tbuckley/cabot-search huggingface dataset:
Abstract 12859: Tissue Doppler Derived Biphasic Velocities During the Pre and Post-Ejection Phases: Patterns, Concordance and Hemodynamic Significance in Health and Disease
Authors: Alaa M Omar, Diana M Ronderos Botero, Javier Arreaza Caraballo, GaHee Kim, Yeraz Khachatoorian, Jaclyn Kliewer, Mohamed A Abdel Rahman, Osama A Rifaie, Jonathan N Bella, Edgar Argulian, Johanna P Contreras
Journal: Circulation (2021)

Introduction: Pre-(PRE) and post-ejection (POE) velocities by mitral annular tissue Doppler (TD) are biphasic and may be related to myocardial deformations. We investigated the predominance and concordance of TD-PRE and POE velocities and their effect on myocardial functions in controls and in HF patients. Methods: Retrospectively, 84 HF patients [57.6±8 years, 28(33%) females, NYHA: 2.3±0.6, EF: 55±15%, 52(62%) preserved EF, and 32(38%) reduced EF], 42 normal young controls [27±4 years, 5(12%) females], and 26 asymptomatic age matched controls without cardiac abnormalities [53±12 years, 28(65%) females] were included. Results: While controls had almost always predominantly positive PRE and negative POE, HF had more negative PRE (Controls: 2%, HFpEF: 10%, HFrEF: 35%, p&lt;0.001) and positive POE (Controls: 4%, HFpEF: 33%, HFrEF: 74%, p&lt;0.001). Moreover, almost all controls exhibited normal concordance (positive PRE and negative POE). HF exhibited more abnormal concordance (Figure 1A,C) which was significantly associated with worse NYHA, and parameters of diastolic and systolic functions. Opposite PRE and POE velocities correlated significantly in all groups (PREp vs POEn: young:r=0.52, p&lt;0.001, age controls:r=0.79, p&lt;0.001, HFpEF: r=0.56, p&lt;0.001, HFrEF: r=0.42, p=0.018; PREn vs POEp: young: r=0.25,p=0.1, age controls: r=0.42, p=0.04, HFpEF: r=0.43, p=0.004, HFrEF: r=0.61, p&lt;0.001) and the ratios PRE-P/N and POE-N/P correlated significantly with E/e’ in HF only (Figure 1B). Conclusions: In physiological state, TD signals are predominantly positive during PRE and negative during POE. Opposite PRE and POE velocities corelate, representing the PRE-generation and POE-reversal of shortening-stretch relationships, the attenuation of which in HF may be related to elevated LV filling pressures. In HF, partially or completely reversed concordance of PRE and POE is associated with progressive worsening of clinical and hemodynamic profiles.
Abstract 11528: Predictors of Ventricular Arrhythmia in Mitral Valve Prolapse
Authors: Abdul Chaudry, Krishan Sivaraj, Thelsa Weickert, Faisal Syed
Journal: Circulation (2021)

Introduction: The arrhythmic form of mitral valve prolapse (AMVP) is characterized by complex or frequent ventricular arrhythmia (cfVA) and associated with increased risk of sudden cardiac death (SCD) from ventricular fibrillation, the majority of reported cases of SCD being in premenopausal women. There is limited data on prevalence and predictors of AMVP. Methods: We studied all 645 patients aged 18 to 90 years with mitral valve prolapse (MVP) on echocardiography between 2016-2019 at our institution (median age [IQR] 63.6 [51.9-73] years; 52.4% female; 16.2% African American). Echocardiogram images were reviewed to analyze valve morphology, mitral regurgitation (MR) severity and ventricular structure and function. cfVA was identified from resting and ambulatory ECG tracings. These and cardiovascular risk factors associated with cfVA were analyzed using multivariate logistic regression. Results: cfVA was present in 188 (29.1%) MVP patients. Independent