tbuckley/cabot-search huggingface dataset:
Abstract P328: Regulation Of Monocyte Physiology By Il-4 Stimulated Memory Cd8+ T-cells
Authors: Philip Broughton, Yusra Zaidi, Miguel Troncoso, Kristine Y DeLeon-Pennell
Journal: Circulation Research (2021)

Following a myocardial infarction (MI) monocytes and T-cells begin to infiltrate into the ischemic area in effort to remove necrotic debris and initiate formation of scar tissue. Interleukin (IL)-4 has been linked to improved cardiac wound healing via alterations in both the macrophage and T-cell populations. The goal of this study was determine if proteins secreted by IL-4 stimulated CD8+ T-cells would regulate monocyte physiology that would ultimately improve cardiac healing after an MI. Isolated splenic naïve CD8+ T-cells from day 0 (no MI) mice (n=5/sex/stimulation)were cultured in RPMI with either 0.1% FBS (unstimulated) or 0.1% FBS+ IL-4. After 24 hours of stimulation, the cells and media were collected and separated by centrifugation. The cell pellet was stained and analyzed for markers of activation (CD44) and memory (CD27) by flowcytometry. Conditioned media (secretome) was collected for stimulation of bone marrow monocytes (n=4; females only). After stimulation with the secretome, monocytes were analyzed for viability, phagocytosis, and macrophage phenotype by flow cytometry. Migration of the monocytes after stimulation was also measured using electric cell-substrate impedance sensing (ECIS). After IL-4 stimulation, there was a shift from effector (CD44+ CD27-) to the memory phenotype (CD44+ CD27+; p&lt;0.05 vs unstimulated cells). Interestingly, bone marrow monocyte viability was decreased by 15% when stimulated with the secretome of IL-4 treated CD8+ T-cells compared to unstimulated CD8+ T-cells (0.1%). Phagocytosis was slightly elevated though not significant (p=0.07) in monocytes that were stimulated with the secretome from the IL-4 group compared to the unstimulated CD8+ T-cells. No differences were found in expression of macrophage markers F4/80 (p=0.532) or M1 marker CD86 (p=0.471). The secretome of IL-4 stimulated T-cells increased monocyte migration after wounding similar to levels of the positive control (monocytes in 10% FBS only). The data collected showed that IL-4 stimulated CD8+ T-cells were able to upregulate memory marker CD27. These memory-like CD8+ T-cells initiated monocyte phagocytosis and migration but decreased monocyte viability suggesting that they may play a role in regulating macrophage biology post-MI.
Abstract P381: <i>Ecklonia Stolonifera</i> Okamura Extract Suppresses Hypertrophic Responses In Cardiomyocytes And Development Of Heart Failure By Inhibiting P300-HAT Activity
Authors: Takahiro Katagiri, Yoichi Sunagawa, Masafumi Funamoto, Yasufumi Katanasaka, Yusuke Miyazaki, Kana Shimizu, Satoshi Shimizu, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation Research (2021)

Introduction: Heart failure is the leading cause of death in the world. Cardiomyocyte hypertrophy is observed during the development of heart failure, suggesting that its inhibition is a potential target for the prevention and treatment of heart failure. In this study, we screened a natural compound library using cultured cardiomyocytes and found that Ecklonia stolonifera Okamura extract (ESE) suppressed cardiomyocyte hypertrophy. ESE, a perennial brown alga, has been reported to have various bioactive effects, such as antioxidant and anti-inflammatory activity, but its effect on heart failure is still unclear. Therefore, we investigated whether ESE has an inhibitory effect on cardiomyocyte hypertrophic response and on the progression of heart failure in post-myocardial infarction (MI) rats. Methods and Results: First, primary cultured cardiomyocytes from neonatal rats were treated with ESE and then stimulated with phenylephrine (PE) for 48 hours. ESE (1000 μg/mL) significantly suppressed PE-induced increases in cardiomyocyte surface area, hypertrophic response gene transcription, and acetylation of histone H3K9. An in vitro p300-HAT assay indicated that ESE directly inhibited p300-HAT activity (IC50: 505 μg/mL). Next, one week after the ligation of the left anterior descending artery, rats with moderate MI (left ventricular fractioning shorting (LVFS) &lt;40%) were randomly assigned to three groups: vehicle (saline) (n=9), ESE (0.3 g/kg) (n=10), or ESE (1 g/kg) (n=10). Daily oral administration was repeated for 8 weeks. After treatment, LVFS was significantly higher in the ESE (1 g/kg) group (23.3 ± 0.7%, p&lt;0.05) than in the vehicle group (16.6 ± 1.3%). Next, the hearts were isolated and histological analysis, evaluation of gene transcription, and measurement of histone H3K9 acetylation. were performed. ESE treatment significantly suppressed MI-induced increases both in myocardial cell diameter and in the mRNA levels of hypertrophic response genes. ESE also inhibited MI-induced perivascular fibrosis and the acetylation of histone H3K9. Conclusion: These results suggest that ESE suppresses both hypertrophic responses in cardiomyocytes and the development of heart failure by inhibiting p300-HAT activity. Further studies are needed to clarify the effectiveness of ESE for heart failure therapy.
