tbuckley/cabot-search huggingface dataset:
Abstract 14379: Polypill Therapy and Risk of Adverse Cardiovascular Events and Mortality: A Systematic Review and Meta-Analysis
Authors: Shreya Rao, Tariq Jamal Siddiqi, Mohammad S Khan, Erin Michos, Ann M Navar, Thomas J Wang, Stephen J Greene, Dorairaj Prabhakaran, Amit Khera, Ambarish Pandey
Journal: Circulation (2021)

Introduction: Prior studies have reported improvements in population-level risk factor burden and cardiovascular outcomes using polypill strategy. We aimed to provide an updated meta-analysis of RCTs evaluating the efficacy of polypill-based strategy in reducing the risk of adverse cardiovascular outcomes. Methods: RCTs examining the association between polypill therapy and cardiovascular outcomes published before 2/1/2021 were included. The outcomes of interest were major adverse cardiovascular events (MACE) and all-cause mortality. Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs. Results: Eight studies representing 25,584 patients were included for analysis. In pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE [RR(95% CI): 0.85(0.70-1.02)] and significant reductions in the risk of all-cause mortality [RR(95% CI): 0.90(0.81-1.00)]. The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population [primary prevention (polypill, 476/10503; control, 684/10509) vs. secondary prevention (polypill, 170/2307; control, 153/2265)], with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among CV risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure, but not for levels of total or LDL-cholesterol. Polypill strategy was also associated with significantly improved drug adherence [RR(95% CI): 1.31(1.11-1.55)]. Conclusions: . Polypill strategy is associated with significant reductions in cardiovascular risk factors and the risk of all-cause mortality and MACE, particularly in the primary prevention population.
Abstract 10567: Systolic and Diastolic Myocardial Stiffness of the Right Ventricle Free Wall Assessed by Ultrafast Ultrasound Imaging in Humans: Comparison with Pressure-Volume Loop in Healthy Volunteers and Pulmonary Arterial Hypertension Patients
Authors: olivier villemain, Rajiv Chaturvedi, Jerome Baranger, Minh Nguyen, Dariusz Mroczek, Luc L Mertens
Journal: Circulation (2021)

Background: Echocardiographic parameters to assess systolic and diastolic RV function are strongly dependent on loading conditions. Myocardial stiffness (MS) is an intrinsic myocardial property that influences both diastolic and systolic cardiac function. MS is independent of loading conditions and pre-clinical studies have demonstrated a correlation between 1) systolic MS and contractility (or ESPVR); 2) end-diastolic MS and compliance (or EDPVR). Shear wave imaging (SWI) by ultrafast ultrasound imaging allows quantitative MS assessment at any time of the cardiac cycle. This noninvasive technique could provide load-independent measure of RV function. Methods (figure 1): Ten children, 5 pulmonary arterial hypertension patients (PAH) undergoing diagnostic right heart catheterization (RHC) were prospectively enrolled as well as 5 age-matched heathy volunteers (HV). MS was assessed at baseline and during FiO2 70%+40ppm NO for the PAH group. MS in the RV free wall using SWI every 100ms during the cardiac cycle. RV-ESPVR and RV-EDPVR were assessed by pressure-volume loops using a pressure catheter and real-time 3D-echo volumes. Results (figure 2): MS increased significatively in systole compared to end-diastole in both groups (p&lt;0.01) and more significantly in the PAH group (p&lt;0.01). In the PAH group, no difference was found in systolic MS between baseline and during FiO2 70%+40ppm NO (p=0.67). Systolic MS correlated with RV-ESPVR (r=0.75). End-diastolic MS correlated with RV-EDP (r=0.76) and RV-EDPVR (r=0.85). Conclusions: Our preliminary data demonstrate that MS could be a quantitative measure of RV contractility and diastolic compliance of the RV.
A Novel Cotinine-Based System for Switchable Chimeric Antigen Receptor T Cell Immunotherapy
Authors: Ki Hyun Kim, Soohwan Kim, Ji-Hyeon Choi, Sung Min Kim, Gae Baik Kim, Jong-Ho Lee, Hyun-Jong Lee, Sang-Ho Ahn, Guewha Lee, LeiGuang Cui, Seong Yeol Kim, Min Yoon, Ki Hyun Kim, Soohyun Kim, Juwon Lee, Youngjin Han, Youngha Lee, In-Sik Hwang, Jong Seo Lee, Yong Sang Song, Marco Ruella, Junho Chung
Journal: Blood (2021)
NIMG-16. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS
Authors: Xianqi Li, Ovidiu Andronesi
Journal: Neuro-Oncology (2021)

