tbuckley/cabot-search huggingface dataset:
Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion
Authors: Anna Morena D'Alise, Guido Leoni, Maria De Lucia, Francesca Langone, Linda Nocchi, Fabio Giovanni Tucci, Elisa Micarelli, Gabriella Cotugno, Fulvia Troise, Irene Garzia, Rosa Vitale, Veronica Bignone, Elena Di Matteo, Rosa Bartolomeo, Deborah H Charych, Armin Lahm, Jonathan Zalevsky, Alfredo Nicosia, Elisa Scarselli
Journal: Journal for ImmunoTherapy of Cancer (2021)

A number of different immune pathways are involved in the effective killing of cancer cells, collectively named as the 'Cancer Immunity Cycle'. Anti-PD-1 checkpoint blockade (CPB) therapy is active on one of these pathways and reinvigorates anticancer T cell immunity, leading to long-term responses in a limited fraction of patients with cancer. We have previously shown that neoantigens-based adenovirus vectored vaccine in combination with anti-PD-1 further expands pre-existing anticancer immunity and elicits novel neoantigen-specific T cells thereby increasing efficacy to 50% of tumor clearance in mice. Here we added a third component to the CPB plus vaccine combination, which is able to modify the suppressive tumor microenvironment by reducing the number of tumor-infiltrating regulatory T cells (Tregs), as strategy for improving the therapeutic efficacy and overcoming resistance.The antitumor efficacy of anti-PD-1, neoantigen vaccine and Treg modulating agents, either Bempegaldesleukin (BEMPEG: NKTR-214) or an anti-CTLA-4 mAb with Treg-depleting activity, was investigated in murine tumor models. We evaluated tumor growth in treated animals, neoantigen-specific T cells in tumors, tumor-infiltrating lymphocytes (TILs) and intratumoral Tregs.The addition of BEMPEG or anti-CTLA-4 to the combination of vaccine and anti-PD-1 led to complete eradication of large tumors in nearby 100% of treated animals, in association with expansion and activation of cancer neoantigen-specific T cells and reduction of tumor-infiltrating Tregs.These data support the notion that the integrated regulation of three steps of the cancer immunity cycle, including expansion of neoantigen-specific T cells, reversal of the exhausted T cell phenotype together with the reduction of intratumoral Tregs may represent a novel rationally designed drug combination approach to achieve higher cure rates.
Abstract 11176: Family Screening in Dilated Cardiomyopathy; Long-Term Incidence and Potential for Limiting Follow-Up
Authors: Christoffer R Vissing, Kiri Espersen, Helen L Mills, Rebecca Jurlander, Sofie V Vinther Skriver, Jens J Thune, Anna A Raja, Alex H Christensen, Henning Bundgaard
Journal: Circulation (2021)

Introduction: Guidelines recommend family screening in dilated cardiomyopathy (DCM) to uncover pre-symptomatic familial DCM (FDC). So far, no guidelines provide specific recommendations on the intensity and frequency of follow-up screening. This study sought to provide the first detailed estimates of the incidence of FDC during follow-up and identify baseline markers which could inform future follow-up of relatives. Methods: The study was a retrospective, observational, longitudinal cohort study of relatives to DCM probands screened at a regional assembly of family screening clinics in Copenhagen, Denmark, from 2006 to 2020. Results: In total, 563 relatives (50% women) from 211 families were included. At baseline, 124 relatives (22%) were diagnosed with FDC: 97 (18%) as a result of screening and 27 (5%) with symptom-onset prior to screening. Genetic sequencing identified the etiology of DCM in 35% of families and classified 90 relatives (17%) as unaffected carriers (n=44) or relatives not at risk of FDC (n=46). As such, the combined clinical and genetic baseline-yield was 31%. In 439 relatives considered unaffected at baseline, 45 (10%) were diagnosed with FDC during follow-up (median 5.0 years). The age-standardized incidence rate of FDC was 2.0% per person-year [CI: 1.4-2.8%] with higher rates in men vs women (3.0% vs 1.4% per person-year). In relatives without predictive genetic findings (n=349), non-diagnostic abnormal baseline-findings on ECG or echocardiography was associated with a higher incidence rate of FDC (figure A), while the risk was low in relatives with normal findings (0.4% vs 4.7% per person-year; figure B). Conclusion: Systematic family screening identified FDC or genetic predisposition to FDC in 1 out of 3 relatives at baseline. Relatives without predictive genetic findings and with normal findings on ECG and echocardiography at baseline had a low risk of developing FDC. Follow-up can be limited and may not be warranted in these relatives.