Association of Maternal Sexually Transmitted Infections With Risk of Preterm Birth in the United States
Authors: Rui Gao, Buyun Liu, Wenhan Yang, Yuxiao Wu, Bo Wang, Mark K. Santillan, Kelli Ryckman, Donna A. Santillan, Wei Bao
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Maternal infection has been implicated in the pathogenesis of preterm birth through intrauterine inflammatory response. Chlamydia, gonorrhea, and syphilis are among the most common sexually transmitted infections worldwide, but studies on their association with preterm birth are sparse. <h3>Objective</h3> To examine the association between maternal chlamydia, gonorrhea, and syphilis infections in pregnancy and the risk of preterm birth in a large population-based study in the US. <h3>Design, Setting, and Participants</h3> This population-based retrospective cohort study examined nationwide birth certificate data from the US National Vital Statistics System between 2016 and 2019. All mothers who had a singleton live birth and available data on chlamydia, gonorrhea, or syphilis infection before or during pregnancy and gestational age at birth were included in analysis. <h3>Exposures</h3> Sexually transmitted infection (chlamydia, gonorrhea, or syphilis) occurring before or during pregnancy. <h3>Main Outcomes and Measures</h3> Preterm birth, defined as gestational age less than 37 weeks. <h3>Results</h3> This study included 14 373 023 mothers (mean [SD] age 29 [5.8] years; Hispanic, 3 435 333 [23.9%]; non-Hispanic Asian, 912 425 [6.3%]; non-Hispanic Black, 2 058 006 [14.3%]; and non-Hispanic White, 7 386 568 [51.4%]). Among the mothers, 267 260 (1.9%) had chlamydia, 43 147 (0.3%) had gonorrhea, and 16 321 (0.1%) had syphilis. Among the newborns, 1 146 800 (8.0%) were preterm births. The rate of preterm birth was 9.9%, 12.2%, and 13.3% among women with chlamydia, gonorrhea, and syphilis infection, respectively. After adjustment for sociodemographic and medical and/or health factors, the adjusted odds ratio of preterm birth was 1.03 (95% CI, 1.02-1.04) for chlamydia, 1.11 (95% CI, 1.08-1.15) for gonorrhea, 1.17 (95% CI, 1.11-1.22) for syphilis, and 1.06 (95% CI, 1.05-1.07) for any of these sexually transmitted infections comparing mothers with these conditions and those without. <h3>Conclusions and Relevance</h3> Maternal sexually transmitted infections (gonorrhea, syphilis, or chlamydia) were associated with an increased risk of preterm birth. Pregnant women with sexually transmitted infections before or during pregnancy might benefit from targeted prevention for preterm birth.
