tbuckley/cabot-search huggingface dataset:
Abstract 9565: Quantitative Assessment of Neonatal Brain Perfusion by Ultrafast Power Doppler in the Operating Room
Authors: Julien Aguet, Nikan Fakhari, Minh Nguyen, Luc L Mertens, David Barron, Jerome Baranger, olivier villemain
Journal: Circulation (2021)

Introduction: The main challenge with cardiopulmonary bypass (CPB) surgery in newborns with congenital heart disease is to prevent ischemic brain injury impacting on the long-term neurodevelopmental outcomes. To date, no quantitative method is available to adapt the CBP parameters for optimal per-operative cerebral perfusion. Ultrafast power Doppler (UPD) is a new portative bedside technique to map and quantify cerebral perfusion. Our objective was to evaluate UPD for quantifying the variation of cerebral perfusion in neonates during CBP surgery. Methods: UPD was performed in 5 newborns with hypoplastic left heart syndrome undergoing a Norwood procedure and 5 age-matched healthy newborns. Using a 6.9 MHz linear array probe (11L, General Electric) connected to a programmable and portable ultrafast ultrasound scanner (Vantage 256, Verasonics Inc.), via a transfontanellar approach, six pre-defined brain imaging planes were acquired in sagittal and coronal views. Assessments were performed pre-operatively, during various perfusions states intra-operatively and 24-48 hours post-operatively. Global and regional cerebral blood volume (CBV) and resistivity index (RI) maps from UPD were obtained. Results: The baseline brain perfusion was the same for both groups (p=0.62). During CPB, whole brain and regional CBV decreases more than 50% compared to baseline and reaching approximately 25% of initial CBV during selective brain perfusion and during the final stages of bypass (Figure). RI maps shows intermittent overall decrease of vascular resistivities below 0.5 on bypass and selective brain perfusion before returning to baseline in post-op, reflecting an overall decrease of the cerebral vascular resistance during CPB. Conclusions: UPD demonstrates variation in cerebral vascular resistance and blood volume in neonates undergoing CPB surgery. UPD paves the road for optimization of CPB parameters in neonates undergoing cardiac surgery.
Abstract 10313: Gender and Strain Background Affect Cardiopulmonary Function in <i>Col4a3</i> <sup>-/-</sup> Alport Mice
Authors: Camila Iansen Irion, Monique Williams, Trevor Eisenberg, Grace Seo, Guerline Lambert, Lauro Takeuchi, Karen C Young, Joshua M Hare, Lina A Shehadeh
Journal: Circulation (2021)

Background: Alport syndrome (AS) is a hereditary form of chronic kidney inflammation that results in renal failure (RF). We previously reported that Col4a3 -/- 129J mice, a model of AS and RF, exemplified multiple features of heart failure with preserved ejection fraction (HFpEF). This study investigates the effect of 3 different genetic backgrounds on cardiopulmonary function in Col4a3 -/- mice. Methods: Male and female Col4a3 -/- (Alport) and WT mice from 129x1/SvJ, C57Bl/6 and BALBC strain were examined using echocardiography, whole body plethysmography (WBP) and pressure-volume (PV) loop analysis. Ttest was used for statistical analysis. Four groups per strain were used (n= 4-15/group). Results: Compared with their respective age-matched WT controls, male and female 8-week-old Col4a3 -/- 129x1/SvJ mice demonstrated impaired systolic function (EF of 56 to 43.7%, p=.002 for females and 50.9 to 42% for males, p=.044; SV, CO, p&lt;.05) and diastolic dysfunction (increased IVRT from 15.3 to 21.7ms, p=.0009 for females; 16.6 to 26.2ms, p&lt;.0001 for males; increased MPI, P&lt;.05). Additionally, PV loop analysis showed an increased EDPVR and end diastolic pressure, prolonged time constant of LV relaxation, and decreased CO and SV (p&lt;0.05). For Col4a3 -/- BalbC and Col4a3 -/- C57Bl/6 strains, only females exhibited systolic (BalbC: EF% 51 to 45.66%, p=0.106 for females and 43.5 to 40.8% for males, p=.51; B6: EF% 51.3 to 40.8% p=.02 for females and 48.4 to 40.9%, p=.31 for males; SV, CO, p&lt;.05) and diastolic dysfunction (IVRT from 16 to 24.1ms for BalbC and 18.20 to 25.63ms for B6, p&lt;0.05). Male Col4a3 -/- BalbC had an increase in minimum and end-systolic pressures, and an increased pressure at dV/dt-max. Male Col4a3 -/- C57Bl/6 mice had an increased ESPVR slope (p&lt;.05). All strains except BalbC males demonstrated alterations (p&lt;.05) in pulmonary function including decreased ventilation rate (MV) and respiratory frequency, decreased peak expiratory flow, EF50, increased expiratory time, relaxation time, inspiratory time, and time of pause at end-of-expiration. Conclusion: Both male and female Col4a3 -/- 129x1/SvJ mice demonstrated impaired cardiopulmonary viability. However, Col4a3 -/- mice on BalbC or C57Bl/6 strains had cardiopulmonary deficits only in females.
Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes
Authors: Juliette Thariat, Francois Chevalier, Daniel Orbach, Luc Ollivier, Pierre-Yves Marcy, Nadege Corradini, Arnaud Beddok, Nicolas Foray, Gaelle Bougeard
Journal: The Lancet Oncology (2021)
Abstract 10492: Preclinical Evaluation of Transient and Cardiomyocyte Specific Gene Therapy for the Treatment of Subacute Ischemic Heart Failure
Authors: Riham Abouleisa, Abou B Salama, Qinghui Ou, Xian-liang Tang, Mitesh Solanki, Yiru Guo, Yibing Nong, Kamal M Kassem, Sally Hammad, Fareeha Abdulwali, Muzammil L. Dastagir, Roberto Bolli, Tamer Mohamed
Journal: Circulation (2021)

Rationale: Treatment of heart failure is limited due to the limited regenerative capacity of cardiomyocytes. Our group has shown that ectopic expression of Cdk1/CyclinB1 and Cdk4/CyclinD1 (named 4F) via adenovirus vector promotes cardiomyocyte proliferation in 20% of infected cardiomyocytes in vitro and in vivo and improves cardiac function after myocardial infarction (MI). Objective: To introduce 4F specifically and transiently into cardiomyocytes to induce selective cardiomyocyte regeneration and limit any tumorigenic potential in other organs. Methods and Results: A polycistronic non-integrating lentivirus encoding 4F, each driven by a TNNT2 promoter (TNNT2-4F-NIL), was generated to induce transient and specific expression of 4F cardiomyocytes. TNNT2-4F-NIL promotes proliferation of 15% of cardiomyocytes in vivo after MI as assessed in lineage-tracing mice (α-MHC-Cre-MADM). Rats and pigs were subjected to coronary occlusion/reperfusion to induce MI. One week later, animals were injected (intramyocardially) with either TNNT2-4F-NIL or control-NIL. Four weeks after injection, TNNT2-4F-NIL treated rats and pigs showed a significant improvement in left ventricular ejection fraction (EF) compared to controls (TNNT2-4F-NIL rats 54.3±1.78% vs control-NIL 42.97±2.60%; n=9/group, p =0.003, TNNT2-4F-NIL pigs 37±2.3% vs control-NIL 28.4±1.2%; n=6/group, p =0.01). Histological analyses showed a 25-30% reduction in scar size in both rats and pigs treated with TNNT2-4F-NIL vs. control-NIL (p&lt;0.05). To assess the long-term efficacy and safety of TNNT2-4F-NIL, a 4-months follow-up experiment after MI and virus treatment was performed during which cardiac function was assessed monthly. TNNT2-4F-NIL treated rats showed sustained improvement in cardiac function (EF in TNNT2-4F-NIL 48.4±3% vs in control-NIL 33.6±3%; n=6/group, p =0.008). There was no obvious development of arrhythmias and no evidence of oncogenicity or toxicity in other organs in TNNT2-4F-NIL treated rats or in the control group. Conclusion: This study provides a novel approach to treat heart failure, with the use of transient and cardiomyocyte-specific gene therapy that promotes long-term functional improvement after a single treatment with no obvious adverse effect.
VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy
Authors: S. Lu, L. Wu, H. Jian, Y. Cheng, Q. Wang, J. Fang, Z. Wang, Y. Hu, M. Sun, L. Han, L. Miao, C. Ding, J. Cui, B. Li, X. Li, K. Wang, S. Cang, Y. Pan, F. Ye, A. Liu
Journal: Annals of Oncology (2021)
Abstract P486: Decellularized Extracellular Matrix Microparticles Promote Heart Regeneration And Neovascularization In Post-mi Mice
Authors: Xinming Wang, Ali Ansari, Valinteshley Pierre, Samuel Senyo
Journal: Circulation Research (2021)

Hypothesis and objective: We hypothesize that solid hydrogel particles will improve therapeutic efficacy of hydrogels derived from decellularized fetal hearts (dECM) on myocardial infarction (MI). In this study we developed dECM microparticles (MPs) to compare with liquid hydrogel. The objectives are 1) develop dECM MPs for increased stability at site of injection; 2) establish reduced degradation in vivo ; and 3) evaluate potential regenerative benefits from dispersed particles of dECM. Methods: Microparticles were generated by electrospray of solubilized dECM. Microparticles were injected immediately after coronary artery ligation in adolescent mice. Echocardiography and histology were conducted 21days post-MI. Results: Electrospray with emulsification produced solid dECM microparticles ranging in size from nanometers to microns depending on parameters. The dECM MPs showed prolonged release of proteins and decreased degradation rate in vitro compared to dECM hydrogel. The dECM MPs were observed to protect cardiac function (Fig. 1), lower fibrosis, stimulate cardiogenesis, and promote vascularization compared to MI control. Cardiogenesis and neovascularization were observed with dECM microparticles treatment compared to hydrogel treatment (Fig. 2). This study suggests the solid dECM particles provides unique advantages as an injectable therapy directed at the ischemic heart.
Abstract 14458: Plasma Gasotransmitter Levels in Atrial Fibrillation
Authors: Gopi Kolluru, Megan Watts, Zoya Mohammad, Javaria Ahmad, Sindhu Thevuthasan, Parinita Dherange, Sibile Pardue, Christopher Kevil, Paari Dominic
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) is associated with oxidative stress. Hydrogen sulfide and nitric oxide (NOx) are gasotransmitters involved in cardiovascular redox homeostasis. Free sulfide is increased in the plasma of human patients with atrial fibrillation. Although nitric oxide synthase expression and polymorphism has been studied in atrial fibrillation, NOx levels have not been measured in AF patients Hypothesis: AF is associated with altered NOx levels, and sulfide: nitrite ratio. Methods: Free NOx, total NOx, and nitrotyrosine levels were measured in patients without AF (n = 65), paroxysmal AF (PAF, n = 26) and persistent AF (n = 25) and compared between groups. Previously published sulfide levels from these patients were used to calculate free sulfide: total NOx ratio. Clinical characteristics of these patients were compared. Student’s t-test and nominal logistic regression were used for statistical analysis. Results: The patients without AF were younger but comparable to AF patients with regard to race, sex, diabetes, sleep apnea, and smoking history. Patients with AF were more likely to have hypertension (82% versus 54% non-AF patients, p = 0.002) and heart failure (47% versus 25% of non-AF, p = 0.02). On the other hand, non-AF patients were more likely to have coronary artery disease and/or peripheral arterial disease (43% versus 17% in patients with AF, p = 0.005). Compared to non-AF patients, AF patients had significantly lower total NOx (212 vs 268nM, p=0.005), free NOx (192 vs 237nM, p=0.039), and total sulfide: total NOx ratio (0.028 vs 0.020, p&lt;0.01). Compared to PAF patients, persistent AF patients had further significant reduction in total NOx (177 vs 243nM, p=0.04). At 3-month follow up, free NOx levels increased from baseline in patients who underwent successful conversion to normal sinus rhythm (n=11, p=0.048). Levels of oxidative stress marker, nitrotyrosine, trended higher in patients with AF compared to non-AF patients (1.10 vs 1.01 p=0.08). Multivariable logistic regression showed that total NOx was associated with AF independent of age, sex, race, HTN, DM and heart failure (OR per 10nM decrease in NOx= 1.04, CI=1.001-1.094, p=0.0471*) Conclusion: Reduced NOx levels and increased free sulfide to NOx ratio are associated with AF.