Abstract MP221: Early Recruitment Of Neutrophils To The Ischemic Heart Is Orchestrated By Catecholamine-induced Demargination
Authors: Albert Dahdah, Prabhakara R Nagareddy, Gopalkrishna Sreejit, Ki Ho H Park, Robert Jaggers, Jillian Johnson, Jianjie Ma
Journal: Circulation Research (2021)

Myocardial infarction (MI) induces a rapid and robust inflammatory response characterized by infiltration of different leukocyte cell types to the infarcted heart. Neutrophils are the first cells to arrive at the infarct where they release a plethora of proteolytic enzymes, exacerbate tissue injury, expand infarct size and promote cardiac dysfunction/ failure. We previously have shown that granulopoiesis (in the bone marrow, BM) is the major source of neutrophils during MI. However, the increase in the number of neutrophils at the infarct begins much earlier than the peak response in the BM (~ 24 hours) suggesting that sources other than granulopoiesis may contribute to the overall neutrophil pool. Because the marginated pool of neutrophils represents the same size of circulating pool, we hypothesized that demargination of neutrophils from the vascular wall contribute to the neutrophil burden in the heart, particularly during the early hours after MI.Using a mouse model of the permanent ligation of the left anterior descending coronary artery, BM ablation of hematopoietic stem cells, flow cytometry and BM transplant techniques, we found that the first wave of neutrophils recruited to the ischemic heart are exclusively sourced from the vasculature and not granulopoiesis in the BM/ spleen. The neutrophils recruited at the heart bore all hallmarks of demargination induced by dexamethasone including decreased F-actin, CD62L, and increased Adam17 expression. The recruitment of neutrophils is orchestrated by catecholamine stress as experimental strategies aimed at blockade of β1 and β2 adrenergic receptors (AR) reduced neutrophil burden in the ischemic heart. Interestingly, despite a decrease in neutrophil burden, the cardiac function did not improve but rather declined. However, short-term inhibition (6-12 hours post-MI) of β AR system either by receptor blockade (propranolol) or inhibition of catecholamine synthesis (AMPT) not only reduced neutrophil burden but also significantly improved cardiac function. Together these data suggest that catecholamine stress induced-demargination constitute the major source of neutrophils during the early hours post-MI. Pharmacological strategies aimed at suppressing the initial onslaught of neutrophils on the ischemic heart may represent a novel and viable approach towards a better resolution of the injury. Currently, studies are underway to define the signaling mechanisms that drive demargination and, to optimize the dose/ duration of a specific β receptor blocker to achieve better functional outcomes.