Abstract Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging in patients due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For initial training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
Abstract 10150: Distinct Gut Microbiota Composition Among Older Adults with Impaired Left Ventricular Diastolic Function
Authors: Jie Jun Wong, Rikky W Purbojati, Ru San Tan, Sven Pettersson, Angela S Koh
Journal: Circulation (2021)

Introduction: Recent research has demonstrated shifts in intestinal microbial composition in response to cardiovascular disease (CVD) development. Left ventricular (LV) diastolic dysfunction is an early manifestation of myocardial ageing. We aimed to examine whether gut microbial composition is associated with LV diastolic function among healthy older adults. Methods: Among community older adults, 15 subjects with preserved LV ejection fraction on echocardiography underwent gut microbial composition examination in this proof-of-concept cross-sectional study. Myocardial relaxation (diastolic function) was impaired in those subjects with lower ratios of peak early (E) to late diastolic (A, atrial contraction) velocities. Metagenomic reads from stool samples were analyzed after excluding human reference genome data, and classified into various microbial taxonomic groups using lowest-common-ancestor algorithm. Statistical analysis was performed using linear discriminant analysis (LDA). Results: The subjects (53% males, mean age 75±4 years) were stratified into Groups 1 (n=8) and 2 (n=7) with more severe and lesser diastolic dysfunction, respectively, based on E/A ratios (0.77 vs. 1.28, p&lt;0.0001). In Group 1, there was significantly higher prevalence of certain bacteria (p&lt;0.05), including Bacteroides sp, Ruminococcus sp., and Paraprevotella (Figure 1). The largest relative effect size was with Bacteroides sp., including Bacteroides xylanisolvens (logarithmic LDA score 3.0). In Group 2, there was significantly higher prevalence (p&lt;0.05) of Oscillibacter sp., Peptostreptococcaceae, Clostridioides difficile, Prevotella timonensis, and Blautia producta. Relative effect size was largest with Oscillibacter sp. (log 2.8). Conclusions: Distinct gut microbiota were associated with more severe vs. lesser LV diastolic dysfunction. Future validation in larger cohorts is warranted for targeting the microbiome in myocardial ageing.
CTIM-15. FIRST-IN-HUMAN PHASE 1 STUDY OF CD200 ACTIVATION RECEPTOR-LIGAND (CD200AR-L) AND ALLOGENEIC TUMOR LYSATE VACCINE IMMUNOTHERAPY FOR RECURRENT GLIOBLASTOMA: INITIAL RESULTS FROM AN ONGOING CLINICAL TRIAL
Authors: Elizabeth Neil, Anne Eaton, Shannon Lunn, Kristen Nelson, Emily Greengard, Christopher Moertel, Michael Olin
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4. METHODS Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28. RESULTS Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS &amp;gt;/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells. CONCLUSION Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.
Abstract 9578: Cholesterol Embolization Syndrome Among Patients With Acute Coronary Syndrome Post-Percutaneous Coronary Intervention: A National Inpatient Analysis
Authors: Oseiwe B Eromosele, IRIAGBONSE ASEMOTA, ISRAEL SAFIRIYU, Ademola Ajibade, Oluwole S Abib, Abiodun B Idowu, Olayinka I Adebolu, Nelson C Okoh, Abdulkareem Lukan, Oluwafisayo S Fasanmi, Oladipo Odeyinka, Omofolarin Babayale, Hawa O Abu
Journal: Circulation (2021)

