tbuckley/cabot-search huggingface dataset:
EXTH-54. PHOTODYNAMIC ONCOLYTIC VIROTHERAPY INCORPORATING GENETICALLY ENGINEERED PHOTOSENSITIZER KILLERRED FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM MALIGNANCIES
Authors: Kazuhide Shimizu, Andranik Kahramanian, Hiroaki Wakimoto
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Photodynamic therapy (PDT) is a targeted cancer therapy utilizing tumor-specific accumulation of photosensitizers and generation of reactive oxygen species (ROS) upon receiving specific light. The deadly CNS malignancies, high-grade gliomas and malignant meningioma, represent excellent candidates for this therapeutic method due to accessibility to light irradiation at the time of surgery. On the other hand, oncolytic virotherapy using a genetically engineered oncolytic herpes simplex virus (oHSV), has been intensively investigated as a multi-mechanistic therapy against these tumors. One of the advantages of oHSV is its ability to incorporate therapeutic transgenes. Our study aims to address our hypothesis that incorporating KillerRed, the first fully genetically encoded photosensitizing fluorescent protein, into oHSV will establish photodynamic oncolytic virotherapy that enhances tumoricidal efficacy as a novel treatment approach to CNS neoplasms. METHOD The optical properties of the intracellular KillerRed protein expressed in cells were determined by scanning by a multi-mode microplate reader to determine the optimal irradiation wavelength. In vitro efficacy of KillerRed-mediated PDT was tested using human glioblastoma and malignant meningioma cell lines. oHSV G47delta expressing KillerRed was constructed by a bacterial artificial chromosome-based method. KillerRed-transduced cells were confirmed to express red fluorescence, followed by irradiation by an amber color LED. Cell death and viability were assessed by DAPI staining and MTS assay, respectively. ROS generation post light treatment was assessed by DCF-DA cellular ROS assay. RESULTS KillerRed had an excitation peak at 580-585nm in transduced cells. Light irradiation by an amber LED after infection with G47delta-KillerRed induced increased cell growth inhibition and death compared with virus infection without light or light alone. Increased ROS production was observed following KillerRed PDT. CONCLUSION G47delta-KillerRed enables a combination of oncolytic virus therapy and PDT to augment tumor killing. This approach is being tested in in vivo mouse models using potent focused laser irradiation.
Abstract 10570: A New Method for Planning the Surgical Repair of Pediatric Aortic Coarctation: In vitro Design and Performance Evaluation
Authors: Fanette Chassagne, Sujatha Buddhe, Lester Permut, David MCMULLAN, Stephen P Seslar, Alberto Aliseda
Journal: Circulation (2021)

Introduction: The surgical treatment of severe aortic coarctation associated with arch hypoplasia combines resection of the stenosed tissue and enlargement of the aortic arch with a patch, designed by the surgeon in the OR. This work aims at creating an a priori design method for the patch and evaluating the success of the treatment by measuring the restoration of flow. Methods: Treatment was virtually implemented on segmented patient’s CT images based on the surgeons’ experience, identifying the zone to resect and the start of the lumen-widening, and optimized through CFD simulations The optimal patch geometry template was 3D-printed and used to perform surgery on in vitro silicon models of the aorta. Repairs were performed by an experienced surgeon using two patch geometries: the optimal patch template designed by our methodology and the patch designed by experience (traditional method). The geometry of the lumen resulting from the surgery was obtained from micro-CTs of the models. Finally, CFD simulations were performed for these geometries to evaluate the two repairs. Results: All repairs showed significant increases in aortic flowrate and decreases in pressure gradient. The virtually repaired geometry resulted in a 3-fold increase in flowrate and complete resolution of the obstruction. The traditional repair and the optimal patch repair showed similar effects on flow rate (+300%), and the traditional repair showed no remaining pressure gradient. All repairs reduced the stenosis-induced jet. However, the traditional repair led to large recirculation zones, potentially increasing the risk of thrombosis and pathological aortic remodeling. Conclusion: A novel method, combining in vitro and in silico approaches, was created to help surgical planning. This approach predicted flow and pressure gradients for the evaluation of the repair, but also provided the flow topology that should be taken into consideration to avoid hemodynamics-related complications.
Abstract 10550: Mental Health Disorders and Readmissions Following Acute Myocardial Infarction
Authors: Jayakumar Sreenivasan, Risheek Kaul, Mohammad S Khan, Aaqib H Malik, Muhammad Usman, Erin Michos
Journal: Circulation (2021)

