the harmful effect of passive smoking on the cardiovascular system and highlight the need for more restrictions on smoking in public areas.
A thermostability perspective on enhancing physicochemical and cytological characteristics of octacalcium phosphate by doping iron and strontium
Authors: Haishan Shi, Xiaoling Ye, Jing Zhang, Tingting Wu, Tao Yu, Changren Zhou, Jiandong Ye
Journal: Bioactive Materials (2020)

Investigation of thermostability will lead the groundbreaking of unraveling the mechanism of influence of ion-doping on the properties of calcium phosphates. In this work, octacalcium phosphate (OCP), a metastable precursor of biological apatite, was used as a stability model for doping ions (Fe3+ and Sr2+) with different ionic charges and radii. After treated under hot air at different temperatures (110-200 °C), the phase, morphology, structure, physicochemical properties, protein affinity, ions release, and cytological responses of the ion-doped OCPs were investigated comparatively. The results showed that the collapse of OCP crystals gradually occurred, accompanying with the dehydration of hydrated layers and the disintegration of plate-like crystals as the temperature increased. The collapsed crystals still retained the typical properties of OCP and the potential of conversion into hydroxyapatite. Compared to the undoped OCP, Fe-OCP, and Sr-OCP had lower and higher thermostability respectively, leading to different material surface properties and ions release. The adjusted thermostability of Fe-OCP and Sr-OCP significantly enhanced the adsorption of proteins (BSA and LSZ) and the cytological behavior (adhesion, spreading, proliferation, and osteogenic differentiation) of bone marrow mesenchymal stem cells to a varying extent under the synergistic effects of corresponding surface characteristics and early active ions release. This work paves the way for understanding the modification mechanism of calcium phosphates utilizing ion doping strategy and developing bioactive OCP-based materials for tissue repair.
Abstract 15012: Lactate Dehydrogenase B and Pyruvate Oxidation Associated With Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: A Multi-omics Study
Authors: Marwa Tantawy, Lakshmi Manasa Chekka, Timothy Garrett, Sonal Singh, chintan SHAH, Michael G Fradley, Robert Cornell, Rachid Baz, Nida Waheed, David DeRemer, Lihui Yuan, Taimour Y Langaee, Keith L March, Carl Pepine, Jan Moreb, Yan Gong
Journal: Circulation (2020)

Introduction: Multiple Myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), a proteasome inhibitor used to treat relapsed and refractory MM, has been associated with cardiotoxicity including heart failure (HF). Hypothesis: We hypothesized that a multi-omics approach integrating data from different omics will provide insights into the mechanisms of CFZ-induced HF. Methods: Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with symptomatic HF and 6 with no HF) at the University of Florida Health Cancer Center. Global metabolomics profiling was performed using a LC/MS metabolomic platform. Global proteomic profiling was performed on LC/MS/MS platform with ~ 370 proteins quantified by iTRAQ analysis. TaqMan ® OpenArray ® Human MicroRNA Panel, containing 754 human microRNAs (miRNAs), was used for miRNA profiling. Pathway integrative analysis was performed to identify genes and pathways that are differentially expressed between those who developed HF versus those who did not. Features with p-value &lt; 0.05 were considered statistically significant. Results: The cohort mean age was 61 years and 38.5% were men. Proteomics data identified up-regulation of lactate dehydrogenase B (LDHB) (fold change [FC]=8.2, p=0.01) in those who developed HF compared to those who did not. Metabolomics data identified lower plasma abundance of pyruvate (FC=0.16, p=0.0004) and higher abundance of lactate (FC=2.4, p=0.0001) in HF patients. Using miRNA target gene prediction tools, we observed that LDHB regulated by miR-139 which downregulated in HF patients (FC=0.03). Multi-omics integrative analysis suggested that the pyruvate fermentation to lactate (pyruvate oxidation) pathway is associated with CFZ-related HF. Conclusion: In this pilot multi-omics integrative analysis, we observed down-regulation of pyruvate and up-regulation of LDHB among patients with CFZ-related HF, which suggests the importance of pyruvate oxidation pathway and mitochondrial dysfunction in CFZ-related HF and that this pathway might be regulated by miR-139. Further investigation in a larger independent cohort is warranted to better understand the mechanisms of CFZ-related HF.
Abstract 13094: Association Between Myocardial Strain Using 2d and 3d Speckle-tracking Echocardiography and Diffuse Myocardial Fibrosis in Heart Transplant Recipients
Authors: Mingxing XIE, Sun Wei, Zhang Li, Wu chun, Lv Qing
Journal: Circulation (2020)