Introduction: Percutaneous coronary intervention (PCI) is associated with an increased risk of cholesterol embolization syndrome (CES), accounting for approximately 70% of iatrogenic cholesterol embolization. The clinical outcomes of patients with acute coronary syndrome (ACS), who develop CES post-PCI is yet to be explored on a national scale. Objectives: To evaluate the length of hospital stay (LOS), cost of hospitalization; proportion of patients with acute kidney injury (AKI), sepsis, cardiogenic shock and in-hospital mortality among those with ACS who develop CES post-PCI. Methods: Adults who had a diagnosis of ACS and PCI done who eventually had CES, were identified from the National In-Patient Sample (NIS) dataset between 2016-2018 using ICD10 codes. Weighted multivariable logistic and linear regression models were used as appropriate. Various sociodemographic, clinical and hospital level factors were adjusted for in the analysis. Results: Of the 365 patients who had ACS and developed CES post-PCI; 48% were women, 76.7% were non-Hispanic White and the average age was 69.5 years. The mean LOS was 8.2 days and the mean cost of hospitalization was $99,958.02. Overall, 32.9% of the patients developed AKI, 6.8% developed sepsis, 4.1% subsequently had cardiogenic shock and 11% had in-hospital mortality. Conclusions: Our study highlights important patient characteristics, resource utilization and clinical outcomes among patients with ACS who develop CES post-PCI, which provides relevant information needed to generate hypothesis linked to this disease condition.
DDRE-17. TARGETING GLIOBLASTOMA’S GALACTOSE SCAVENGING PATHWAY
Authors: Martyn Sharpe, Alexandra Baskin, Brianna Baskin, David Baskin, Sudhir Raghavan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND We have recently shown that GBM use D-galactose (Gal) as a substrate, in vitro and in vivo. Gal is imported via Glut3 and/or Glut14 and metabolized through the Leloir pathway. We investigated 4-deoxy-4-fluorogalactose (4DFG) as the lead compound in a family of galactose-based antimetabolites. 4DFG is a potent chemotherapeutic in monotherapy and can bolster existing therapies. METHODS We examined the alteration of glioma metabolism in vitro and in vivo induced by 4DFG. 1H/13C-NMR and optical probes were used to interrogate the effects of 4DFG on glycolysis and mitochondrial respiration in primary glioma cell cultures. Labeled lectins were used to assay for the disruption of glycan synthesis induced by 4DFG. An intracranial model of primary GBM was used to assess efficacy and toxicity in vivo. RESULTS NMR reveals that at physiological concentrations of glucose, low concentrations of 4DFG (5 μM) is able to inhibit glycolytic and mitochondrial flux by approximately 12%, p&amp;lt; 0.05. Analysis using lectins shows a collapse in general glycan synthesis, but most especially in the incorporation of both Gal and GalNAc sugars. In nude mice with intracranial primary GBM, six treatments of 4DFG increased survival from 23 to 50 days, p&amp;lt; 0.002. DISCUSSION The ability of GBM to scavenge galactose allows us to target the Glut3/14 import and Leloir metabolic pathway using galactose-based anti-metabolites. Our first-generation compound is highly effective as a monotherapy, inhibiting glucose metabolism and glycan synthesis.
Abstract 10240: Key Pathomechanisms of Cardiomyopathy Due to TTN Truncation
Authors: Andrey Fomin, Anna Gaertner, Lukas Cyganek, Malte Tiburcy, Marion von Frieling-Salewsky, Wolfram H Zimmermann, Hendrik Milting, Wolfgang A Linke
Journal: Circulation (2021)

Introduction: Heterozygous truncating variants in TTN (TTNtv) coding for titin cause dilated cardiomyopathy (DCM) but the underlying pathomechanisms are unclear and disease management remains uncertain. Here, we aim to elucidate the key pathomechanisms of TTNtv-DCM. Hypothesis: Stable expression of truncated titin proteins and titin haploinsufficiency characterize TTNtv-DCM and represent potential targets for therapy. Methods and Results: We studied left ventricular tissues from 14 nonfailing donor hearts and 113 endstage failing DCM patients and identified a TTNtv in 22 DCM patients (19.5%) by next generation sequencing. Using titin protein gel electrophoresis and western blot we demonstrate, for the first time, titin haploinsufficiency in TTNtv-DCM hearts. Strikingly, all 21 adult TTNtv-DCM hearts of our cohort showed stable expression of truncated titin proteins. Expression was variable, up to one-half of the total titin protein pool, and negatively correlated to patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates. Deregulated ubiquitin-dependent protein quality control was apparent. Next, we produced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), comparing wildtype controls to cells with a patient-derived, prototypical A-band TTNtv or a CRISPR/Cas9-edited M-band TTNtv. TTNtv hiPSC-CMs showed reduced wildtype titin expression and contained truncated titin proteins, whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR/Cas9, thereby eliminating truncated titin proteins and raising wildtype titin content. Functional improvement also occurred when titin protein content was increased by proteasome inhibition. Conclusions: Our study reveals the major pathomechanisms of TTNtv-DCM, which include titin haploinsufficiency as a life-long condition and truncated titin protein enrichment with aggregate formation, along with aberrant protein quality control. Results can be exploited for new therapies of TTNtv cardiomyopathies.
Abstract 13784: Thrombopoietin Restores Megakaryopoiesis By Protecting Bone Marrow Endothelial Progenitor Cells Of Patients With Hematologic Malignancies Undergoing Chemotherapy
Authors: Hui Chen, Huimin Kong, Jieyu Ye, chun chen, Hongman Xue, Liang Li, Hua Zhang, Mo Yang
Journal: Circulation (2021)

