tbuckley/cabot-search huggingface dataset:
EXTH-44. SYSTEMIC CCL3 TREATMENT ENHANCES IMMUNOTHERAPY EFFICACY THROUGH IMPROVED DENDRITIC CELL MIGRATION
Authors: Kelly Hotchkiss, Kristen Batich, Mrinaj Janampalli, Pam Norberg, John Sampson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Dendritic cell (DC) vaccines have shown marginal success in treating glioblastoma (GBM), with inefficient vaccine migration a major limitation. Prior evidence from our clinical trials demonstrated that tetanus diphtheria (Td) preconditioning produced greater DC migration to vaccine draining lymph nodes (VDLNs) and long-term survival. Greater DC numbers reaching VDLNs was also associated with long-term survival. We found from preclinical studies and our patients that increased DC migration was dependent upon the chemokine (C-C motif) ligand 3 (CCL3). METHODS The effect of systemic CCL3 treatment on DC vaccine migration (n=5), antigen-specific T cell responses (n=5) and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. Median overall survival (mOS) was measure in days (d) post-intracranial implantation. RESULTS Intravenous CCL3 at the time of intradermal DC vaccination resulted in a dose-dependent increase in migration to VDLN (10ug p=0.036, 20ug p&amp;lt; 0.0001, 50ug p&amp;lt; 0.0001). Mean migration levels following CCL3 treatment were similar to Td-preconditioning (p=0.52) but showed significantly less variability between mice. Combined CCL3 and DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells 7 days compared to DC vaccine alone (p=0.0045). CCL3+OVA-DC treatment resulted in significantly greater survival compared to OVA-DC alone (mOS 37 vs 19.5 d; p=0.0174) in established GL261-OVA. CCL3 treatment increased survival in mice with established SMA560 tumors treated with neoantigen ODC1 peptide-pulsed DCs (Tumor alone mOS: 21d, DCvac: 25d, CCL3+DCvac: 48d, p=0.002). CONCLUSIONS These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing.
EXTH-06. ATR INHIBITORS AS MONOTHERAPY AND COMBINATORIAL THERAPY WITH TEMOZOLOMIDE IN PRECLINICAL GLIOBLASTOMA MODELS
Authors: Dimpy Koul, Xiaolong Li, Shaofang Wu, Sanjay Kumar singh, Kadir Caner Akdemir, W K Alfred Yung
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is an aggressive brain tumor and has an extremely poor prognosis despite the use of multiple treatment modalities. DNA damage response (DDR) signaling plays an important role in inducing radiation and temozolomide (TMZ) resistance and hence has emerged as a molecular target for therapeutic development. The Ataxia Telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR machinery, activated by DNA damage. Here, we show that three clinical-grade ATR inhibitors (Bay1895344, AZD6738 and Berzosertib) had similar selective sensitivity pattern across 16 glioma-like stem cell (GSC) lines tested. ATR inhibitors inhibited the growth of GSCs at low nanomolar range concentrations. Interestingly, all three ATR inhibitors showed a significant synergism with TMZ in a selective group of GSCs (Combination index and Bliss model). Importantly, we demonstrate that MGMT promoter methylation status was associated with cellular response to combination treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. Further, we compared the RNA-seq data from GSCs in the synergism and non-synergism group and used multiple complementary approaches to identify the response marker that confer sensitivity to combination therapy. Our preliminary data analysis identified several genes that confer sensitivity to combination treatment and studies are underway to validate the data. We also investigated the efficacy of BBB penetrant ATR inhibitor BAY 1895344 in orthotropic xenografts and administration of BAY 1895344 and TMZ combination significantly reduced tumor size and extended survival in an intracranial animal model. Combining ATR inhibitor with TMZ was well tolerated and did not confer additional toxicity as the body weights of TMZ and combination groups were comparable. The findings from this study provides a rationale to use ATR inhibitors in combination with TMZ in MGMT methylated tumors to improve therapeutic efficacy of standard of care for GBM patients.
Abstract 10474: The Bet Protein Inhibitor Apabetalone Rescues Diabetes Induced Impairment of Angiogenic Response
Authors: Shafeeq Ahmed A Mohammed, Mattia Albiero, Samuele Ambrosini, Karsai Gergely, Florian Wenzl, Era Gorica, Vincenzo Calderone, Paolo Madeddu, Gaia Spinetti, Thomas F Luscher, Sarah Costantino, Gian P Fadini, Francesco Paneni
Journal: Circulation (2021)