Background: Myocardial fibrosis (MF) is a well-described histopathologic featurein patients after heart transplant (HT). The two-dimensional speckle-tracking echocardiography (2D-STE) derived strain has been reported as a noninvasive tool to predict myocardial fibrosis (MF). Nevertheless, the relation between three-dimensional (3D)-myocardial strain and MF, and which directions of strain components correlated best with MF in HT recipients have not been reported. Objective: The study aimed to 1) explore whether diffuse left ventricular (LV) MF defined by cardiovascular magnetic resonance (CMR)- extracellular volume fraction (ECV) is expanded; 2) evaluate the association between LV MF and LV strain measured by 2D- and 3D-STE, and investigate which strain parameter is the more robust predictor of LV MF in patients after HT. Methods: A total of 60 subjects (40 patients after HT and 20 healthy controls) were prospectively enrolled. All subjects underwent the 2D, 3D echocardiography and CMR examination. The LV ejection fraction (EF) was measured by 3D-STE. The LV- global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) were measured by 2D- and 3D-STE. And LV diffuse MF was defined by ECV using the modified Look-Locker inversion recovery (MOLLI) sequence. Results: The HT recipients had higher native T1 and ECV than healthy controls (1042.8±35.3ms vs 1006.3±19.6ms, p&lt;0.001; 26.8±3.4% vs 24.6±1.3%, p=0.02). And compared with healthy controls, the 3D-GLS, 3D-GCS, 3D-GRS and 2D-GLS were all lower (p&lt;.005) in the HT recipients. But 3D-LVEF was similar in HT patients and healthy controls. And in the HT group, the increased ECV only correlated with 2D-GLS (r=0.57, p=0.001) and 3D-GLS (r=0.51, p &lt; 0.001), not correlated with 2D- and 3D-GCS, GRS. The separate stepwise multivariate analysis showed that both 2D-GLS (β=0.74, p=0.001) and 3D-GLS (β=0.69, p &lt; 0.001) were independently associated with LVECV. Conclusions: Patients after HT have higher LV MF and reduced LV strain compared with control subjects. Moreover, both 2D- and 3D-GLS are the independent predictor of diffuse LV MF. Therefore, the measurement 2D- and 3D-GLS may be provide a noninvasive assessment of LV MF in the transplanted hearts.
Abstract 15829: Temporal Characteristics of Intra-thoracic Impedance Before and After Heart Failure Hospitalizations in a Large Real-world Population of Patients With Cardiovascular Implanted Electronic Devices
Authors: Shantanu Sarkar, Jodi L Koehler, Eddy Warman
Journal: Circulation (2020)

Introduction: Intrathoracic impedance (IMP), measured in ICD/CRTD implantable devices, is a measure of intravascular blood volume and have been shown to correlate with intracardiac pressures. We investigated the temporal characteristics of IMP before and after HF events (HFE) in a large real-world cohort of patients (pts) with ICD/CRTD devices. Methods: We linked Optum© deidentified EHR dataset during the period from 2007-2017 to the Medtronic CareLink data warehouse. Pts with ICD/CRTD implants with IMP measurements were included. HFE was defined as an inpatient, ED, or observation unit stay with primary diagnosis of HF and IV diuretics administration. Temporal average of IMP measurement across all pts in the 60 days pre and post HFE were compared for HFE with and without readmission for HF within 60 days and in pts with no HFE. Results: A total of 17,886 pts with 1.8±1.2 years of follow-up met inclusion criteria. The average age was 66.6 ±12.3 years, with 72% being males, and 51% with ICD devices. A total of 1174 pts had 1425 HFE with no readmission and 282 pts had 295 HFE which were followed by readmission. A total of 17,839 pts had no HFE over 86,858 follow-up months. The average IMP during HFE, with and without readmission, and in pts with no HFE are shown in Fig. IMP decreases over a period of time prior to HFE and recovers due to treatment during HFE. The average IMP across all patients was lower on all 60 days pre and post HFE with readmission compared to HFE with no readmission (p&lt;0.001) and both were lower compared to follow-up period with no HFE (p&lt;0.001). The IMP recovers less often after HF events which are followed by readmission within 60 days compared to HF events with no readmission. Conclusions: In a large real-world population of pts with ICD/CRTD devices, on an average IMP reduces prior to and recovers during HFE. IMP was lower before and after HFE with readmission compared to HFE with no readmission. Readmission is more likely in pts with smaller impedance recovery after HF events.
Abstract 14499: Impact of Pre-existing and New Incident Atrial Fibrillation on Outcomes of Patients With Acute Pulmonary Embolism: Findings From an International Registry
Authors: Behnood Bikdeli, David Jimenez, Jorg Del Toro, Gregory Piazza, Augussina Rivas, José Luis Fernández-Reyes, Ángel Sampériz, Remedios Otero, José María Suriñach, Carmine Siniscalchi, Javier Miguel Martín-Guerra, Joaquín Castro, Alfonso Muriel, Gregory Lip, Samuel Z Goldhaber, Manuel Monreal
Journal: Circulation (2020)