Introduction and Objective: Thrombocytopenia is the most common side effect of patients with hematologic malignancies undergoing chemotherapy. Platelet production depends on a good bone marrow (BM) microenvironment, especially the endothelial progenitor cells (EPC), which play an important role in angiogenesis and thus supporting megakaryopoiesis. However, little is known regarding the function of EPC in patients with hematologic malignancies. Therefore, the present study aimed to examine the role of EPC in angiogenesis and megakaryopoiesis, and the effect of thrombopoietin (TPO) on EPC in patients with hematologic malignancies. Methods: Twenty-three patients with ALL or AML, and ten age-matched healthy donors were recruited in the present study. EPCs were isolated from BM mononuclear cells. The cell count, proliferation, migration, and tube formation assays were conducted. Megakaryocytes were quantified by flow cytometry after coculturing with EPC in the absence and presence of TPO (100 ng/ml). In addition, transgenic zebrafish with vascular endothelial cells expressing EGFP [Tg(fli-1:EGFP)] were used to examine the angiogenic effect of TPO. Simvastatin was used to induce vascular defects in zebrafish embryos. The embryos were then treated with or without TPO (10 -3 U/μl) by intravenous injection before fluorescent images were captured. Results: The number of BM EPC was significantly smaller in patients with ALL and AML than in healthy donors. The BM EPCs from patients showed significantly reduced proliferation, migration and tube formation when compared to those from healthy donors. TPO (100 ng/ml) significantly improved those functions of EPC, and significantly increased the number of megakaryocytes after coculture. In Tg(fli-1:EGFP) zebrafish embryos, TPO (10 -3 U/μl) significantly increased the SIV vascularized area in the presence of simvastatin. Conclusion: The present study shows that dysfunctional BM EPC contributes to the pathogenesis of thrombocytopenia in patients with hematologic malignancies undergoing chemotherapy; and such impaired functions of BM EPC could be restored by TPO. In addition, TPO increases the number of megakaryocytes after coculture with EPC in vitro and promotes angiogenesis in zebrafish embryos.
Chronic Lymphocytic Leukemia (CLL) Patients Quality of Life (QoL): A Cross-Sectional Analysis of the Italian Experience in the Choice Study during the First Wave of the COVID-19 Pandemic
Authors: Alessandra Tedeschi, Idanna Innocenti, Francesco Albano, Alessandro Gozzetti, Luciano Levato, Marika Porrazzo, Gianluigi Reda, Elisa Albi, Annalisa Chiarenza, Giuliana Gualberti, Simona Malgieri, Paola Finsinger, Livio Trentin
Journal: Blood (2021)
EXTH-64. COMPARISON OF PANOBINOSTAT CSF PENETRATION WITH CNS PENETRATION FOLLOWING SYSTEMIC ADMINISTRATION IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL
Authors: Cynthia Lester McCully, Katherine Warren, Sara Zimmerman, Cody Peer, Cruz Garcia Rafael, Joshua Kramer, Matthew Breed, William Douglas Figg, Nathalie Agar, Brigitte Widemann
Journal: Neuro-Oncology (2021)

Abstract Targeted therapies developed for diffuse midline gliomas (DMG) expressing H3K27M have focused on histone deacetylase inhibitors (HDACi). High-throughput drug screening with patient derived DMG cell lines identified the HDACi panobinostat as a prominent clinical agent as well as pre-clinical studies with orthotopic mouse tumors models proving efficacious. Diametrically there is a pronounced lack of measurable panobinostat CSF concentrations in a non-human primate (NHP) non-tumor bearing pre-clinical model and in pediatric brain tumor patients. Notwithstanding, adult and pediatric glioma clinical trials and clinical observation with panobinostat alone or in combination have demonstrated minor responses. Pharmacokinetic models utilize the premise that CSF drug penetration is a surrogate of CNS drug penetration. However, the direct correlation between CSF and CNS drug levels is undefined especially in lieu of geographic CNS extracellular fluid drug variability previously demonstrated in the same NHP pre-clinical model. Utilizing the same NHP model, this study sought to compare panobinostat CSF penetration to CNS penetration via analysis of homogenized normal cerebrum, cerebellum, and brainstem tissue utilizing LC-MS/MS. METHODS: Panobinostat was administered orally as a single dose to three non-human primates. Pre panobinostat plasma and CSF were collected. Following panobinostat administration (1-hr Tmax) CSF, cerebrum, cerebellum, and brain stem tissue were collected as well as plasma to confirm the presence of panobinostat. Tissue slices were individually homogenized and panobinostat extracted via protein precipitation. Plasma, CSF, and tissue panobinostat concentrations were quantified using a LC-MS/MS assay. The lower limit of quantitation (LLOQ) for plasma-0.1 ng/ml, CSF-0.5 ng/ml, and tissue-10.0 pg/mg. RESULTS: Panobinostat was quantifiable in plasma (n=2) at the 1 hour (20.033 ng/mL and 0.153 ng/mL). CSF and CNS tissue samples were below the LLOQ for panobinostat in all samples. CONCLUSIONS: Panobinostat was not measurable from CSF and homogenized brain tissue in a non-tumor bearing NHP model at 1-hour post-administration using LC-MS/MS.