Abstract 10448: Combined Associations of Physical Activity and Particulate Matter with Subsequent Cardiovascular Disease Risk Among 5-Year Cancer Survivors
Authors: Daein Choi, Seulggie Choi, Kyae Hyung Kim, Kyuwoong Kim, Jooyoung Chang, Sung Min Kim, Seong Rae Kim, Yoosun Cho, Gyeongsil Lee, Joung Sik Son, Sang Min Park
Journal: Circulation (2021)

Introduction: Cardiovascular disease (CVD) is considered an important cause of death among cancer survivors. While engaging in physical activity is known to reduce the risk for CVD, it exposes participants to particulate matter (PM). The combined association of physical activity and PM with subsequent CVD risk is yet unclear. Methods: The study population consisted of 18,846 cancer survivors who survived for at least 5 years after an initial cancer diagnosis from the Korean National Health Insurance Service database. For PM, 4-year average levels were determined in administrative district areas and moderate-to-vigorous physical activity (MVPA) information was acquired from the results of national health screening examinations. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of CVD were calculated by multivariate Cox proportional hazards regression. Considered covariates were age, sex, household income, area of residence, smoking, alcohol intake, body mass index, systolic blood pressure, fasting serum glucose, total cholesterol, and comorbidities. Results: Among patients with low PM2.5 (19.8-25.6 μg/m 3 ) exposure, ≥5 times/week of MVPA was associated with lower CVD risk (adjuster hazard ratio; aHR 0.77, 95% confidence interval; CI 0.60-0.99) compared to 0 times/week of MVPA. In contrast, ≥5 times/week of MVPA among patients with high PM2.5 (25.8-33.8 μg/m 3 ) exposure was not associated with lower CVD risk (aHR 0.98, 95% CI 0.79-1.21). Compared to patients with low PM2.5 and MVPA ≥3 times/week, low PM2.5 and MVPA ≤2 times/week (aHR 1.26, 95% CI 1.03-1.55), high PM2.5 and MVPA ≥3 times/week (aHR 1.34, 95% CI 1.07-1.67), and high PM2.5 and MVPA ≤2 times/week (aHR 1.38, 95% CI 1.12-1.70) was associated with higher CVD risk. Conclusions: Cancer survivors who conducted ≥5 times/week of MVPA benefited from lower CVD risk upon low PM2.5 exposure. High levels of PM2.5 exposure may attenuate the risk-reducing effects of MVPA on the risk of CVD.
Abstract 10216: Sinus Node Dysfunction After Pulmonary Thromboendarterectomy Surgery
Authors: Sai Vanam, Muhammad Munir, Douglas Darden, Masihullah Barat, Lucas Keyt, Tanner Long, Gregory K Feld, Jonathan C Hsu, Ulrika Birgersdotter-green, Gordon Ho, David Krummen, Farshad Raissi, Timothy Fernandes, David Poch, Nick Kim, Demosthenes G Papamatheakis, Kim Kerr, Victor Pretorius, Michael M Madani, Frederick Han, Kurt S Hoffmayer
Journal: Circulation (2021)

Background: Pulmonary Thromboendarterectomy (PTE) is a specialized cardiac surgery for treating chronic thromboembolic pulmonary hypertension (CTEPH). Sinus node dysfunction is seen in this population as patients often require epicardial pacing after cardiac surgeries. We aimed to define the incidence, predictors, and outcomes of sinus node dysfunction after PTE surgery. Hypothesis: We hypothesized that sinus node dysfunction requiring epicardial pacing is common after PTE surgery. Methods: We reviewed the charts of 883 consecutive patients who were referred to University of California San Diego for PTE. Demographics, lab results and imaging were extracted from chart review. Predictors and outcomes were analyzed using multivariate backward logistic regression model or independent samples T test respectively. Results: Overall, 60% (n=533) of patients required epicardial pacing for an average of 3.9 +/- 2.2 days. Strongest predictors of epicardial pacing were coronary artery disease (OR 2.6, p=&lt;0.01) and tobacco abuse (OR 2.1, p=0.01). Of the patients who required epicardial pacing, only 1% (n=4) required permanent pacemaker placement. Patients who required epicardial pacing had significantly longer post-operative length of stays (12.9 days vs 11.3 days, p=&lt;0.01) and ventilator days (2.3 days vs 1.8 days, p=0.02). Conclusions: The majority of patients undergoing PTE for chronic thromboembolic pulmonary hypertension develop sinus node dysfunction requiring temporary epicardial pacing. The mechanism of sinus node dysfunction appears transient as the average pacing requirement is 3.9 +/- 2.2 days, and ultimately only 1% (n=4) require permanent pacemaker placement. Patients who required epicardial pacing had significantly longer post-operative length of stay and ventilator days.
