tbuckley/cabot-search huggingface dataset:
Abstract 12932: An Epigenetic Upregulation of Dynamin 2, a Regulator of Mitochondrial Fission, Promotes Human and Experimental Pulmonary Arterial Hypertension
Authors: Asish Das Gupta, Kuang-Huieh Chen, Lian Tian, Danchen Wu, Jeffrey Mewburn, Patricia Lima, Stephen L Archer
Journal: Circulation (2021)

Introduction: Increase in mitotic fission in pulmonary arterial smooth muscle cells (PASMC) contributes to the obstructive vasculopathy in pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype is due, in part, to excessive mitochondrial fission caused by activation of dynamin related protein-1 (Drp1). Recent observation suggests that to complete mitochondrial fission, Drp1 requires assistance from the GTPase dynamin 2 (DNM2). In this study we explore the role of DNM2 in the pathogenesis of PAH. Hypothesis: In PAH, increased expression of DNM2 increases mitochondrial fission and proliferation of PASMC. Methods: Immunoblot was used to quantify the expression of DNM2 in control (n=4) and PAH PASMC (n=5). Immunofluorescence was used to quantify the expression of DNM2 in the pulmonary arteries of monocrotaline (MCT) vs control rats. Flow cytometry was used to assess the effects of manipulating the expression of DNM2 on cell proliferation, cell cycle progression and rates of unstimulated apoptosis. Mitochondrial network structure was assessed using confocal imaging of cells infected with Adv-TOM20 mNeon green. Results: The expression of DNM2 was increased in human PAH PASMC vs control PASMC. Increase in the expression of DNM2 expression was also observed in the pulmonary arteries of MCT-PAH rats. Silencing DNM2 inhibited mitochondrial fission in PAH PASMC. Furthermore, silencing DNM2 inhibited proliferation in PAH PASMC by blocking the cell cycle at G1/G0. Conversely, augmenting DNM2 in normal PASMC induced mitochondrial fission and accelerated cell proliferation, recapitulating the PAH phenotype. In silico analysis identified miR-124-3p as a putative negative regulator of DNM2. Augmenting miR-124-3p decreased DNM2 expression, inhibited proliferation and induced apoptosis in PAH PASMC. Conclusion: DNM2 promotes mitochondrial fission and regulates cell proliferation in human PAH PASMC. Decreased miR-124-3p expression may contribute to upregulation of DNM2 in PAH. This work highlights the importance of DNM2 as partner with Drp1 in regulation of mitochondrial fission and shows that like Drp1, DNM2 is increased in human PAH. DNM2 may constitute new therapeutic target for PAH.
Abstract 9955: Impact of a Heart Failure Clinical Pathway on Hospital Readmission in Medically Underserved Community
Authors: Hasan Imanli, Richard Mitchell, Deepa Krishnan, Dragos Besliu, Fahad Alkhalfan, Akemini Udoro, Sandra Kaldas, Gloria Okpah, Shajetha Iyathurai, Alex Gyftopoulos, Reyaz Haque
Journal: Circulation (2021)

Introduction: Heart failure (HF) is a global medical problem with high rates of readmission. Care pathways allow for a means of implementing a systematic guideline for treatment via EMR software and have been increasingly utilized with the goal of improving patient outcomes. However, these pathways have mostly been studied in medically well-served communities, whereas their impact in those that are underserved is unknown. This study was conducted in a community hospital in Baltimore, Maryland. Methods: Patients admitted for acute