Introduction: Therapeutic modulation of blood vessel growth is a promising therapeutic strategy for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and extra-terminal (BET) proteins, prevents BRD4 interactions with chromatin thus modulating transcriptional programs in different organs. Hypothesis: We sought to investigate whether APA affects angiogenic response in diabetes. Methods: Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 20 mM) for 48 hours in presence of RVX-208 (20μM) or vehicle (DMSO). Streptozotocin-induced diabetic mice were orally treated with APA or vehicle for 5 days. Hindlimb ischemia was induced in diabetic mice and blood flow recovery analyzed at 30 minutes, 7, &amp; 14 days by laser Doppler imaging. Gastrocnemius muscle samples from patients with and without diabetes were employed to translate our experimental findings. Results: APA restored tube formation and migration in human endothelial aortic cells (HAECs) exposed to HG levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the anti-angiogenic molecule thrombospondin (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active regulatory marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing VEGFA signaling, while APA prevents these detrimental changes. In diabetic mice with hindlimb ischemia, epigenetic editing by APA restored THSB1/VEGFA axis thus improving limb vascularization and perfusion. Finally, epigenetic regulation of THSB1 by BRD4/H3K27ac was also reported in DM patients with PAD as compared to non-diabetic controls. Conclusion: Our findings set the stage for clinical trials testing APA in DM patients with PAD.
Abstract 13614: Pulmonary Artery Catheter Guided Therapy of Cardiogenic Shock is Associated With Lower Short-Term Mortality: A Systematic Review and Meta-Analysis
Authors: Rohit Vyas, Mohammed Mhanna, Salik Nazir, Zachary Holtzapple, Zafrullah Brohi, Samer Khouri, Ehab Eltahawy
Journal: Circulation (2021)

The utility of pulmonary artery catheterization (PAC) in treatment of cardiogenic shock (CS) is questionable. In this meta-analysis we aimed to evaluate the impact of PAC guided treatment on survival in CS patients. We performed a comprehensive literature search of multiple databases for studies that evaluated the clinical utility of PAC-guided management versus standard care for patients with CS. The primary outcome of interest was short-term mortality. The secondary outcomes were the use of mechanical circulatory support (MCS) and inotropes. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were calculated and combined using random effects model meta-analysis. A total of 9 studies including 364,001 patients with CS (29609 managed with PAC guided therapy vs. 334392 managed with slandered of care) were included in the final analysis. There was a significant difference in short-term mortality favoring PAC guided management (RR:0.83; 95% CI:0.76-0.92; P &lt;0.00001). Standard of care guided management was associated with higher use of MCS and inotropic agents (RR:1.30; 95% CI:1.15-1.46; P &lt;0.0001) and (RR:1.18; 95% CI:1.09-1.29; P &lt;0.001) respectively. Our meta-analysis demonstrates that PAC-guided therapy for patients with CS was associated with lower short-term mortality and a lower likelihood to use MCS and inotropes with their potential associated complications. Further randomized clinical trials are needed to evaluate the utility of PAC as an adjunct tool in the management of CS.
CXCL12/CXCR4 Axis Drives Mitochondrial Trafficking in Tumor Myeloma Microenvironment
Authors: Cesarina Giallongo, Ilaria Dulcamare, Daniele Tibullo, Vittorio Del Fabro, Nunzio Vicario, Nunziatina Laura Parrinello, Alessandra Romano, Grazia Scandura, Alessandro Barbato, Enrico La Spina, Daniela Cambria, Giacomo Lazzarino, Concetta Conticello, Giovanni Li Volti, Giuseppe Musumeci, Giuseppe A. Palumbo, Francesco Di Raimondo
Journal: Blood (2021)
Can geopolitics derail the pandemic treaty?
Authors: Ilona Kickbusch, Anna Holzscheiter
Journal: BMJ (2021)