Abstract 13231: Semaphorin3F Reduces Atherosclerosis by Decreasing Endothelial Activation and Barrier Permeability and Smooth Muscle Cell Migration
Authors: Roshni R Singaraja, Chutima Rattanasopa, David Castano Mayan, Sujoy Ghosh
Journal: Circulation (2021)

Coronary artery disease (CAD) remains a leading cause of death worldwide. To identify genes causally linked to CAD, we previously conducted large-scale genetic analyses, and identified an association between genes in the semaphorin pathway and CAD. Expression profiling in human atherosclerosis-relevant cell types and atherosclerotic plaques identified semaphorin3F (SEMA3F) as a possible candidate causally linked to atherosclerosis. Administration of SEMA3F reduced aortic lesion area in western-type diet-fed Ldlr -/- mice (Control: 12.1±1.4; SEMA3F: 8.1±0.8, % lesion area/total aortic sinus area, p=0.02). In contrast, neointimal formation was increased in Sema3f -/- mice with partial carotid artery ligation ( WT : 22.8±2.8; Sema3f -/- : 39.2±4.0; % intimal area/total vessel area, p=0.004). Additionally, SEMA3F administration increased re-endothelialization and reduced restenosis in Ldlr -/- mice that underwent carotid endothelial denudation (Control: 53.3±3.5; SEMA3F: 21.4±3.1; % intimal plaque area/vessel area, p=0.0006). Monocyte adhesion to aortic vascular endothelial cells (VECs) from Sema3f -/- mice was elevated, driven by increased NF-κB activation and increased expression of its target adhesion molecules, VCAM1 and ICAM1, in VECs. Monocyte transmigration through VECs from Sema3f -/- mice was also increased, likely due to increased membrane permeability, assessed by in-vivo intravital two-photon microscopy. The increased membrane permeability was modulated in part by decreased mTOR phosphorylation that in turn suppressed vascular endothelial cadherin protein expression. SEMA3F increased thick actomyosin filaments and elicited larger focal adhesions in VECs, suggesting decreased migration. In line with this, SEMA3F inhibited vascular smooth muscle cell (VSMC) migration and maintained the contractile phenotype of VSMCs, which was mediated by the Rho pathway. SEMA3F is causally atheroprotective in models of atherosclerosis and restenosis, mediated, in part, through the modulation of vascular endothelial cell permeability and adhesion molecule expression, and vascular smooth muscle cell migration and phenotype switching.
PRDM1 Is Sufficient for Inducing Human Primary T Cell Hyporesponsiveness and Implicates Low Gvhd Occurrence after Allo-HSCT
Authors: Ming Wang, Ming Wang, Bixia Wang, Liping Guo, Yifei Cheng, Zhidong Wang, Yuqian Sun, Yu Wang, Yingjun Chang, Xiaojun Huang
Journal: Blood (2021)
Abstract 11925: Comparison of Right Ventricular Outflow Tract-Dominant Hypertrophic Type With Diffuse Type Using Cardiac CT for J Waves and Clinical Parameters in Pulmonary Hypertensive Patients
Authors: Nobusada Funabashi, Koya Ozawa, Kohki Nakamura, takehio sasaki, Shigeto Naito, Yoshio Kobayashi
Journal: Circulation (2021)