Introduction: Hospital readmissions following an acute myocardial infarction (AMI) are associated with increased mortality and morbidity. The association of mental health disorders (MHD) and risk of readmission following AMI is not well studied. Hypothesis: We hypothesized that among patients with AMI, a co-morbid diagnosis of MHD is associated with increased risk of readmission. Methods: We analyzed the National Readmission Database for all adult AMI hospitalizations from 2016 to 2017. Co-morbid diagnoses of major depression, bipolar disorders, anxiety disorder and schizophrenia/other psychotic disorders were obtained using appropriate ICD-10 CM diagnostic codes. The primary outcome was 30-day all-cause unplanned readmission. A Cox-regression analysis was used to identify the association of MHD and risk of 30-day readmission adjusted for demographics, medical and cardiac comorbidities, and coronary revascularization. Results: We identified a total of 10,45,752 hospitalizations for AMI with a mean age of 66.6±12.9 years with 37.6% being females. The prevalence of any MHD was 15.0±0.9%. Readmission rates after AMI were higher for those with MHD compared to those without ( Figure ). After adjusting for potential confounders, comorbid diagnosis of major depression [rate 12.2%±0.5%, hazard ratio (HR) 1.11 (95% CI 1.07-1.15), p&lt;0.001], bipolar disorders (rate 13.6±0.5%, HR 1.32 (1.19-1.45), p&lt;0.001), anxiety disorders (rate 10.9±0.4%, HR 1.09 (1.05-1.13), p&lt;0.001) and schizophrenia/other psychotic disorders (rate 17.5±0.6%, HR 1.56 (1.43-1.69), p&lt;0.001) were independently associated with a higher risk of 30-day readmission compared to those with no comorbid MHD. Conclusions: Major depression, bipolar disorders, anxiety disorders and schizophrenia/other psychotic disorders are significantly associated with a higher independent risk of 30-day all-cause hospital readmissions among AMI hospitalizations in the United States.
Abstract 12649: Associations Between Diet Adherence Scores and Cardiac Structure and Function in the Hispanic Community Health Study/Study of Latinos
Authors: David Flomenbaum, Ayana April-Sanders, Un Jung Lee, Robert Kaplan, Yasmin Mossavar-Rahmani, Robert Ostfeld, Daniela Sotres-Alvarez, Josiemer Mattei, Amanda McClain, Martha L Daviglus, Mayank M Kansal, Linda Van Horn, Bonnie Shook-Sa, Carlos Rodriguez
Journal: Circulation (2021)

Introduction: The Alternative Healthy Eating Index (AHEI) and Dietary Approaches to Stop Hypertension (DASH) diets are associated with improved cardiovascular outcomes. We assessed associations between adherence to these diets and measures of left ventricular (LV) structure and function from the Echocardiographic Study of Latinos (Echo-SOL) ancillary study. Hypothesis: We hypothesized that increased adherence to AHEI or DASH diets would be associated with better cardiac structure and function. Methods: Cross-sectional baseline data from two 24-hour dietary recalls were used to calculate AHEI and DASH adherence scores among 1818 adults (57% female, mean age 56 ± 0.17) with complete echocardiographic assessments. Adherence scores were calculated based on decile of each food group for each score, with higher scores signifying higher adherence (AHEI: 0-110, DASH: 0-80). Associations between adherence scores and echo outcomes were analyzed via simple linear regression as well as ANOVA across quintiles of each score. All analyses were weighted to account for complex survey design. Results: Mean ± SE diet scores were 49.9 ± 0.32 for AHEI and 43.2 ± 0.33 for DASH. Higher AHEI scores were associated with better ejection fraction (EF) (1.1% per 10-point increase, p &lt; 0.01) and higher left atrial volume index (1.6 ml/m 2 per 10-point increase, p &lt; 0.01). Higher DASH scores were directly associated with EF (0.3% per 10-point increase, p &lt; 0.01) and inversely associated with LV mass (-4.4g per 10-point increase, p &lt; 0.01). In quintile analysis, better global longitudinal strain was seen across increasing quintiles of AHEI score (Figure). Conclusions: Adherence to AHEI and DASH diets was associated with more favorable cardiac structure and function. Pre-heart failure (HF) is an independent risk factor for incident clinical HF development. These findings have important implications for HF prevention.
A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Bijal D. Shah, Nicole Rozario, Elyce P. Turba, Celeste Bello, Julio C. Chavez, Lubomir Sokol, Jason Brayer, Jeffrey E. Lancet
Journal: Blood (2021)
Abstract 13732: Left Ventricular End Diastolic Pressure in Women With Ischemia and No Obstructive Coronary Artery Disease: An Analysis From the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study
Authors: Benita Tjoe, C N Bairey Merz, Galen Cook-Wiens, David Anderson, John W Petersen, Bruce Samuels, Michael Nelson, Chrisandra Shufelt, Eileen M Handberg, Carl Pepine, Janet Wei
Journal: Circulation (2021)