During the pandemic, the world has experienced how the geopolitics of global health have immediate, ruthless repercussions for the lives and livelihoods of billions, say <b>Ilona Kickbusch and Anna Holzscheiter</b>. The challenge of a pandemic treaty negotiation process is to be responsive to these interconnected levels of geopolitics
Elucidation of Biological Role and Regulatory Landscape of PD-L2 in B-Cell Lymphoma
Authors: Sumito Shingaki, Junji Koya, Mitsuhiro Yuasa, Yuki Saito, Marni B McClure, Mariko Tabata, Kentaro Yamaguchi, Yuta Ito, Yasunori Kogure, Keisuke Kataoka
Journal: Blood (2021)
Economic Cost of Injury — United States, 2019
Authors: Cora Peterson, Gabrielle F. Miller, Sarah Beth L. Barnett, Curtis Florence
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Unintentional and violence-related injuries, including suicide, homicide, overdoses, motor vehicle crashes, and falls, were among the top 10 causes of death for all age groups in the United States and caused nearly 27 million nonfatal emergency department (ED) visits in 2019.*,† CDC estimated the economic cost of injuries that occurred in 2019 by assigning costs for medical care, work loss, value of statistical life, and quality of life losses to injury records from the CDC's Web-based Injury Statistics Query and Reporting System (WISQARS).§ In 2019, the economic cost of injury was $4.2 trillion, including $327 billion in medical care, $69 billion in work loss, and $3.8 trillion in value of statistical life and quality of life losses. More than one half of this cost ($2.4 trillion) was among working-aged adults (aged 25-64 years). Individual persons, families, organizations, communities, and policymakers can use targeted proven strategies to prevent injuries and violence. Resources for best practices for preventing injuries and violence are available online from CDC's National Center for Injury Prevention and Control.¶.
Heterozygous NUDT15 Gene Polymorphism Would Not Associate with the Severity of 6-Mercaptopurine Side Effects in Early Intensification Therapy for Childhood Acute Lymphoblastic Leukemia
Authors: Jimei Zhao, Masahiro Ueki, Saori Sawai, Minako Sugiyama, Yukayo Terashita, Shinsuke Hirabayashi, Yuko Cho, Yoichi Tanaka, Atsushi Manabe
Journal: Blood (2021)
Abstract 11633: Three-Dimensional Speckle-Tracking Echocardiographic Assessment of Ventricular Dyssynchrony and Arrhythmic Risk in Mitral Valve Prolapse
Authors: Lidia Capotosto, Bich Lien L Nguyen, Gaetano Tanzilli, Maria Ciardi, Enrico Mangieri, Maurizio Muscaritoli, Fabio Miraldi, Antonio Vitarelli
Journal: Circulation (2021)

Introduction: Dyssynchrony indices based on two-dimensional speckle tracking echocardiography have demonstrated added value in identifying patients with mitral valve prolapse (MVP) with a higher prevalence of arrhythmic complications and the potential for sudden cardiac death, but measurements are restricted to a single plane, and complex left ventricular (LV) dyssynchrony patterns may be overlooked. Hypothesis: The purpose of this study was to investigate whether three-dimensional speckle-tracking echocardiography helps in detecting MVP at higher arrhythmic risk. Methods: We studied 21 arrhythmic MVP patients (group 1) with a history of complex ventricular ectopy on holter and/or event monitor (n=17) or defibrillator implant (n=2), 21 MVPs with no arrhythmic complications (group 2) and 21 healthy controls (group 3). 3D LV longitudinal strain (3DE-LVLS) and area strain (3DE-LVAS) were determined (17 segments). 3D LV dyssynchrony index (3DE-LVDI) was obtained as the standard deviation of the times to peak area strain in 17 segments, normalized to RR interval. Results: MVP patients had significantly higher LV dyssynchrony index compared to controls (9.4±3.9% vs 4.3±2.5%, p=0.002) although they had similar LV ejection fraction (64% vs 61%, p=0.51). Group 1 and group 2 had similar LV ejection fraction and clinical data (p&gt;0.05). Bileaflet prolapse was more frequent in group 1 pts (52% vs 24%, p=0.03). Moderate mitral regurgitation was present in 9/21 group 1 pts and 3/21 group 2 pts (p=0.04). Group 1 pts had greater LV dyssynchrony index when compared with group 2 (10.7±4.1% vs 5.1±2.9%, p=0.0001). By ROC (receiver operating characteristics) curves, 3DE-LVDI and 3DE-LVAS cutoff values of 10.2% and -23.8%, respectively, had 89% and 85% sensitivity and 79% and 76% specificity in identifying the presence of significant arrhythmias with areas under the curve 0.87 and 0.84. Conclusions: Impairment of LV deformation parameters determined by three-dimensional speckle tracking echocardiography may help detect increased arrhythmic risk in patients with MVP.
Abstract 8859: Hematopoietic Calr Frameshift Mutation Exacerbates Hypoxia-Induced Pulmonary Hypertension in Mice
Authors: Tetsuro Yokokawa, Tomofumi Misaka, Yusuke Kimishima, Keiji Minakawa, Koichi Sugimoto, Kazuhiko Nakazato, Kazuhiko Ikeda, Yasuchika Takeishi
Journal: Circulation (2021)