decompensated HF within 45 days before or after the implementation of the care pathway were identified retrospectively. Patients requiring ionotropic support were excluded from this analysis. Patients admitted before implementation of the pathway were designated to non-pathway and served as the control. Patients admitted after implementation of HF pathway were designated to the pathway group. The pathway included reminders for optimal goal-directed medical therapy (GDMT), patient education, nursing orders such as diuresis goals, and consults to case management, pharmacy, and cardiology. Data about length of hospital stay (LoS), medications at discharge, and readmission for HF at 30-, 60-, and 90-days post-discharge were collected. Results: The pathway group included 44 patients compared to 38 patients in the non-pathway group. There was no difference in the LoS between the two groups (4±3 days for both). Pathway patients were prescribed optimal GDMT at discharge more frequently compared to the non-pathway group (beta-blockers: 68% vs 61%, ACEi/ARBs: 82% vs 76%, ARNI: 30% vs 18%, MRAs: 14% vs 11%, loop diuretics 80% vs 74%; p = 0.002). Pathway patients had fewer HF readmissions at 30 days (16 vs 18%; RR=0.89), 60 days (25% vs 34%, RR=0.74) and 90 days (27% vs 42%, RR=0.64). Readmission rates were lower at 90 days in both HFrEF (0.33% vs 0.48%, RR = 0.69) and HFpEF (0.18% vs 0.31%, RR = 0.58), male (0.26% vs 0.42%, RR = 0.62) and female (0.29% vs 0.43%, RR = 0.67), and in patients without ESRD (0.25% vs 0.48%, RR = 0.52). Conclusion: In a medically underserved community, implementing a HF pathway for patients admitted with ADHF may reduce readmission rates without affecting length of stay and may ensure adequate GDMT upon discharge.
Abstract 10937: Incidence of Cardiac Complications During Index Hospitalisation with COVID-19 in Australia: AUS-COVID Study
Authors: Kunwardeep S Bhatia, Hari P Sritharan, Chia Justin, Jonathan Ciofani, Usaid Allahwala, Karina Chui, Daniel Nour, Sheran Vasanthakumar, Dhanvee Kandadai, Rohan Bhagwandeen, David Brieger, Christopher Choong, Anthony Delaney, Girish Dwivedi, Benjamin Harris, Graham Hillis, Bernard Hudson, George Javorsky, Nigel Jepson, Logan Kanagaratnam, George Kotsiou, Astin Lee, Sidney Lo, Andrew I Macisaac, Brendan McQuillan, Isuru Ranasinghe, Tony Walton, James Weaver, William Wilson, Andy Yong, John Zhu, William van Gaal, Leonard Kritharides, Clara K Chow, Ravinay Bhindi
Journal: Circulation (2021)

Introduction: Cardiac complications of COVID-19 include acute cardiac injury, myopericarditis, cardiomyopathy and arrhythmias. This study aimed to describe the incidence of cardiac complications in patients admitted to hospital with COVID-19 in Australia. Methods: AUS-COVID is a multicentre observational cohort study across 21 Australian hospitals including all index hospitalisations with laboratory-proven COVID-19 in patients aged 18 years or older. All consecutive patients entered in the AUS-COVID Registry by 28 th January 2021 were included in the present study. Results: Six hundred and forty-four hospitalised patients (62.5 ± 20.1 years old, 51.1% male) with COVID-19 were enrolled in the study. Overall in-hospital mortality was 14.3%. Twenty (3.6%) patients developed new atrial fibrillation or flutter during admission and 9 (1.6%) patients were diagnosed with new heart failure or cardiomyopathy. Three (0.5%) patients developed