predictors of cfVA were mitral annular disjunction (MAD, odds ratio [OR, 95% CI] 2.45 [1.48 – 4.06], p=0.0005), bi-leaflet prolapse (2.10 [1.42 – 3.11] vs. uni-leaflet, p=0.0002), inferior ECG T-wave inversion (TWI, 1.79 [1.17-2.75], p=0.007) and moderate+ MR (1.52 [1.01-2.27], p=0.044). AMVP, defined as bi-leaflet MVP with cfVA, was present in 102 (15.8%), with MAD in 38 (37.3%, vs. 58 [10.7%] without AMVP, p&lt;0.0001), inferior lead TWI in 45 (44.1%, vs. 97 [17.9%], p&lt;0.0001) and moderate+ MR in 47 (46.1% vs 134 [24.7 %], p&lt;0.0001). After median 1221 (IQR 1013 – 1456) days follow-up, 12 with AMVP died (11.7%, vs. 45 [8.3%] without, p=0.256) with SCD in 2 (2.0%, vs. 4 [0.9%], p=1.00). Conclusion: Ventricular arrhythmia in MVP is predicted by MAD, bi-leaflet prolapse, inferior ECG TWI and MR. These findings may help identify otherwise asymptomatic individuals, such as premenopausal women with MVP, at increased risk of SCD.
Abstract 11350: DNP-PhD Collaboration in NIH-funded Physical Activity Trials for Women at Risk for Cardiovascular Disease: A Team Science Approach
Authors: Shannon Halloway, Susan W Buchholz, Manju Daniel, Sally Lemke, Margaret Bavis, janice A odiaga, Phyllis Pelt, Lynne T Braun, Susan Tafini, Melissa Kalensky, Anita Opdycke, Krista Knudson, Heide R Cygan, Joellen Wilbur
Journal: Circulation (2021)

Doctorally prepared nurse scholars with the doctor of nursing practice (DNP) and the doctor of philosophy (PhD) degrees are equally well suited to engage in scholarship to advance cardiovascular nursing and health outcomes. Collaboration between DNP and PhD scholars is crucial to develop interventions to improve cardiovascular outcomes and encourage efficient translation of research findings into practice. The purpose of this paper is to (1) provide a targeted review of the current state of literature on examples of DNP-PhD collaboration, and (2) describe ongoing DNP-PhD collaborations across three NIH-funded trials (1 completed, 2 ongoing) testing physical activity interventions for women at risk for cardiovascular disease. First, a targeted review was conducted to identify examples of DNP-PhD collaboration, and identified 12 published articles. Articles described the DNP-PhD collaborations in research/scholarship ( n = 8) and education ( n = 5). Of the research articles, there was evidence of collaboration in evidence-based practice projects for various health outcomes. However, none of the articles described DNP-PhD collaboration in NIH-funded clinical trials, including behavioral interventions for cardiovascular health. Three physical activity interventions for women at risk for cardiovascular disease were or are being tested in three trials (NCT01700894, NCT03558828, NCT04556305). Examples of DNP-PhD collaboration are categorized according to the four Team Science Phases. Research teams are led by PhD nurse scholars who oversee design and implementation (Development, Conceptualization, Implementation, Translation). DNP scholars provide clinical feedback in advisory panels and focus groups (Development, Conceptualization), provide training to intervention teams, lead personal call and group interventions (Implementation), facilitate patient referrals for participation (Implementation), oversee intervention safety (Implementation, Translation), and contribute to dissemination (Translation). DNP-PhD collaboration is important for all phases of NIH behavioral trials to optimize outcomes. There is a need for additional publications to detail applicable DNP-PhD collaborations in NIH-funded nursing research.