Introduction: Calreticulin (CALR) frameshift is the second frequent driving mutation in myeloproliferative neoplasms (MPNs). MPNs are complicated with pulmonary hypertension (PH), but the mechanist...
Abstract 13064: Sex-Related Differences in Chest Pain and Asymptomatic Myocardial Ischemia Experienced During Exercise Stress Echocardiogram
Authors: Nikhil Patel, Jeremy Brooks, Mark Sokolsky, Bharathi Upadhya, Min Pu, Brandon Stacey
Journal: Circulation (2021)

Background: Coronary artery disease (CAD) continues to account for significant morbidity and mortality for both men and women. Women present with greater variability in symptoms from coronary artery disease than men. This study seeks to describe the potential differences between men and women in the association between stress test-related chest pain and obstructive CAD. Methods: Patients with an exercise stress test who underwent a coronary angiogram from September 2013 to January 2019 were included in our analyses. The patients’ clinical characteristics, symptoms, coronary angiography and ECGs were analyzed to determine the relationship between ischemia, chest pain, and obstructive coronary artery disease (CAD; stenosis &gt; 70%). T-tests and chi-square tests described differences in continuous and categorical variables, respectively. Logistic regression was used to adjust for demographic, imaging, and stress testing factors. Results: A total of 368 patients were included in our analyses: 297 patients had a positive stress echocardiogram or ECG; 71 patients had negative stress tests but continued to have persistent symptoms. The study population had a mean age of 63 years and included 29% female, 11% African-American, and 61% obstructive CAD. In those with obstructive CAD, only 39% of women experienced chest pain during stress (p&gt;0.2), but in men, 48% experienced stress test related chest pain (p&lt;0.001). Adjusting for baseline demographics in sex-stratified models, echo-based ischemia and ECG-based ischemia were significantly associated with obstructive CAD in women, but stress-test related chest pain was not (p=0.02; p&lt;0.001; p&gt;0.2, respectively). In men, echo-based ischemia, ECG-based ischemia, and stress-test related chest pain all associated with obstructive CAD (p&lt;0.001; p&lt;0.001; p=0.008, respectively). These changes persisted with adjustment for stress test performance (METS, heart rate achieved) as well as baseline left ventricular ejection fraction. Conclusion: In women, stress test-related chest pain during stress testing was not associated with obstructive CAD. Further studies are needed to understand the role, significance, and management of potential myocardial ischemia without chest pain in women.
Abstract P502: Abnormal Myocyte Calcium Dynamics And The Resultant Contraction Band Formation Of The Rat Heart Under Irreversible Injury By Membrane Permeabilization
Authors: Yuma Morishita, Shoko Tamura, Kentaro Mochizuki, Yoshinori Harada, Hideo Tanaka
Journal: Circulation Research (2021)

Ca 2+ overload is a cardinal feature of cardiomyocyte injury, and its progression to irreversible state leads to cell death. However, unknowns are the precise spatiotemporal changes in the myocyte Ca 2+ dynamics and the relevant cell morphology of irreversibly injured hearts. On the hypothesis that myocytes exhibit high-frequency Ca 2+ waves and contraction band necrosis in saponin-permeabilized injured heart, we observed changes in the Ca 2+ dynamics and the relevant morphological changes in the subepicardial myocardium of the Fluo4-loaded rat hearts (n = 14) by rapid-scanning confocal microscopy (100 frames/s) under Langendorff perfusion with 0.3 mM Ca 2+ -Tyrode solution including 0.4 % saponin at 30°C. Also performed was confocal imaging of tetramethylrhodamine methyl ester (TMRM) fluorescence of the myocardium. Under quasi-quiescence of the heart after dissection of the SA node, individual myocytes barely exhibited spontaneous Ca 2+ waves, whereas after commencement of saponin perfusion high-frequency (118 ± 9.7 /min/cell, mean ± SEM) Ca 2+ waves (hereafter, “agonal waves”) emerged within 1 min, showing asynchronous, oscillatory contractions in the individual myocytes with a V prop of 124 ± 2.5 μm/s (n = 60). Subsequently, the waves gradually decreased in frequency with concomitant slowing of its decay time course, and eventually, disappeared in 6 min; myocytes exhibited high, static Fluo4-fluorescence intensity. Along with the progression of Ca 2+ overload by saponin, the TMRM fluorescence intensity was discretely lost in individual myocytes. The myocytes showing the agonal waves exhibited contraction bands, i.e., band-like aggregations of the actin fibers. Under mechanical arrest of the heart by 2,3-butanedione monoxime (20 mM), saponin still induced the agonal waves with a frequency of 253 ± 10.6 /cell/min and V prop of 118 ± 2.1 μm/s (n = 60); however, contraction bands were barely seen.In conclusion, irreversible myocyte injury by saponin provoked agonal Ca 2+ waves and oscillatory contractions indicating progressive Ca 2+ overload and the following mitochondrial damage, which may provide deeper insights into understanding the mechanism of contraction band necrosis.
Abstract 14339: Disparities in Transcatheter Mitral Valve Repair in Racial Minorities - From the National Inpatient Sample
Authors: Muhammmad Zia Khan, Muhammad U Khan, Salman Zahid, Waqas Ullah, Sudarshan balla
Journal: Circulation (2021)