Introduction: Coronary microvascular dysfunction (CMD) has been proposed as a pathophysiological mechanism in heart failure with preserved ejection fraction (HFpEF). Elevated left ventricular end-diastolic pressure (LVEDP) is often present in patients with CMD. Hypothesis: We hypothesized that CMD-mediated impairment in LV relaxation may contribute to elevated LVEDP. Methods: Women (n=253; age 53.6 ± 11.5) with signs and symptoms of ischemia and no obstructive coronary artery disease underwent invasive coronary functional testing (CFT) for measurement of resting LVEDP, coronary flow reserve to adenosine, change in coronary blood flow and coronary artery diameter to acetylcholine, and diameter change to nitroglycerin. A subset (n=208) had rest-stress CMR at mean 47 days from CFT. Two sample t-test, Fisher’s exact test and Spearman correlation were performed. Results: All women had normal LVEF and no significant valvular disease. Mean LVEDP was 14.4±5.0 mmHg, with 150 women (59%) having LVEDP &gt;12 mmHg. Comorbidities and medications were similar between groups ( Table ). LVEDP correlated with body mass index (BMI) (r=0.324, p&lt;0.001), systolic (r=0.176, p=0.01) and diastolic systemic blood pressure (r=0.13, p=0.059) at time of CFT, as well as with time to peak filling rate (r=0.13, p=0.050), a CMR measure of diastolic function. LVEDP did not relate to invasive CFT measures nor CMR myocardial perfusion reserve index. LVEDP also did not correlate with CMR measures of LV function or structure, adjusted for body-surface area. Conclusions: Among women with suspected CMD, elevated resting LVEDP is prevalent and associated with higher BMI and systemic blood pressure. There were no significant associations between LVEDP and measurements of CMD in this cross-sectional analysis. Further analyses are underway to evaluate whether raised LVEDP initially from hypertension and obesity may lead to CMD, myocardial ischemia, structural impairment and development of HFpEF.
Human Papillomavirus Vaccination and Trends in Cervical Cancer Incidence and Mortality in the US
Authors: Tara Tabibi, Justin M. Barnes, Aneri Shah, Nosayaba Osazuwa-Peters, Kimberly J. Johnson, Derek S. Brown
Journal: JAMA Pediatrics (2021)

This cohort study examines the association of human papillomvirus vaccination with cervical cancer incidence and mortality rates in the US, comparing age groups understood to have differing levels of vaccination.
Venetoclax Combined with Dose-Adjusted R-EPOCH (VR-DA-EPOCH) As Treatment of Richter's Syndrome: A Real-World Study
Authors: Huayuan Zhu, Rui Jiang, Hui Shen, Wei Wu, Yilian Yang, Chen Peng, Jingyan Qiu, Chongyang Ding, Chuanbing Shi, Ruize Chen, Li Wang, Lei Fan, Wei Xu, Jianyong Li
Journal: Blood (2021)
Arthur David Bethune
Authors: Andrew Bethune, David Bethune
Journal: BMJ (2021)

Arthur David Bethune was born in Edinburgh and, thanks to a bursary gained at George Watson’s College, was able to study medicine at Edinburgh University, inspired by his older sister, who was working as a doctor in Peel Hospital near Galashiels. As one of a group of students whose studies were accelerated because of the war, he graduated at the tender age of 22.