Biomarkers for Thrombosis in COVID-19: A Role for High Sensitivity Troponin-I and Immature Platelet Fraction?
Authors: Bilal Ashraf, Haekyung Jeon-slaughter, Christopher Webb, Nicholas C.J. Lee, Weina Chen, Sung-Hee Choi, Taha Bat, Ibrahim F. Ibrahim
Journal: Blood (2021)
Steroid-Free Deep Remission at One Year Does Not Prevent Crohn's Disease Progression: Long-Term Data From the TAILORIX Trial
Authors: David Laharie, Geert D’Haens, Maria Nachury, Guy Lambrecht, Peter Bossuyt, Yoram Bouhnik, Edouard Louis, Christien Janneke van der Woude, Anthony Buisson, Philippe Van Hootegem, Matthieu Allez, Jérôme Filippi, Hedia Brixi, Cyrielle Gilletta, Laurence Picon, Filip Baert, Séverine Vermeire, Nicolas Duveau, Laurent Peyrin-Biroulet
Journal: Clinical Gastroenterology and Hepatology (2021)
A Study of Ribonucleotide Reductase mRNA Expression and Its Prognostic Role in Patients with Chronic Lymphocytic Leukemia
Authors: Sevastianos Chatzidavid, Christina-Nefeli Kontandreopoulou, Panagiotis T Diamantopoulos, Nefeli Giannakopoulou, Panagiota Katsiampoura, Christos Stafylidis, Georgios Dryllis, Marie-Christine Kyrtsonis, Maria Dimou, Panagiotis Panagiotidis, Nora-Athina Viniou
Journal: Blood (2021)
Abstract 13343: Cognitive Impairment in Older Adults With Peripheral Arterial Disease
Authors: James C Iannuzzi, Siqi Gan, Eric Smith, Warren J Gasper, Emily Finlayson, Louise Walter, Michael S Conte, kenneth covinsky
Journal: Circulation (2021)

Introduction: Peripheral arterial disease (PAD) is common among older adults and shares a pathophysiologic mechanism with vascular dementia, yet there remains a paucity of data about the prevalence of cognitive impairment (CI) in this population. The aim of this study was to estimate CI prevalence in a nationally representative sample of adults with PAD and identify independent risk factors for CI. Hypothesis: We hypothesized CI would be common and that risk factors would include advancing age. Methods: The U.S. Health and Retirement Study with Medicare Linkage and CI assessment was utilized for years 2000-2016. PAD was identified using ICD-9/10 and CPT codes. CI was defined using the Langa-Weir classification based on CI assessment within 2.5 years prior to first documented PAD diagnosis in the Medicare. Bivariate analysis for association with CI was performed appropriate to the data followed by multivariable logistic regression for the primary endpoint of CI. Results: Overall, 4,383 PAD individuals aged 65 and over at time of PAD diagnosis were included. Overall, 39% had CI. CI was associated with increasing age (p&lt;0.01) female gender (42% females vs. 35% males, p&lt;0.01) Race (60% Black, 66% Hispanics, 31% white, p&lt;0.01) and Charlson score&gt;2 (p&lt;0.01). Geriatric syndromes were common with mean 1.7 (SD 1.5, p&lt;0.01) and were associated with CI (2.7 in CI vs. 1.0 in no CI, p&lt;0.01). On multivariable analysis risk factors included age, education, Race, vision impairment, depression, falls within the past year, and any dependency in activities of daily living (Table 1). Conclusions: Cognitive impairment is common in adults living with PAD and is associated with age, race/ethnicity, education, depression, geriatric syndromes and functional status, similar to those without PAD. Given CI’s prevalence in individuals with PAD, future study is imperative to understand how CI impacts PAD related health. These findings can be used to risk stratify patients for CI screening.