Abstract 12452: Prevalence and Prognostic Significance of Diastolic Dysfunction Among Hospitalized Patients Referred for Echocardiography
Authors: Mady S Moriel, Adi Butnaru, Ziv Dadon, Mohammad Karmi, Rivka Farkash, Marc W Klutstein, David Rosenmann, Zahi Khoury, Michael Glikson, Shmuel Gottlieb
Journal: Circulation (2021)

Introduction: Left ventricular diastolic dysfunction (LVDD) is frequent among elderly patients (pts) with cardiovascular risk factors and is related to heart failure. Purpose: To assess the prevalence and prognostic significance of LVDD among hospitalized pts referred for echocardiography. Methods: 3828 consecutive pts who underwent echocardiography, demonstrating normal/ preserved LV systolic function were included. LVDD grades I/II/II were defined according to 2016 ASE/EACVI recommendations. Mortality data were derived from the Israel National Population Registry. Results: The clinical characteristics and outcomes are shown in the table and figure. Independent predictors for all-cause mortality (Cox proportional hazards regression model) [HR, (95% CI)] were: Age, 1-year increment 1.07 (1.06-1.09); CHF 1.82 (1.35-2.46); moderate-severe AS/AR/MR 1.78 (1.37-2.32); Diabetes 1.74 (1.36-2.22); LVDD-II 1.75 (1.20-2.58); LVDD-III 2.55 (1.90-3.44); Hyperlipidemia 0.64 (0.50-0.81). Conclusions: LVDD grade II and more prominently grade III, were independent predictors of mortality among hospitalized pts with normal/preserved LV systolic function. It is conceivable that treatment targeting LVDD may improve pts outcomes.
Abstract 12397: Polygenic Risk Score and Deep Learning Using Chest Radiographs: Complementary Prediction of Incident Coronary Artery Disease
Authors: Kaavya Paruchuri, Vineet Raghu, Udo Hoffmann, Pradeep Natarajan, Michael T Lu
Journal: Circulation (2021)

Introduction: Individual genomic and phenotypic characteristics may improve cardiovascular risk prediction beyond traditional clinical risk factors such as age, sex, diabetes mellitus, hypertension, and hyperlipidemia. We assessed the prognostic value of a polygenic risk score (PRS) and a chest radiograph (CXR) based deep learning (DL) risk score to predict incident coronary artery disease (CAD). Methods: The Mass General Brigham (MGB) Biobank is a prospective cohort of adult patients within the MGB healthcare system. A 6.6M variant CAD PRS using externally derived weights and an externally derived deep learning model (CXR-Risk) predicting long term mortality from CXR images were calculated for individuals with array-derived genotypes and CXRs. International Classification of Disease code-based incident CAD outcomes were defined as the first event after CXR and assessed by Cox Proportional Hazards. Results: Of 7,237 patients without known CAD (mean age 63.4 [SD 8.0] years; 3,259 [45.0%] male), 585 (8.1%) developed incident CAD over median follow-up of 4.7 [IQR 2.7-7.2] years. Adjusted for traditional clinical risk factors (age, gender, diabetes mellitus, hypertension, hyperlipidemia) and the first five principal components of ancestry, both CAD PRS (HR 1.19 per SD, 95% CI 1.09-1.31, p&lt;0.001) and CXR-Risk (HR 1.27 per SD, 95% CI 1.15-1.39, p&lt;0.001) were independently associated with incident CAD. Incorporation of both improved incident CAD discrimination (c-statistic 0.67 vs 0.65, p&lt;0.01) beyond traditional cardiac risk factors alone. CXR-Risk addition significantly improved a model with both traditional cardiac risk factors and CAD PRS (c-statistic 0.67 vs 0.66, p = 0.02). Conclusions: Advanced genomic (CAD PRS) and phenotypic (DL based CXR-Risk) measures independently predict and jointly improve risk prognostication for incident CAD.