high grade atrioventricular (AV) block. Two (0.3%) patients were clinically diagnosed with pericarditis or myopericarditis. Among the 295 (45.8%) patients with at least one troponin measurement, 99 (33.6%) had a peak troponin above the upper limit of normal (ULN). In-hospital mortality was higher in patients with raised troponin (32.3% vs 6.1%, p&lt;.001). New onset atrial fibrillation or flutter (6.4% vs 1.0%, p=.001) and troponin elevation above the ULN (50.3% vs 16.4%, p&lt;.001) were more common in patients 65 years and older. There was no significant difference in the rate of cardiac complications between males and females. Conclusions: Among patients with COVID-19 requiring hospitalisation in Australia, troponin elevation was common but clinical cardiac sequelae were uncommon. The incidence of atrial arrhythmias and troponin elevation was greatest in patients 65 years and older. Trial registration: AUS-COVID. ACTRN12620000486921. http://www.anzctr.org.au/
Abstract 14150: Evaluation of Real-World Long-Term Mortality Following Paclitaxel-Eluting Devices Use in Femoropopliteal Disease Among Veterans
Authors: Neil Maitra, Mariam Baig, Kartik Mani
Journal: Circulation (2021)

Introduction: Use of paclitaxel eluting devices have been shown to improve endpoints following femoropopliteal interventions, driven by decreased need for repeat procedures. Post hoc analysis of clinical trials suggest that use of these devices may be associated with increased mortality, without evidence of causation. To assess if relevance of this in usual clinical use, analysis of real-world data is necessary. Methods: The Long-term Excess All-Cause Death with Paclitaxel-eluting device in Infrainguinal Peripheral Endovascular procedures - Veterans’ Administration (LEADPIPE-VA) study is a single-center retrospective evaluation of 134 consecutive patients undergoing infrainguinal femoropopliteal interventions from 2010 to 2019 at the Cardiology Division in the St. Louis VA Medical Center. Baseline Data Age Total DCB Non-DCB p-value&lt;60 11 2 (18.2%) 9 (81.8%) 0.034860-75 92 51(55.4%) 41(44.6%) 0.2971&gt;75 31 17 (54.8%) 14(45.2%) 0.59Mean 71.2 ± 6.6 71.2 ± 6.6 71.2 ± 6.8 0.9527Gender Male 129 67 (51.9%) 62 (48.1%) 0.6598Female 5 3(60%) 2 (40%) Comorbidities HTN 134 (100%) 70 (52.2%) 64 (47.8%) 0.2687DM 82 (61.2%) 41 (30.6%) 41 (30.6%) 0.5147HLD 134 (100%) 70 (52.2%) 64 (47.8% 0.2687Ever smoker 132 (93.9%) 68 (51.5%) 56 (42.4%) 0.1012Current smoker 55 (41.7%) 27 (20.5%) 28 (21.2%) 0.4434CAD 118 (88.1%) 65 (48.5%) 53 (39.6%) 0.0733Carotid disease 45 (33.6%) 28 (20.9%) 17 (12.7%) 0.0999History of MI 95 (70.9%) 56 (41.8%) 39 (29.1%) 0.0404Mean BMI 26.8 ± 5.4 26.7 ± 5.3 26.9 ± 5.7 0.8335Rutherford cl. 3.1 ± 0.6 3.2 ± 0.5 3.1 ± 0. Results: Mortality Total Population DCB Non-DCB p-value30-day 4 (3.0%) 0 (0%) 4 (6.3%) 0.04761-year 6 (4.9%) 3 (4.4%) 3 (5.5%) 0.30752-year 16 (16.0%) 10 (10.0%) 6 (6.0%) 0.31543-year 7 (9.9%) 6 (8.5%) 1 (1.4%) 0.01224-year 7 (15.2%) 2 (4.4%) 5 (10.9%) 0.22595-year 2 (6.3%) NA 2 (6.3%) No significant differences were noted between groups with regards to clinical improvement, repeat interventions, or need for amputation. Conclusions: Given the limitation of a small single center retrospective analysis in a real-world population with higher overall complexity, morbidity and mortality, differences between the two groups are small and unlikely to represent a clinical hazard.