Abstract 10314: Post-GWAS Functional Genomics Analysis of CBLN2 Locus to Define the Pathogenic Role of CUX1 in Pulmonary Arterial Hypertension
Authors: Wei Sun, Danli Jiang, Ting Wu, Meijuan Zou, Gang Li, Stephen Y Chan
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a rare but morbid disease and highly relevant to genetic susceptibility. Genome-wide Association Studies (GWAS) have identified 12 SNPs on 9 PAH- associated loci. However, GWAS is unable to identify the causative functional SNPs (fSNP) or define the mechanisms by which a fSNP regulates the risk gene expression. Methods: We developed a novel functional genomics analysis to identify PAH-associated fSNPs. It includes Reel-seq (Regulatory element-sequencing), an EMSA-based high-throughput technique, to identify fSNPs in a synthetic DNA library containing PAH-associated SNPs; SDCP-MS (SNP-specific DNA competition pulldown-mass spectrometry) to identify proteins that specifically bind to fSNPs; and AIDP-Wb (allele-imbalanced DNA pulldown-Western blot) to show allele-imbalanced binding of these proteins to fSNPs. The regulation of risk gene expression by these fSNP-binding proteins was determined in PAECs and confirmed in PAH patients. Results: By Reel-seq, rs11151770 is identified a fSNP in the CBLN2 locus, and its risk allele A is associated with a 1.97-fold increase in PAH susceptibility. By using SDCP-MS and AIDP-Wb, transcription factor CUX1 was found to specifically bind to this fSNP, with higher affinity to the risk allele A than non-risk allele G, thus controlling the expression of CBLN2. CUX1 knockdown prevented, but CUX1 overexpression induced, the pathophenotypes in PAECs that are associated with PAH. CUX1-CBLN2 was upregulated by the acquired PAH trigger IL-1β, and was also increased in PAH lungs. Genotyping of this fSNP showed a 2.1-fold risk allele A enrichment in PAH patients associated with connective tissue disorders, supporting a pathogenic mechanism of an inflammation-sensitive pathway (CUX1-CBLN2) combined with a PAH susceptible genotype (risk allele A) for the manifestation of clinical PAH. Conclusion: We demonstrate that CUX1 regulates the expression of target gene CBLN2 via binding to fSNP rs11151770. Alteration of CBLN2 expression, in turn, controls crucial endothelial function relevant to PAH. These results identify a novel role of CUX1 in PAH, clarifying the pathogenic function of this PAH-associated locus and providing a potential target for PAH intervention.