Novel CD19-Specific γ/δ TCR-T Cells in Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Authors: Chenggong Li, Qi Chang, Jing Wang, Mengyi Du, Lin Liu, Haiming Kou, Cong Lu, Lu Tang, Jianghua Wu, Wenjing Luo, Yinqiang Zhang, Sha Ke, Jun Deng, Cheng Liu, Yu Hu, Heng Mei
Journal: Blood (2021)
IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY
Authors: Elizabeth Ogando-Rivas, Paul Castillo, Noah Jones, Vrunda Trivedi, Jeffrey Drake, Anjelika Dechkovskaia, Kate Candelario, Changlin Yang, Duane Mitchell
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms. METHODS Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides. RESULTS CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= &amp;lt; 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004). CONCLUSION In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.
CT pectoralis muscle area is associated with DXA lean mass and correlates with emphysema progression in a tobacco-exposed cohort
Authors: Michael Emmet O'Brien, Richard H Zou, Nathan Hyre, Joseph K Leader, Carl R Fuhrman, Frank C Sciurba, Mehdi Nouraie, Jessica Bon
Journal: Thorax (2021)

Introduction Muscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression. Methods Participants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (β) with 95% CI. Results PMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: β=0.76 (95% CI 0.65 to 0.86), p&lt;0.001; ASMI: β=0.76 (95% CI 0.66 to 0.86), p&lt;0.001; BMI: β=0.36 (95% CI 0.25 to 0.47), p&lt;0.001) and longitudinal (ΔFFMI: β=0.43 (95% CI 0.28 to 0.57), p&lt;0.001; ΔASMI: β=0.42 (95% CI 0.27 to 0.57), p&lt;0.001; ΔBMI: β=0.34 (95% CI 0.22 to 0.46), p&lt;0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (β=0.39 (95% CI 0.23 to 0.56), p&lt;0.001) but not with 6-year change in airflow obstruction. Conclusions PMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.
Abstract 103: Mechanistic Interplay Between Cardioprotection And Heart Regeneration Mediated By The ER-bound Transcription Factor Nrf1
Authors: Miao Cui, Atmanli Ayhan, Ning Liu, Rhonda S Bassel-duby, Eric N Olson
Journal: Circulation Research (2021)

Cardiomyocyte loss is the underlying basis for a majority of heart diseases. Preventing cardiomyocytes from death (cardioprotection) and replenishing the lost myocardium (regeneration) are the central goals for heart repair. Although cardioprotection and heart regeneration have been traditionally thought to involve separate mechanisms, protection of cardiomyocytes from injury or disease stimuli is a prerequisite to any meaningful regenerative response. In our study, we sought to understand how neonatal cardiomyocytes cope with injury-induced stress to regenerate damaged myocardium and whether the underlying mechanisms could be leveraged to promote heart regeneration and repair in adults. Using spatial transcriptomic profiling, we visualized regenerative cardiomyocytes reconstituting damaged myocardium after ischemia, and found that they are marked by expression of Nrf1, an ER-bound stress responsive transcription factor. Single-nucleus RNA sequencing revealed that genetic deletion of Nrf1 prevented neonatal cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, overexpression of Nrf1 protected the adult mouse heart from ischemia/reperfusion injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from cardiotoxicity induced by the chemotherapeutic drug doxorubicin. The cardioprotective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and maintenance of redox balance. Taken together, our study uncovers a unique adaptive mechanism activated in response to injury that maintains the tissue homeostatic balance required for heart regeneration. Reactivating these mechanisms in the adult heart represents a potential therapeutic approach for cardiac repair.