For the following five years he took on a variety of jobs. He was house physician at Edinburgh’s Western General Hospital, where he encountered penicillin for the first time; assistant GP in Lockerbie; a formative spell in North Uist assisting the renowned Dr McLeod, visiting remote crofts by car, on foot, by boat or even on horseback; a year as …
NIMG-45. DIFFUSION MRI AS AN EARLY BIOMARKER OF OVERALL SURVIVAL BENEFIT IN RECURRENT GLIOBLASTOMA TREATED WITH IMMUNE CHECKPOINT INHIBITORS
Authors: Akifumi Hagiwara, Yao Jingwen, Talia Oughourlian, Chencai Wang, Catalina Raymond, Richard Everson, Kunal Patel, Sergey Mareninov, William Yong, Noriko Salamon, Whitney Pope, Phioanh Nghiemphu, Linda Liau, Robert Prins, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2021)

Abstract Diffusion magnetic resonance imaging (MRI) estimates of the apparent diffusion coefficient (ADC) has been revealed to be useful for predicting treatment response in patients with glioblastoma (GBM), with an increase in ADC indicating tumor cell death. The aim of the current study was to investigate whether quantitative changes in diffusion MRI after treatment with immune checkpoint inhibitors (ICI) could predict OS in patients with recurrent GBM. A total of 61 patients were included in this retrospective study with the following inclusion criteria: (i) diagnosis of recurrent GBM treated either with pembrolizumab or nivolumab and (ii) availability of diffusion data in pre- and post-ICI MRI. Tumor volume and median relative apparent diffusion coefficient (rADC) within enhancing tumor with respect to normal-appearing white matter were calculated. Median OS for all patients was 7.6 months (range, 1.0–30.6 months). Results showed that higher post-treatment rADC was associated with significantly longer OS (median, 372 days for rADC ≧ 1.42 versus 211 days for rADC &amp;lt; 1.42; P = 0.01, log-rank test), whereas tumor volume and pre-treatment rADC were not significantly associated with OS. Cox regression analysis revealed post-treatment rADC significantly influences OS (P = 0.02, univariate analysis), even after controlling for age, sex, and IDH status (P = 0.007, multivariate analysis), and additionally controlling for whether surgery was performed after ICI treatment (P = 0.049, multivariate analysis). In conclusion, a high post-treatment rADC may be an early imaging biomarker for identifying OS benefit in recurrent GBM patients receiving ICI treatment.
Abstract 13668: Out-of-Pocket Health Spending and Subjective Financial Hardship in Atherosclerotic Cardiovascular Disease and Heart Failure in the United States
Authors: Stephen Y Wang, Javier Valero Elizondo, Khurram Nasir, Rohan Khera
Journal: Circulation (2021)

Introduction: Financial burden from healthcare expenses in families with members with CVD like ASCVD and HF have focused on studying either the costs incurred by patients or their subjective challenges with paying medical bills. We evaluated the full extent of financial toxicity of healthcare on patients with CVD, which has implications for cost-based quality measures and designing interventions. Methods: All families with ≥1 member with ASCVD or HF in the Medical Expenditure Panel Survey (MEPS), 2014-18, were included. Objective financial hardship (OFH) was defined as annual out-of-pocket medical expenses exceeding 20% of annual income. Expenses included care costs and insurance premiums. Subjective financial hardship (SFH) was defined as self-reported problems with paying medical bills, medical bills being paid over time or inability to pay medical bills. Results: There were 10,390 families in MEPS with ≥1 member with ASCVD, representing 21 million families nationally, and 783 families in MEPS with ≥1 HF member, representing 1.7 million families nationally. Among families with ASCVD, 12.4% (95% CI 11.5% - 13.3%) experienced OFH, and 26.6% (25.4% - 27.7%) reported SFH. Collectively, 35% (33% - 36%) experienced either OFH or SFH, but only 4.4% (3.9% - 4.8%) experienced both (Fig A). Similarly, in HF, 43% families experienced at least one form of financial burden, but fewer experiencing OFB rather than SFB burden (14.1% vs 35.5%), and only 6.1% (95% CI 3.9% - 8.4%) experienced both. There patterns were consistent across key subgroups, but younger age and high income were associated with discordant OFH and SFH (Fig B). Conclusions: In 2014-18, nearly 50% of families with ASCVD or HF experienced financial hardship from medical expenses, but a focus on objective or subjective measures alone would have captured only half the burden. Measurements of financial toxicity and a study of mechanisms would need to assess factors underlying both objective and subjective measures.
Abstract 12396: Association of Lipid Profiles With Presence of Aortic Stenosis in Older Adults: Atherosclerosis Risk in Communities Study
Authors: Ali M Agha, Mahmoud Al Rifai, Matthew Deshotels, Wensheng Sun, Ron C Hoogeveen, Christie M Ballantyne, Salim S Virani, Amil M Shah, Elizabeth Selvin, Kunihiro Matsushita, vijay nambi
Journal: Circulation (2021)