Abstract P313: Over-expression Of Serine Threonine Kinase 35 Improves Cardiac Function In Streptozotocin Induced Diabetic Mice
Authors: Darukeshwara Joladarashi, Yanana Zhu, Maria Cimini, Rajarajan Thandavarayan, Keith Youker, Kevin Nash, Matthew Willman, Xuehong Song, Di Ren, Li L Ji, Raj Kishore, Prasanna Krishnamurthy, Lianchun Wang
Journal: Circulation Research (2021)

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associatedwith impaired responsiveness of ischemic myocardium to proangiogenic factors, subsequentlyleading to heart failure. STK35, a novel kinase that binds to nuclear actin, has been shown toregulate important cellular functions such as cell migration, proliferation, survival, andangiogenesis. Currently, the contribution of altered STK35 expression in human diseases remainsunexplored. In initial studies, we observed that human cardiac biopsies from diabetic patientsshowed a significant decrease in STK35 expression as compared to non-diabetic control hearts.Intriguingly, in a STZ-induced mouse model of diabetes, i.v . injection of rAAV9-STK35 to expressconstitutive STK35 in heart in FVB/N male mice promoted neovascularization and lowered cardiacfibrosis, leading to improved cardiac function of diabetic heart. Our in vitro studies observed highglucose decreased STK35 expression in mouse cardiac endothelial cells (MCEC), whereasSTK35 overexpression increased MCEC migration and vascular tube formation, and upregulatedMCEC to expression of multiple pro-angiogenic proteins. Taken together, our results demonstratethat cardiac-targeted STK35 gene therapy exerts a marked beneficial action by attenuating bothcardiac remodeling and cardiac function in a mouse model of diabetes mellitus. Mechanistically,the beneficial effect may be attributed, at least partially, to enhanced neovascularization in heart.
Abstract 11203: Providing Transcatheter Aortic Valve Replacement Therapies to VA Patients Through a Public-Private Partnership
Authors: Helena Dickens, Manoj Ambalavanan, Nicole Cho, Brody D Slostad, Aamir Twing, Erik Simon, Mayank M Kansal, Elliott Groves, Yolanda Rodríguez-Rivera, Sanket Gokhale, Adhir R Shroff
Journal: Circulation (2021)

Introduction: Despite the success of Transcatheter Aortic Valve Replacement (TAVR) in improving morbidity and mortality among patients with aortic stenosis, few stand-alone programs currently exist within the VA system. Many VA centers have developed transfer arrangements with partner institutions to provide TAVR for their patients. There is minimal data for VA patients in such programs. We compared the outcomes of VA patients to non-VA patients undergoing TAVR at a partner institution. Methods: We performed a single-center retrospective study on all patients undergoing TAVR between March 2018 and June 2020. All procedures were performed at an academic medical center (AMC) in Chicago where VA patients were referred for TAVR. Primary outcomes included composite MACE (death from any cause, MI, CVA). Secondary outcomes included length of stay, bleeding events, AKI, change in ejection fraction, CHF exacerbations, and device-related complications. We assessed outcomes at hospital discharge, 6-month and 12-months. Results: There was a total of 115 patients (AMC: 56, VA: 59). Patient demographics between the two groups were significant for the VA group being 57.6% Caucasian and 96.6% male while the AMC group was 33.9% Caucasian and 56.6% male (for both p&lt;0.01). There was no in-hospital mortality in either group. Total length of stay (p=0.6), ICU length of stay (p=0.4), procedure time (p=0.4) and baseline ejection fraction (p=0.8) were similar between both groups. At 6 months, the VA patients experienced a trend towards a higher incidence of composite MACE (VA: 11.9%, AMC: 5.4%, p=0.2). None of the secondary outcomes reached statistical significance. Ejection fraction and CHF exacerbations were similar between groups (p=0.9 and p=0.59). At 12 months there was no statistical difference in primary or secondary outcomes. Similar ejection fractions and CHF exacerbations at 12 months were also recorded. Conclusions: No difference between procedural, 6-month or 12-month outcomes between VA patients and non-VA patients undergoing TAVR were observed. Public-private partnerships can provide state of the art therapies to VA patients in an efficient and safe manner.