Abstract 12568: Angptl2 is Essential for Aortic Valve Development in Mice
Authors: Pauline Labbe, Victoria Munoz Goyette, Louis Villeneuve, Ines Desanlis, Azadeh Alikashani, constance delwarde, Nathalie Thorin-Trescases, Marie Kmita, Eric Thorin
Journal: Circulation (2021)

Introduction: Angiopoietin-like 2 (Angptl2) is a pro-inflammatory anti-apoptotic protein, secreted by senescent cells. Angptl2 also contributes to maintain tissue homeostasis, and we previously reported that adult Angptl2-knockdown (KD) mice exhibit spontaneous Aortic Valve (AoV) stenosis with thickened leaflets compared to wild-type (WT) littermates. It is unknown whether and how Angptl2 contributes to AoV development. Hypothesis: Angptl2 is expressed in the AoV at the embryonic stage and is essential for its development, by contributing to programmed apoptosis/senescence and proliferation occurring during organogenesis. Methods: Embryonic hearts aged 14.5 (E14.5) and 18 days (E18) of Angptl2 -KD and WT mice were dissected. Protein expression (immunofluorescence) and leaflets/hinges thickness of AoV (hematoxylin &amp; eosin) were quantified in histological sections. Data are mean±SEM of n embryos. Results: Compared to WT mice, in AoV leaflets from Angptl2 -KD mice at E14.5, we observed a decrease in apoptotic cells (determined by TUNEL;-47%, p&lt;0.05, n=4), mostly in Valve Interstitial Cells (VICs), a decreased number of Valve Endothelial Cells (VECs) expressing the senescence marker p21 (-48%, p&lt;0.05, n=4), together with a trend towards an increased cell proliferation (Ki67; +396%, p=0.13, n≥6). In turn, a premature thickening of both the leaflets (from 73±18 to 91±33μm, p&lt;0.05, n≥8) and the hinges (from 38±10 to 49±20μm, p&lt;0.01, n≥8) of the valves was measured in Angptl2 -KD mice at E18. Concomitantly, Angptl2 is dynamically expressed during AoV development in WT mice: at E14.5, Angptl2 is expressed in all cell types, suggesting that it could effectively contribute to regulate apoptosis/senescence in both VICs and VECs. At E18, Angptl2 expression in WT mice is restricted to VICs at the border of the leaflet, where the mechanical stress is high, a pattern also observed in adult WT mice. Conclusions: Knockdown of Angptl2 is deleterious to AoV development by disturbing the fine balance between embryonic cell apoptosis/senescence and proliferation, which is essential to adequate AoV maturation; this unbalance progresses to severe AoV stenosis in adult mice. Angptl2 -KD is a new mouse model of spontaneous AoV stenosis, a disease in high medical needs.
TAMI-12. CANCER-IMMUNE CELL INTERACTIONS DRIVE TRANSITIONS TO MESENCHYMAL-LIKE STATES IN GLIOBLASTOMA
Authors: Toshiro Hara, Rony Chanoch-Myers, Nathan Mathewson, Chad Myskiw, Lyla Atta, Lillian Bussema, Stephen Eichhorn, Alissa Greenwald, Gabriela Kinker, Christopher Rodman, L Nicolas Gonzalez Castro, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Xiaowei Zhuang, Jean Fan, Tony Hunter, Inder Verma, Kai Wucherpfennig, Aviv Regev, Mario Suva, Itay Tirosh
Journal: Neuro-Oncology (2021)

Abstract Communication between cancer cells and immune cells is a key determinant of the glioblastoma ecosystem and its response to therapies, but remains poorly understood. Here we leveraged single-cell RNA-sequencing (scRNA-seq) of human samples and mouse models, deconvolution analysis of bulk specimens from The Cancer Genome Atlas (TCGA) and functional approaches to dissect cellular states and cross-talk in glioblastoma. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived Oncostatin M (OSM) and its cognate receptor OSMR on glioblastoma cells. We show that MES-like glioblastoma states are associated with increased T cells cytotoxicity and potentially with better clinical response to immunotherapies. Overall, our work dissects the cellular interactions within the glioblastoma microenvironment, with potential implications for therapies.