Introduction: J waves are specific in patients with hypothermia, idiopathic ventricular fibrillation, or brain damage. Patients with pulmonary hypertension (PH) may show right ventricular (RV) hypertrophy and fibrosis, leading to abnormal ECG findings. On cardiac CT of PH, two RV hypertrophic (RVH) types are seen, namely RV outflow tract dominant and RV diffuse. Hypothesis: We hypothesize that these two morphological RVH types might have different effects on ECG findings including J waves, and clinical severity in PH patients. Method: We retrospectively analyzed 43 PH patients (33 females, 55±15 yrs, 31 chronic thromboembolic PH, 7 idiopathic pulmonary arterial (PA) hypertension). Cases were divided into 3 groups: RV outflow tract dominant RVH (gp 1) (N=6), RVH diffuse (gp 2) (N=26), and no RVH (gp 3) (N=11). Results: In gp 1, one (17%) had J waves in II, III, and aVF leads with a maximum RV wall thickness on end-diastole 7.5mm. In gp 2, three (12%) had J waves in II, III, and aVF leads with maximum RV wall thickness on end-diastole 6.7, 6.1, and 5.6mm, respectively. In gp 3, none (0%) had J waves. In gp 1, all six (100%) had a negative T wave in V1-3 leads or beyond and in gp 2, 24 (92%) had a negative T wave in V1-3 leads or beyond (P=0.483). There were significant positive correlations between maximum RV wall thickness in end-diastole and plasma brain natriuretic peptide (BNP) in gp 1 (R=0.44) but no correlations in gp 2. There were significant positive correlations between maximum RV wall thickness in end-diastole and estimated PA systolic pressure (PASP) on TTE in gp 1 (R=0.38) but no correlations in gp 2. Conclusions: In 32 PH participants with an organized RV myocardial change, such as RV outflow tract dominant and diffuse type RVH, 17% and 12% had J waves in II, III, and aVF leads and most of them had a negative T wave in V1-3 leads or beyond. Only RV outflow tract dominant RVH showed significant positive correlations between maximum RV wall thickness in end-diastole, plasma BNP and estimated PASP.
CBIO-23. ANTIAPOPTOTIC Bcl-xL RESTRICTS APOPTOSIS IN SHH MEDULLOBLASTOMA AND PROMOTES PROGRESSION
Authors: Abigail Cleveland, Katherine Veleta, Timothy Gershon
Journal: Neuro-Oncology (2021)

Abstract Medulloblastomas in most patients are distinctively sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Current treatments still fail 20%-60% of patients with SHH medulloblastoma and can leave survivors with long-term neurocognitive and social deficits. Understanding the mechanisms driving the typical radiation-sensitivity may identify less-toxic therapeutic strategies and provide insight into treatment failure. We previously showed that radiation sensitivity depends on the intrinsic apoptotic pathway, mediated by pro-apoptotic BAX. In cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH medulloblastoma, BAX activity is directly inhibited by anti-apoptotic BCL-xL; Bcl-xL-deleted CGNPs undergo spontaneous apoptosis. To test the therapeutic potential of disrupting BCL-xL in medulloblastoma, we conditionally deleted Bcl-xL in mice genetically engineered to develop SHH medulloblastoma. Here, I show that Bcl-xL deletion slows SHH medulloblastoma growth and prolongs survival of medulloblastoma-bearing mice. Bcl-xL-deleted tumors initially showed increased rates of spontaneous apoptosis, but this effect waned over time, suggesting the emergence of BCL-xL-independent survival mechanisms. We also noted increased microglial infiltration in Bcl-xL-deleted medulloblastomas. We hypothesize that IGF1 produced by microglia in the tumor microenvironment may be contributing to tumor resistance by upregulating translation of MCL-1, an anti-apoptotic BCL-xL homolog. IGF1 is known to upregulate translation through the mTOR pathway, while anti-apoptotic MCL-1 protein abundance is dependent upon translation regulation. Our on-going studies are testing the efficacy of pharmacologically targeting BCL-xL in mice with medulloblastoma, in combination with targeting IGF1 signaling using mTORC1 inhibitors.