Abstract 14119: Aortic Stiffness is Associated With Cognitive Decline and Cardiovascular Disease Manifestation in Cancer Survivors
Authors: Zach J White, Shannon K Parr, Vanessa-Rose G Turpin, Stephen T Hammond, Carl Ade
Journal: Circulation (2021)

Introduction: Cancer survivors experience a high prevalence of cognitive deficits and risk of CVD. Aortic stiffening, which increases following cancer diagnosis, inhibits pulsatile flow damping and potentiates microvascular damage within the cerebral circulation, which may contribute to associations observed between stiffness, cognitive decline, and mild cognitive impairment (MCI) in the general population. However, there is a paucity of evidence on the association between arterial stiffness and cognitive decline among cancer survivors. Methods: We evaluated dementia-free cancer survivors in the Framingham Original and Offspring Cohorts (n=277, 80±12.3 years old, 56.7% women, 9.3±8.8 years from first diagnosis) with carotid-femoral pulse wave velocity (cfPWV) measurements. Over a mean follow-up of 7.7±3.9 years, the Mini-Mental State Examination (MMSE; global cognitive function) and neuropsychological exams (NP; executive function, learning and memory) were completed. We noted cognitive decline and incident MCI per clinically relevant standards. We used linear and logistic regression models to determine the relationship between cfPWV and cognitive decline/MCI. Cox Regression related cfPWV and cognitive function to the risk of CVD. Multivariate models were adjusted for age, sex, depressive symptoms, and traditional CVD risk factors. Results: cfPWV was significantly associated with the rate of decline for global cognitive function (ΔMMSE). Higher cfPWV was significantly associated with clinically defined MCI, denoted by an impaired MMSE (OR(95%CI): 9.2(2.5-33.5)) and NP score (4.3 (1.4-13.0)) in univariate logistic models. We observed a 3.4 times higher risk of CVD in cancer survivors with high cfPWV (HR(95%CI): 3.45 (1.04-11.66)) in the final model. Changes in cognitive function were not associated with CVD. Conclusion: Our findings suggests an association between aortic stiffness, future cognitive decline, and an increased risk of CVD in a diverse cohort of cancer survivors. Our findings support the potential adverse consequences of a stiffening arterial vasculature following cancer diagnosis; specifically those related to cognitive function and long-term CVD outcomes.
Outcomes of Haploidentical Stem Cell Transplantation in Patients with Fanconi Anemia; A Systematic Review
Authors: Zunairah Shah, Israr Khan, Ali Shahbaz Baloch, Talha Awal, Sobia Aamir, Ali Anjum, Norina Usman, Mobeen Zaka Haider, Faiz Anwer, Raheel Iftikhar
Journal: Blood (2021)
DDRE-11. SECOND GENERATION IDO INHIBITORS FOR IMPROVING IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA
Authors: Lakshmi Bollu, Prashant Bommi, Derek Wainwright, Erik Ladomersky, Lijie Zhai, April Bell, Kristen Lauing
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes tryptophan and is expressed in &amp;gt;90% of patient-resected glioblastoma (GBM). IDO-mediated tryptophan metabolism has been the proposed mechanism for suppressing the immune response in GBM. Recently, we discovered that IDO also possesses non-enzymic functions that contribute to suppress the anti-GBM immune response. This finding motivated us to develop IDO-Proteolysis Targeting Chimeras (IDO-PROTACs) to degrade IDO protein rather than simply inhibiting IDO enzyme activity. METHODS Western blot analysis was used to determine IDO-PROTAC efficiency of IDO protein degradation among human and mouse GBM cell lines and PDX. Our lead IDO-PROTAC was tested for toxicity, blood brain barrier penetration, and pharmacokinetics (PK) in wild-type C57BL/6 mice. RESULTS IDO-PROTACs degrade IDO protein in both tumor and non-tumor cells with a DC50 value of ~0.5µM in human GBM tumor cells. Biolayer interferometry (BLI) studies show that IDO-PROTAC forms a binary complex with IDO protein with similar affinity comparable to parental compound – BMS986205. IDO-PROTACs induced IDO ubiquitination and the pretreatment with ubiquitin proteasome inhibitors, MG132 or MLN4924, inhibited IDO protein degradation. In vivo toxicity studies showed that treatment with IDO-PROTAC at 25 mg/kg for 3-weeks did not develop any apparent toxicity in C57BL/6 mice. PK analysis revealed that IDO-PROTAC bioavailabilty reached a peak serum and brain concentration within 30 minutes after intraperitoneal administration. CONCLUSIONS This study developed a lead IDO-PROTAC compound that efficiently degrades IDO protein in human GBM cells with a moderate bioavailability and blood-brain barrier (BBB) penetration. Future work will focus on the enhancement of BBB penetration, increased bioavailability, and route of administration to improve IDO-PROTAC potency for combination with other forms of immunotherapy for GBM patient treatment.