Abstract 10732: Systemic Administration of Telomerase RNA Reverses Vascular Senescence and Extends Lifespan in Progeria Mice
Authors: Christian Boada, Brandon Walther, Rhonda Holgate, Elisa Morales, Xu Qiu, John P Cooke, Anahita Mojiri
Journal: Circulation (2021)

Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS) is an accelerated aging syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS, a mutation in lamin A (progerin) alters nuclear morphology and gene expression. iPSCs derived endothelium from progeria patients show impairment in their morphology and function including replication arrest, DNA damage, increased expression of inflammatory markers, and telomere erosion, compared to iPSCs derived endothelial cells from their unaffected parents. We have shown that hTERT mRNA therapy rescues their senescent phenotypes and restores normal function and gene expression in-vitro. To validate our finding in-vivo, we have used lentivirus harboring mouse telomerase to treat mice model of progeria and investigated the beneficial effects on mice vasculature in different organs. Hypothesis: Gene therapy with mRNA encoding mice telomerase improves survival and reversing cell senescence in a mice model of HGPS. Methods: HGPS mice were injected twice with a lentivirus construct encoding mice telomerase via tail vein. Mice were monitored for survival; endothelial cells were isolated at the time of euthanasia and concentrations of cytokines, chemokines, and growth factors were analyzed using Elisa, PCR and immunofluorescence staining. For clinical translation we developed a lipid nanoparticle formulation to deliver mRNA encoding mTERT to mice, validating its function using mRNA encoding Luciferase to demonstrate biodistribution and safety profile. Results: Two treatments with lentiviral mTERT increased the lifespan of HGPS mice by 20% and reduced mediators of inflammation and thrombosis in HGPS such as thrombomodulin. HGPS mice treated with mTERT had lower DNA damage markers and increased SIRT1 in their vasculature and other organs. A Lipid nanoparticle encapsulating mTERT RNA and shows a favorable safety profile and the capacity to systemically and safely deliver luciferase mRNA, generating active luciferase, documenting a predominantly hepatic biodistribution. Conclusions: Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases. Further development in systemic delivery is thus underway
Abstract 11286: Human-Induced Pluripotent Stem Cell Derived Exosomal Protein Induces Cardiac Regeneration
Authors: Ajit Magadum, Vandana Mallaredy, Rajika Roy, Darukeshwara Joladarashi, Charan Thej Gurrala, Zhongjian Cheng, Maria Cimini, Grace Huang, Chunlin Wang, Anna Maria Lucchese, May Truongcao, Cindy Benedict, Raj Kishore
Journal: Circulation (2021)

Introduction: Cardiovascular diseases are the leading causes of death worldwide. After myocardial infarction (MI), there is a permanent loss of cardiomyocytes (CMs), and as the mammalian heart has limited regenerative capacity, it leads to Heart Failure. Recent studies from zebrafish and 1-day old mice showed that they could regenerate their heart through inducing existing CM proliferation. Attempts have been made to transiently reconstitute embryonic signaling in adult hearts, including overexpression of cell cycle activating genes with limited success. iPSC-derived extracellular vesicles (EV)/exosomes have been shown to improve cardiac function and some degree of CM renewal. However, the iPSC-EVs-mediated cardiac regeneration mechanism remains unclear and largely pertains to microRNAs and other RNAs, with a little elucidation of the role of iPSC-exosome proteins. Hypothesis: The myocardial delivery of iPSC-EV-specific protein improves cardiac function and remodeling post-MI by activating pro-proliferative and anti-oxidative stress molecular pathways. Methods and Results: Our preliminary studies showed that hiPSC-EVs induced the CM cell cycle in mice post-MI, and by employing a proteomic approach, we found a novel protein exclusively expressed in iPSC-EVs. The overexpression of hiPSC-EV enriched protein in the form of modRNA (modified mRNA) induced a robust CM cell cycle in rat neonatal CMs and in adult hearts post-MI. This increase in the CMs cell cycle by the modRNA was associated with reduced scar size, improved cardiac function (%EF 49.76 ± 5.8 vs. 27.47 ± 6.9 (control, Luc modRNA), respectively), and mice survival 28 days post-MI. Furthermore, using the siRNA and modRNA (inhibition and over-expression) approach, we found that the protein-induced Yap1-β-catenin molecular pathway stimulates CM proliferation. Furthermore, the overexpression protein post-MI inhibited the CM apoptosis (TUNEL + CMs, 1.3% ± 0.1 vs. 2.1% ± 0.11 (control)) by reducing oxidative stress and DNA damage response. Conclusion: The myocardial injection of iPSC-EV specific protein through a highly therapeutic modRNA tool improve cardiac function by inducing CMs proliferation, inhibiting oxidative stress, and reactivating cardiac regeneration post-injury.