Abstract P375: Gender-based Cardio-protective Functional Dimorphism Of Bone Marrow Endothelial Progenitor Cells And Their Exosomes: Estrogen-independent Epigenetic Mechanisms
Authors: Charan T Gurrala, Venkata Garikipati, Zhongjian Cheng, Vandana Mallaredy, Maria Cimini, Darukeshwara Joladarashi, MAY TRUONGCAO, Chunlin Wang, Grace Huang, Carolina Gonzalez, Ajit Magadum, Rajika Roy, Cindy Benedict, Walter J Koch, Raj Kishore
Journal: Circulation Research (2021)

Introduction: Estrogen or estrogen receptor-dependent mechanisms in enhancing the cardioprotective efficacy of bone marrow endothelial progenitor cells (BM-EPC) is well-established in preclinical studies. However, the efficacy of estrogen does not reflect in the data from randomized cardiovascular clinical trials, suggesting an estrogen-independent role of female BM-EPC in eliciting enhanced cardiac protection compared to males. Hypothesis: Epigenetic mechanisms may contribute to the sex-specific dimorphism of Sca-1 + /CD31 + BM-EPC in regulating cell-homing, pro-angiogenic and anti-inflammatory functions in the ischemic myocardium leading to enhanced reparative function of female progenitor cells. Methods &amp; Results: Transplantation of GFP-BM-mononuclear cells from male and female GFP transgenic mice into the BM of lethally irradiated recipient male C57BL/6 mice resulted in the enhanced mobilization of female Sca-1 + CD31 + /GFP + BM-EPC into circulation post-MI. A higher number of female BM-EPC homed to the ischemic myocardium and significantly improved LV functions and capillary density post-MI compared to male BM-EPC. Female BM-EPC showed increased expression of bFGF, VEGFR2, SDF-1α, and IL-10 genes, thereby efficiently promoted endothelial tube formation in vitro compared to male BM-EPC. Transplantation of female BM-EPC and their exosomes into post-MI male mice improved LV cardiac function, reduced scar size, and improved capillary density compared to male BM-EPC and exosomes. Male BM-EPC showed an increased expression of G9a/Ehmt2, an H3K9me3 methyltransferase, and Dnmt3a DNA methyltransferase compared to female BM-EPC. In contrast, Kdm6b/JMJD3, H3K27me3 demethylase was highly expressed in female BM-EPC compared to males. Treatment of BM-EPC of both sexes with 17-β-estradiol did not alter the expression of Kdm6b/JMJD3. Male BM-EPC highly expressed repressive gene marks, H3K9me3, and H3K27me3 compared to females. Compared to the male, BM-EPC from female and ovariectomized (OXV) female mice showed equally high expression of angiogenic genes ANGPT-1, MDK, PLAU, Tie-2, and VEGFR2 and lower levels of inflammatory cytokines, TNFα, IFNγ, IL-1β, and CCL3. Conditioned medium from female and OVX BM-EPC equally promoted enhanced migration and tube formation of HUVEC in vitro, compared to male BM-EPC. Conclusions: An estrogen-independent epigenetic mechanism likely governs the enhanced cardiac reparative properties of female BM-EPC.
T Cell Co-Stimulation by CD28-CD80/86 and Its Negative Regulator CTLA-4 strongly Influence Accelerated Atherosclerosis Development
Authors: J.C. Karper, M.M. Ewing, R. Arens, R.C. de Jong, E.A. Peters, S. Abdul, M.R. de Vries, A. Redeker, R.E. Toes, J.W. Jukema, P.H. Quax
Journal: Circulation (2011)
Abstract P321: Chronic Central Nervous System Leptin Infusion Increases Cardiomyocyte Mitochondrial Function And Biogenesis And Improves Cardiac Function After Ischemia-reperfusion Injury.