Introduction: Many risk factors for atherosclerosis are also risk factors for aortic stenosis. We sought to determine if novel and traditional lipid parameters are associated with aortic stenosis in a population-based study. Methods: We conducted a prospective analysis of participants without aortic stenosis at visit 4 (1996-98) of the ARIC Study. We used logistic regression to assess the association between lipoprotein (a) [Lp(a)], remnant-like particle cholesterol (RLP-C), low-density lipoprotein triglycerides (LDL-TG), small dense low-density lipoprotein-cholesterol (sdLDLc), non-high-density lipoprotein-cholesterol (non-HDLc), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) and incident aortic stenosis (defined as peak aortic valve velocity ≥2.0 m/s) on transthoracic echocardiogram (TTE) performed during visits 5 (2011-13) and 7 (2018-19). Results: Our study population included 11,587 individuals (mean age (SD): 76 (5) years, 56% women, 23% Black). 49% and 24.8% had TTE performed at visits 5 and 7 and the presence of aortic stenosis was 5% and 8%, respectively. In adjusted models, LDL-TG, RLP-C, sdLDLc, non-HDLc, TG, and LDLc at visit 4 were associated with aortic stenosis at visit 5. Lp(a) at visit 4 was predictive of aortic stenosis at visit 7 (table). Conclusions: Among persons who survived to old age, novel lipid parameters (including Lp(a), LDL-TG, RLP-C, and sdLDLc) in mid-life were associated with aortic stenosis in late-life. Further studies should determine if lipid-lowering therapies can prevent the development of aortic stenosis.
Abstract 13903: Adipocyte PGC1-α and NOV/CCN3: Novel Targets in the Management of Obesity-Linked Cardiomyopathy
Authors: Maayan Waldman, Ragin Alex, Ran Kornowski, Edith Hochhauser, Michael Arad, Nader G Abraham
Journal: Circulation (2021)

Introduction: Chronic Obesity is frequently associated cardiac remodeling and the development of myocardial dysfunction. Oxidative stress and mitochondrial dysfunction are major factors in the development of obesity-related cardiomyopathy. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha &amp;ltPGC-1α &amp;gt is key in maintaining energy homeostasis and promotes reprogram white adipose into beige adipose tissue. We have reported a downregulation in epicardial PGC-1α levels in human and mice are associated with a reduction in cardiac function while increases in nephroblastoma overexpressed NOV/CCN3 is associated with severe inflammation and oxidative stress in multiple tissues. Hypothesis: Concomitant activation of PGC-1α and inhibition of NOV in the epicardial fat promotes adipocyte browning and alleviates obesity-related cardiomyopathy. Methods: Effect of PGC-1α over expression and NOV inhibition &amp;ltshNOV&amp;gt in transgenic mic selectively in adipose tissue on the heart in mice fed a high-fat diet &amp;ltHFD&amp;gt Mice were randomly divided into 4 groups &amp;ltn= 5 -6&amp;gt; 1; lean &amp;ltnormal diet&amp;gt, 2; HFD , 3; transgenic mice on HFD + shNOV or 4; PGC-1α . Blood pressure, cardiac and adipose fibrosis and oxygen consumption , metabolic and mitochondrial markers were studied. Results: Mice fed a HFD developed decreased mitochondrial respiration. Inhibiting NOV expression in adipose tissue of obese mice in transgenic mice resulted in an increased heart mitochondria biogenesis &amp;ltPGC-1α&amp;gt, HO-1 and activation of mitophagy and autophagy &amp;ltLC3B and PINK1&amp;gt. Transgenic PGC-1α mice exhibited increased mitochondria biogenesis, integrity and beige adipocyte markers &amp;ltPRDM16, FGF21&amp;gt, insulin receptor phosphorylation and reduced inflammation. Conclusion: Inhibiting NOV or overexpression of PGC-1α in the epicardial fat improve the quality of adipose tissue with a positive impact on the heart by inducing mitophagy and improving mitochondrial function. Tissue-targeted manipulation of the NOV and/or PGC-1α signaling to reprogram white fat into brown fat may constitute a novel therapeutic strategy in the treatment of obesity-related cardiomyopathy.