Introduction: Racial disparities in cardiovascular diseases and interventions have been widely reported in previous studies, Whether the racial disparities exist with transcatheter mitral valve repair (TMVr) is largely unknown. Hypothesis: The purpose of this study is to assess racial disparities in the utilization and outcome of TMVr procedure in the United States using the National Inpatient Sample (NIS) database. Methods: We analyzed NIS data from January 2013 to December 2017 using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes and International Classification of Diseases, 10th Revision, Clinical Modification ICD-10-CM codes. Multivariable analysis was done by using logistic regression model to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs) to determine variability in mortality, home discharges, vascular complications, cardiac complications, pulmonary complications, post op stroke and acute kidney injury by race. Results: A total of 13,410 weighted hospitalizations for TMVr procedure were included in our analysis. Multiple logistic regression analysis showed no significant difference in hospital mortality among the three racial groups. Pulmonary complications were more likely in the African American (adjusted Odds Ratio [aOR], 1.326[95% CI, 1.03-1.706], p-value= 0.03) and Hispanic population (aOR, 1.362[95% CI, 1.034-1.794], p-value= 0.03) (Figure). Conclusions: No significant difference in hospital mortality was noted among Caucasian, African American and Hispanic patients undergoing TMVr, however, we report a higher rate of post procedure respiratory complications in the minority races compared to Caucasian race.
Abstract 9757: Frequency of Atrial Fibrillation in a Contemporary Elderly Primary Care Population: A Vital-af Trial Study
Authors: Shaan Khurshid, Jeffrey M Ashburner, Yuchiao Chang, Ana T Trisini Lipsanopoulos, Leila H Borowsky, Wyliena Guan, Patrick T Ellinor, David D McManus, Steven Atlas, Daniel Singer, Steven A Lubitz
Journal: Circulation (2021)

Introduction: Reliable estimates of atrial fibrillation (AF) frequency can inform our understanding of population disease burden and shape interventions to reduce AF-related morbidity. Methods: We quantified the prevalence and incidence of AF in VITAL-AF (NCT035115057), a cluster-randomized trial of AF screening using single-lead handheld electrocardiograms within 16 primary care practices affiliated with Massachusetts General Hospital. Potential AF events were identified using the electronic health record. AF events satisfying a high specificity electronic algorithm for prevalent AF (positive predictive value 98.4%) were classified as prevalent AF, while all other potential AF events (including all incident AF events) were manually adjudicated. We calculated AF prevalence and incidence overall and within clinical strata, among individuals who were not screened. Results: Of 18,812 individuals enrolled but not screened between 7/31/2018-10/8/2019 (mean age 74.6±7.2 years, 56.3% women), 2,503 (13.3%) had prevalent AF. AF prevalence was particularly high among individuals aged ≥85 years (29.1%) and individuals with heart failure (43.4%). The AF incidence rate among 16,309 individuals without prevalent AF was 20.1 per 1,000 person-years (95% CI 20.9-26.4). AF incidence also increased markedly with age (e.g., 13.6 at ages 65-69 to 37.1 at ages ≥85 years, p&lt;0.01), was greater in men versus women (26.9 vs. 15.0, p&lt;0.01), and was particularly high among individuals with heart failure (30.7, 95% CI 43.8-69.0). Detailed estimates of AF prevalence and incidence across clinical strata are shown in the Table . Conclusions: Using rigorous methodology within a contemporary, elderly primary care population, we observed the highest reported prevalence of diagnosed AF, including nearly a third of individuals aged 85 years and older. The incidence of new AF is also substantial. Preventive efforts are warranted to reduce the risk of AF and associated complications.