INNV-32. ACCESS TO SPECIALTY RADIATION CARE FOR PATIENTS WITH RESECTABLE BRAIN TUMORS
Authors: Mehee Choi, Brian Martin, Joseph Zabramski, Lisa Misell, David Brachman
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Many patients with brain tumors face challenges with access to care. For rural patients, prolonged travel times may limit access to appropriate radiotherapy. Radiation centers (RCs) offering specialized brain radiotherapy, e.g., stereotactic radiosurgery (SRS), are geographically limited. Brain brachytherapy at the time of resection offers an option for such patients, but technical challenges have limited the adoption. To address the limitations of traditional brachytherapy, a device with Cs-131 seeds embedded in a bioresorbable collagen tile (GammaTile (GT), GT Medical Technologies, Tempe, AZ) was developed. The device is FDA-cleared for permanent implantation at the time of resection for all recurrent intracranial tumors and newly diagnosed malignant intracranial neoplasms. To investigate if wider availability of this treatment could possibly lower the geographic barrier to access to care, we mapped the US population against existing RCs with brain tumor expertise and neurosurgery centers (NSCs) performing craniotomies. METHODS We analyzed 2018 CMS claims data using CPT codes for single- and multi-fraction SRS to identify RCs with brain tumor treatment expertise and mapped these against the population. Using similar methodology, using CPT codes for craniotomies, we identified NSCs, as any facility performing craniotomies is potentially eligible to implant the device. RESULTS 135 RCs used CPT codes for SRS. 193-, 119-, 82-, and 52-million Americans lived &amp;gt;30-, &amp;gt;60-, &amp;gt;90-, and &amp;gt;120-minutes from one of these centers, respectively. 530 NSCs preform craniotomies, including ≥ 1 in every state, a 4-fold increase over the number of RCs offering SRS. CONCLUSIONS For many patients, substantial travel distances limit access to RCs with brain tumor treatment expertise. In contrast, the 530 craniotomy-performing NSCs have far greater geographic dispersion. The option of undergoing brain radiation with GT implantation at the time of brain tumor craniotomy brings treatment closer to millions, ensures compliance, and reduces additional travel for follow-up radiation treatment.
Abstract 13132: A Community Program to Prevent Cardiovascular Disease: The Ask About Aspirin Project
Authors: Russell V Luepker, Milton Eder, John R Finnegan, Jeremy R Vant Hof, Sue Duval
Journal: Circulation (2021)

Objectives: To test a statewide population and clinic education project to improve guideline-based (2009 USPSTF) appropriate use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD). Methods: Minnesota was the education target and the four adjacent Upper Midwest states were controls. The 2015-2020 Ask About Aspirin campaign used digital and traditional media to encourage eligible adults to ask their clinicians about aspirin use for CVD prevention. The clinical strategy included professional education and clinical support tools to improve aspirin candidacy identification and appropriate use indications.Three cross-sectional random telephone surveys of men age 45-79 and women age 55-79 (5,626 in MN, 2,716 controls) evaluated aspirin use. Results: The Ask About Aspirin website had over one million visits (Figure 1). Over 1000 clinicians were trained in 124 primary care clinics. The project resulted in small but non-significant changes in campaign awareness (5.3% to 4.7%) and discussions with clinicians (34.1% to 36.5%). After the release of new guidelines (2016) and several controversial aspirin trials (2018-20), the overall use of aspirin fell (41.3% to 34.2%) (Figure 2). Appropriate aspirin use also declined (50.3% to 38.9%) (Figure 2). These changes did not differ significantly from controls. Conclusions: A multiyear statewide campaign failed to increase guideline-based aspirin use for CVD prevention. Contextual factors including guideline change and public controversy over aspirin use likely influenced this finding.
Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells
Authors: Songbo Zhao, Chunhua Wang, Ping Lu, Yalin Lou, Huimin Liu, Ting Wang, Shanshan Yang, Ziyou Bao, Lin Han, Xiaohong Liang, Chunhong Ma, Lifen Gao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Chimeric antigen receptor (CAR) T cells have been successfully used in tumor immunotherapy due to their strong antitumor responses, especially in hematological malignancies such as B cell acute lymphoid leukemia. However, on-target off-tumor toxicity and poor persistence severely limit the clinical application of CAR-T cell therapy. Methods T-cell immunoglobulin mucin domain molecule 3 (TIM-3) was used to develop a second-generation 41BB CD19 CAR linked with a T3/28 chimera, in which truncated extracellular TIM-3 was fused with the CD28 transmembrane and cytoplasmic domains. The efficacy of T3/28 CAR-T cells was evaluated in vitro and in vivo. Results We demonstrated that the switch receptor T3/28 preserved the T CM phenotype, improved proliferative capacity, and reduced exhaustion of CAR-T cells, resulting in superior in vitro and in vivo antitumor activity in B lymphoma. Importantly, the switch receptor T3/28 substantially prolonged the persistence of CAR-T cells, and the interleukin-21/Stat3 axis probably contributed to the enhanced cytotoxicity of T3/28 CAR-T cells. Conclusion Overall, the T3/28 chimera significantly prolonged the persistence of CAR-T cells, and T3/28 CAR-T cells possessed potent antitumor activity in mice, shedding new light on potential improvements in adoptive T cell therapies.