Background: Atrial fibrillation (AF) may occur prior to or early in the course of acute pulmonary embolism (PE). The impact of AF on outcomes of patients with PE remains uncertain. Methods: Using the data from a large prospective multicenter registry of patients with objectively-confirmed PE (04/2014 to 01/2020), we identified three patient groups: 1) those with pre-existing AF 2) patients with newly identified AF within 2 days from the index PE (incident AF) and 3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, in unadjusted and multivariable adjusted models considering those without AF as referent. Results: Among 16,497 patients with PE, 792 had pre-existing AF. Compared with those without AF, patients with pre-existing AF, had increased odds of 90-day all-cause (Odds ratio [OR]: 2.81 (95% confidence interval [CI]: 2.33-3.38) and PE-related mortality (OR: 2.38, 95% CI: 1.37-4.14). After multivariable adjustment, pre-existing AF significantly increased the odds of all-cause mortality (OR: 1.91, 95% CI: 1.57-2.32) but not PE-related mortality (OR: 1.50; 95% CI: 0.85-2.66). Pre-existing AF was associated with increased hazard for ischemic stroke at 1-year follow-up (hazard ratio [HR]: 5.48; 95% CI: 3.10-9.69). Among 16,497 patients with PE, 445 developed incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR: 2.28; 95% CI: 1.75-2.97) and PE-related (OR: 3.64; 95% CI: 2.01-6.59) mortality. Findings were similar in multivariable analyses and at 1-year follow-up (Figure). No patients with incident AF developed ischemic stroke. Conclusion: In patients with acute symptomatic PE, both pre-existing AF and incident AF predict an adverse clinical course, although the type of adverse outcomes may be different depending on the timing of AF onset.
Testing Clinical Prediction Models
Authors: Benjamin A. Goldstein, Michael J. Pencina
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 12976: Computational Protein Modeling to Engineer a C-X-C Chemokine Receptor Type 4 (CXCR-4) Agonist to Prevent Ischemic Heart Failure
Authors: Patpilai Kasinpila, Rohan Shad, Vandon Duong, Robyn Fong, Nicolas Quach, Sandra Kong, Carla Perez, Possu Huang, William Hiesinger
Journal: Circulation (2019)

Introduction: Current interventions of coronary artery disease do not address residual microvascular perfusion deficits after myocardial infarction, leading to ischemic cardiomyopathy. Stromal cell...
Abstract 11302: Comprehensive Atrial and Circulating Transcriptome Analyses Revealed Distinctive Pathophysiological Mechanisms in Post-Operative Atrial Fibrillation
Authors: Cheng-Yuan Lu, Hsiang-Chun Lee, Yi-Shuan Tseng, Tzu-Han Lee, Chong-Chao Hsieh, Jiann-Woei Huang, Chaw-Chi Chiu, Kai-Chien Yang
Journal: Circulation (2018)

Introduction: Post-operative atrial fibrillation (POAF) occurs in up to 50% of cardiac surgery cases and increases the risks of stroke, organ failure and death. The pathophysiological mechanisms le...