Authors: Ana Carolina M Omoto, Jussara Do Carmo, Xuan Li, Zhen Wang, Alan J Mouton, Nikaela Aitken, Sydney Moak, Xuemei Dai, John E Hall, Alexandre A Da Silva
Journal: Circulation Research (2021)

Mitochondrial (MT) dysfunction plays an important role in the pathophysiology of myocardial ischemia/reperfusion injury (I/R). We recently showed that leptin, via its actions in the central nervous system (CNS), improves left ventricular (LV) function in a model of heart failure induced by permanent ligation of the left anterior descending coronary artery (LAD). In the present study, we examined if the CNS effects of leptin protect against myocardial ischemia/reperfusion (I/R) injury, and whether chronic intracerebroventricular (ICV) leptin infusion increases MT function and biogenesis in the non-infarcted area of the LV that is at risk but still viable. Male Wistar rats were instrumented with an ICV cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO), myocardial I/R was induced by temporary (60 min) ligation of the LAD. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/day) was infused chronically for 28 days starting 20 min after reperfusion using osmotic minipumps connected to the ICV cannula. ECHO assessment of cardiac function was performed every week. At the end of week 4, +dP/dt max and Tau were accessed by LV catheterization. Hearts were then collected for evaluation of MT function in isolated cardiac fibers using Oroboros oxygraphy-2k respirometer. ICV leptin treatment improved systolic and diastolic function as evidenced by increased ejection fraction 4 weeks after I/R (46±3 vs. 26±3 %), stroke volume (353±19 vs. 193±27 μL), +dP/dt max (10387±1686 vs. 5022±442 mmHg/s) and reduced Tau (6.5±0.3 vs. 8±0.3 ms) when compared with vehicle-treated rats. In addition, ICV leptin infusion significantly increased ATP-linked respiration (55±3 vs. 39±1 %), reduced proton leak (45±3 vs. 61±1 %), and improved MT reserve capacity (42±5 vs. 27±2 %). Improved MT function was associated with increased MT Complex I- mediated respiration (47±6 vs. 26±1 pmolO 2 /s - mg). ICV leptin treatment also increased PGC1 α protein expression and COX3 gene expression, indicating enhanced MT biogenesis. These results demonstrate that chronic ICV leptin infusion improves cardiac function following I/R injury and suggests that leptin’s CNS-mediated cardioprotective effects may involve improved myocardial MT function and biogenesis.
Abstract 12512: Antithrombotic Strategies According to Age in Patients With Atrial Fibrillation and a Recent Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the Augustus Trial
Authors: Patricia Guimaraes, Renato D Lopes, Daniel Wojdyla, John H Alexander, Shaun G Goodman, Ronald Aronson, Sigrun Halvorsen, Peter R Sinnaeve, Dragos Vinereanu, Robert F Storey, Otavio B Berwanger, Stephan Windecker, Roxana Mehran, Christopher Granger, Karen P Alexander
Journal: Circulation (2021)

Background: In AUGUSTUS, apixaban led to lower rates of bleeding and hospitalization than VKA, and aspirin caused more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor. We evaluated the safety and efficacy of different antithrombotic strategies by age in this population. Methods: Patients were stratified into 3 age groups: &lt;65, 65-74, and ≥75 years. Outcomes of interest were adjudicated ISTH major or clinically relevant nonmajor (CRNM) bleeding, ISTH major bleeding, death or rehospitalization, and death or ischemic events. The treatment effects of apixaban vs. VKA and aspirin vs. placebo were assessed across age categories using Cox models. Results: Of 4614 patients, 1267 (27.5%) were &lt;65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. All events, including bleeding, rehospitalization, and ischemic events, were more common with older age. Compared with VKA, apixaban was associated with lower rates of ISTH major or CRNM bleeding, ISTH major bleeding, and death or hospitalization, regardless of age (Fig). Apixaban was associated with greater absolute reduction in ISTH major bleeding than VKA in the older age groups, reflecting the higher bleeding risk in these groups. No differences were observed in rates of death or ischemic events between apixaban and VKA according to age. Patients who received aspirin had higher rates of bleeding than those receiving placebo in all age groups. Rates of death or rehospitalization and death or ischemic events were similar among patients receiving aspirin or placebo in different age categories. Conclusions: The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of age. Aspirin compared with placebo increased ISTH major or CRNM bleeding in all age groups. Our findings support the use of apixaban plus a P2Y12 inhibitor without aspirin as the standard therapy for this patient population, regardless of age. Figure: Outcomes by Age