COVID-19 Vaccine Makers Plan for Annual Boosters, but It’s Not Clear They’ll Be Needed
Authors: Rita Rubin
Journal: JAMA (2021)

Avishay Spitzer, MD; Yoel Angel, MD, MBA; Or Marudi, MSc; David Zeltser, MD, MHA; Esther Saiag, MD, MHA; Hanoch Goldshmidt, PhD, MBA; Ilana Goldiner, PhD, MHA; Moshe Stark, PhD; Ora Halutz, MSc; Ronni Gamzu, MD, PhD, MBA, LLB; Marina Slobodkin, MD; Nadav Amrami, MD; Eugene Feigin, MD; Meital Elbaz, MD; Moran Furman, MD; Yotam Bronstein, MD; Amanda Chikly, MD; Anna Eshkol, MD; Victoria Furer, MD; Talia Mayer, MD, MHA; Suzy Meijer, MD; Ariel Melloul, MD; Michal Mizrahi, MD; Michal Yakubovsky, MD; Dana Rosenberg, MD; Ari Safir, MD; Liron Spitzer, MD; Eyal Taleb, MD; Ori Elkayam, MD; Adi Silberman, MD; Tali Eviatar, MD; Ofir Elalouf, MD; Tal Levinson, MD; Katia Pozyuchenko, MSc; Ayelet Itzhaki-Alfia, PhD; Eli Sprecher, MD, PhD, MBA; Ronen Ben-Ami, MD; Oryan Henig, MD
Abstract 13335: Elevated Protease Inhibitor SERPINA3 is Associated With Increased Mortality and Improves Prognostic Stratification in a <i>de novo</i> or Worsened Heart Failure
Authors: Leen Delrue, Marc Vanderheyden, Monika Beles, Riet Dierckx, sofie verstreken, Ward Heggermont, Jozef Bartunek
Journal: Circulation (2021)

Introduction: Overexpression of serpin peptidase inhibitor, clade A member 3 (SERPINA3) has been associated with poor prognosis in cancer. Hypothesis: SERPINA3 in a de novo or worsened heart failure (HF) bears a prognostic information alone and in addition to established biomarkers NT-proBNP and ST2 or clinical risk factors. Methods: Circulating SERPINA3 levels were examined in HFpatients who died within 5 years (n=44) and compared with age- and hemodynamically matched survivors (n=39). Prognostic value of circulating SERPINA3 levels alone and in combination with ST2 and NT-proBNP was then analyzed in an independent cohort with a de novo or worsened HF (n=384). Results: Plasma SERPINA3 levels were significantly higher in HF non-survivors compared to survivors (334.7 ± 138.7 vs 228.2 ± 83.1 μg/mL, p&lt;0.01). In the spline curve analysis,SERPINA3 level of 316 μg/mL emerged as optimal cut-off value for mortality. In the validation cohort with a de novo or worsened HF (n=384), circulating SERPINA3 levels &gt;316 μg/mL were associated with increased all-cause mortality (HR (95% CI): 2.4 (1.5-3.9), p=0.0002) and its composite with unplanned cardiac admission (HR (95% CI): 2.0 (1.2-3.3), p=0.004). In a multivariate analysis, including established clinical risk factors and ST2 and NT-proBNP, SERPINA3 remained independent predictor of all-cause mortality together with age, ST2, glomerular filtration and pulmonary capillary wedge pressure. Conclusions: Elevated SERPINA3 appears to provide additional prognostic information in models incorporating clinical, hemodynamic and laboratory risk including ST2 and NT-proBNP by identifying a subgroup of heart failure patients at increased mortality risk.