Estimating the environmental impact of disposable endoscopic equipment and endoscopes
Authors: Sathvik Namburar, Daniel von Renteln, John Damianos, Lisa Bradish, Jeanne Barrett, Andres Aguilera-Fish, Benoit Cushman-Roisin, Heiko Pohl
Journal: Gut (2021)

Procedure-intense specialties, such as surgery or endoscopy, are a major contributor to the impact of the healthcare sector on the environment. We aimed to measure the amount of waste generated during endoscopic procedures and to understand the impact on waste of changing from reusable to single use endoscopes in the USA.We conducted a 5-day audit (cross-sectional study) of all endoscopies performed at two US academic medical centres with low and a high endoscopy volume (2000 and 13 000 procedures annually, respectively). We calculated the average disposable waste (excluding waste from reprocessing) generated during one endoscopic procedure to estimate waste of all endoscopic procedures generated in the USA annually (18 million). We further estimated the impact of changing from reusable to single-use endoscopes taking reprocessing waste into account.278 endoscopies were performed for 243 patients. Each endoscopy generated 2.1 kg of disposable waste (46 L volume). 64% of waste was going to the landfill, 28% represented biohazard waste and 9% was recycled. The estimated total waste generated during all endoscopic procedures performed in the USA annually would weigh 38 000 metric tons (equivalent of 25 000 passenger cars) and cover 117 soccer fields to 1 m depth. If all endoscopic procedures were performed with single-use endoscopes and accounting for reprocessing, the net waste mass would increase by 40%. Excluding waste from ancillary supplies, net waste generated from reprocessing and endoscope disposal would quadruple with only using single-use endoscopes.This quantitative assessment of the environmental impact of endoscopic procedures highlights that a large amount of waste is generated from disposable instruments. Transitioning to single-use endoscopes may reduce reprocessing waste but would increase net waste.
Abstract 11932: Outcome Predictions Using Machine Learning in Atrial Fibrillation-Related Stroke
Authors: Jin-Man Jung, Eun-Tae Jeon
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) is one of the most important risk factor for poor clinical outcomes in stroke patients, however, until now, there has been no outcome prediction model in stroke concomitant with AF. The aim of study was to build a powerful machine learning model for predicting outcomes in AF-related stroke. Methods: Using a multi-center prospective stroke registry from 11 tertiary centers in South Korea performed between January 2013 and December 2015, a total of 3090 patients were included. Various clinical, laboratory and imaging factors and medications at discharge were collected. Outcomes included recurrent stroke, all-cause death, major adverse cardiovascular events (MACE), major hemorrhage, and any gastrointestinal hemorrhage. Random survival forest and eXtreme Gradient Boosting (XGBoost) were used for machine learning and Cox proportional hazard method as a baseline model and five stroke prediction scoring systems including CHADS 2 , CHA 2 DS 2 -VASc, ATRIA, ESRS (Essen Stroke Risk Score), and FSS (Fukuoka stroke scale) were selected. Among the data, 25% was randomly held out and used only in model performance evaluation. The remaining 75% data was used in model construction with 10-fold cross validation scheme. To compare performance between models, prediction power and error were evaluated as concordance index and integrated brier score, respectively. Results: The highest concordance index was achieved with XGBoost for all-cause death (0.899, 95% CI, 0.893 -0.905) and MACE (0.843, 95% CI, 0.838 - 0.848) and with random survival forest for predicting major hemorrhage (0.789, 95% CI, 0.729 - 0.838) and any gastrointestinal hemorrhage (0.819, 95% CI, 0.767 - 0.861). For predicting recurrent stroke, all models showed very poor performances and Fukuoka stroke scale achieved the highest concordance index (0.580, 95% CI, 0.561 - 0.598). Machine learning models achieved the lowest prediction error in all outcome predictions among models. Conclusions: Machine learning model can be useful for predicting outcomes in AF-related stroke. However, the performance of all models was relatively low with regards to recurrent stroke. Further study is needed to validate this machine learning approach.