Abstract 10467: Rising Burden of Cardiovascular Disease Risk and Major Adverse Cardiac Events in Young African American Patients: A National Analysis of Two Cohorts 10-Years Apart (2017 vs. 2007)
Authors: Rupak Desai, Terry R Went, Hiren Koshiya, Dwayne Wiltshire, Vibhor Garg, Theresa Allagoa, Arashpreet Chhina, Mir Zeeshan Ali Khan, Ankit Vyas
Journal: Circulation (2021)

Background: Previous reports have suggested disparities in healthcare access in the US. We aim to compare the burden of CVD risk factors and major adverse cardiac events (MACE) and in-hospital outcomes among young hospitalized African Americans (18-44 years) selecting two nationally representative samples a decade apart. Methods: Hospitalizations among young (18-44 years) African Americans were identified using The National Inpatient Sample databases in 2007 and 2017. Then, we compared the sociodemographic, comorbidities, and inpatient outcomes including MACE (all-cause mortality, AMI, cardiogenic shock, cardiac arrest, ventricular fibrillation/flutter, pulmonary embolism, coronary intervention) between 2017 vs. 2007 cohort. Multivariable analyses were performed controlling potential covariates. Results: A total of 2,922,743 (mean age 31 years, 70.3% female) admissions among young African Americans were studied (1,341,068 in 2007 &amp; 1,581,675 in 2017). The 2017 cohort often had younger (mean 30 vs. 31 years), male (30.4% vs. 28.8%) patients with higher non-elective admissions (76.8% vs. 75%) (p&lt;0.001) and showed a rising burden of traditional cardiometabolic comorbidities, congestive heart failure, chronic pulmonary disease, coagulopathy, depression, along with notable reductions in alcohol abuse and drug abuse compared to the 2007 cohort. The adjusted multivariable analysis showed worsening in-hospital outcomes including MACE (aOR 1.21), AMI (aOR1.34), cardiogenic shock (aOR 3.12), Afib/flutter (aOR 1.34), Vfib/flutter (aOR 1.32), cardiac arrest (aOR 2.55), pulmonary embolism (aOR 1.89) and stroke (aOR 1.53). Of note, the 2017 cohort showed a decreased rate of PCI/CABG and all-cause mortality vs. 2007 (p&lt;0.001). Conclusion: Young African American patients have had an increasing burden of CVD risk factors and worsened in-hospital outcomes including MACE and stroke in the last decade, though with improved survival odds.
Efficacy and Safety of Chidamide Combined with Thalidomide, Cyclophosphamide, and Dexamethasone (TC2D) As a Novel Oral Quadruplet Regimen for the Treatment of Relapsed/Refractory Multiple Myeloma: Initial Results of a Phase IIa, Multicenter Clinical Trial
Authors: Yi Li, Jingsong He, Xiaoyan Han, Gaofeng Zheng, Enfan Zhang, Qingxiao Chen, Donghua He, Yi Zhao, Jiaping Fu, Lihong Shou, Wenhua Jiang, Wei Jiang, Shenxian Qian, Huixian Hu, He Huang, Zhen Cai
Journal: Blood (2021)
Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies
Authors: Lauren C Shapiro, Ioannis Mantzaris, Aditi Shastri, R. Alejandro Sica, Lizamarie Bachier-Rodriguez, Noah Kornblum, Kira Gritsman, Eric J. Feldman, Amit Verma, Ira Braunschweig, Yogenthiran Saunthararajah, Mendel Goldfinger
Journal: Blood (2021)