tbuckley/cabot-search huggingface dataset:
Metformin reduces PD-L1 on tumor cells and enhances the anti-tumor immune response generated by vaccine immunotherapy
Authors: Luis Enrique Munoz, Lei Huang, Ramireddy Bommireddy, Richa Sharma, Lenore Monterroza, Rohini N. Guin, Sarah G. Samaranayake, Christopher D. Pack, Sampath Ramachandiran, Shaker J.C. Reddy, Mala Shanmugam, Periasamy Selvaraj
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background PD-L1 is one of the major immune checkpoints which limits the effectiveness of antitumor immunity. Blockade of PD-L1/PD-1 has been a major improvement in the treatment of certain cancers, however, the response rate to checkpoint blockade remains low suggesting a need for new therapies. Metformin has emerged as a potential new drug for the treatment of cancer due to its effects on PD-L1 expression, T cell responses, and the immunosuppressive environment within tumors. While the benefits of metformin in combination with checkpoint blockade have been reported in animal models, little remains known about its effect on other types of immunotherapy. Methods Vaccine immunotherapy and metformin were administered to mice inoculated with tumors to investigate the effect of metformin and TMV vaccine on tumor growth, metastasis, PD-L1 expression, immune cell infiltration, and CD8 T cell phenotype. The effect of metformin on IFN-γ induced PD-L1 expression in tumor cells was assessed by flow cytometry, western blot, and RT-qPCR. Results We observed that tumors that respond to metformin and vaccine immunotherapy combination show a reduction in surface PD-L1 expression compared with tumor models that do not respond to metformin. In vitro assays showed that the effect of metformin on tumor cell PD-L1 expression was mediated in part by AMP-activated protein kinase signaling. Vaccination results in increased T cell infiltration in all tumor models, and this was not further enhanced by metformin. However, we observed an increased number of CD8 T cells expressing PD-1, Ki-67, Tim-3, and CD62L as well as increased effector cytokine production after treatment with metformin and tumor membrane vesicle vaccine. Conclusions Our data suggest that metformin can synergize with vaccine immunotherapy to augment the antitumor response through tumor-intrinsic mechanisms and also alter the phenotype and function of CD8 T cells within the tumor, which could provide insights for its use in the clinic.
Abstract 11564: Epicardial Adipose Tissue Thickness as a Mortality Risk Marker in Covid-19
Authors: Douglas Salguero Lopez, Juliana Ferri-Guerra, Angel Porras, Jonathan Friedman, Marissa A Donatelle, Everett Rogers, Lee Seifer, Ruben Porudominsky, Francisco Ujueta, Ayoola Olayiwola, Viky Loescher, William F. Burke, Christos G. Mihos, Claudio Tuda
Journal: Circulation (2021)

Intro: Cardiac involvement in COVID-19 infection is common. Epicardial adipose tissue functions as an inflammatory depot, and a thickness (EAT-T) &gt;5mm is associated with increased cardiovascular risk. The present study assessed the significance of increased EAT-T in patients with COVID-19. Methods: A retrospective cohort study of 149 consecutive patients diagnosed with COVID-19 between March 2020 to January 2021 was performed. Inclusion criteria were lab-confirmed COVID-19 infection and having a Chest CT scan without contrast during hospitalization. EAT-T was measure in right ventricle free wall (Figure 1). Characteristic of patients and comparisons were analyzed by T-Test and Chi-square. Log-linear analysis and cumulative logistic regression was carried out to predict effect between EAT-T and mortality Results: The mean age was 67 ± 15 years, 65% were male, and time from onset of symptoms was 7 ± 5 days. Forty-seven (31.5%) patients required mechanical ventilation, and 34 (22.8%) required vasopressors. Medical therapy included convalescent plasma (36%), Remdesivir (28%), Tocilizumab (46%), Enoxaparin (64%), and Dexamethasone (39%). There were 36 (24.2%) in-hospital deaths, with a greater incidence amongst patients with an EAT-T &gt; 5 mm versus ≤ 5 mm (95 vs 5%, p=.001). Notably, age was not significantly different on patients with in-hospital mortality (69 vs 66 years, p=0.5), and higher EAT-T by 2.17 mm on patient with acute respiratory distress syndrome (p=.001) and 10.9 mm in myocardial infarction (p=.02). In multivariable analysis an EAT-T &gt;5mm was associated with an increased risk of mortality (OR 12.3, 95% CI 3-55, p=.001). In the presence of EAT-T &gt; 5 mm, no effect was observed by chronic kidney disease, hypertension, coronary artery disease, dyslipidemia, or body mass index (p &gt;0.5). Conclusions: In patients with COVID-19, an EAT-T &gt; 5 mm is associated with increased risk of in-hospital mortality and may provide important risk stratification.
Abstract 12238: Pressure Overload-Induced Impairment in Gut Wall Permeability Exacerbates Cardiac Dysfunction in IL10 KO Mice
Authors: Sumanta Goswami, Prabhat Ranjan, Dutta Roshan, Ram Prasad, qinkun zhang, Hind Lal, Suresh K Verma
Journal: Circulation (2021)

Introduction: Heart failure is the leading cause of morbidity and mortality in the USA. Recently, impaired intestinal permeability is known to augment cardiac dysfunction. Though the cardioprotective role of IL10 is well known, its role in reducing gut dysbiosis and maintaining intestinal permeability during hypertrophic heart failure is not known. Hypothesis: We hypothesized that IL10 maintains intestinal permeability and inhibits the release of gut microbial peptides (GMPs) which ultimately improves cardiac function. Methods: WT &amp; IL10KO mice were subjected to TAC or sham surgery. Heart and intestine were collected to evaluate inflammation genes expression, immune cell infiltration (flow cytometry), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify peptidoglycan (PGN) and other bacterial metabolites (TMAO) levels. The effect of PGN on mitochondrial functions was evaluated in neonatal cardiomyocytes. Results: Cardiac functions were significantly reduced in IL10KO mice following TAC. IL10 KO mice showed exacerbated inflammation (IL1β, IL6 and TNFα genes expression) following TAC. TAC induced leukocytes (monocyte/macrophage, T-cell and neutrophils) recruitments in the intestine in IL10KO mice. TAC mice showed gut dysbiosis (16S rRNA sequencing) in IL10KO mice. Further, IL10KO mice exhibited higher intestinal permeability as shown by increase in PV1 level and reduction in zonulin-1 (ZO-1) protein. Plasma PGN level was significantly increased in IL10KO mice following TAC. Pathway-based cardiotoxicity array showed a significant increase in uncoupler protein 2 (UCP2) and phospholamban (PLN; a calcium handling protein) gene expression in cardiomyocytes following PGN treatment. Finally, IL10 treatment restores PGN-induced decrease in mitochondrial membrane potential (TMRE assay) in cardiomyocytes. Conclusions: Taken together, data suggest that IL-10 helps to maintain gut wall permeability and reduced gut microbial peptide circulation to the heart and thus improves cardiac function by improving mitochondrial function. Ongoing investigations using molecular approaches will provide a better understanding of gut-heart signaling and its impact on the progress of heart failure.
Abstract 13792: Integration of Proteomic and Transcriptomic Signatures in the Failing Right Ventricle of Rats With Monocrotaline Induced Pulmonary Arterial Hypertension
Authors: Charles C Hindmarch, Lian Tian, Ping Y Xiong, Francois Potus, Rachel Bentley, Ruaa Al-qazazi, Kurt W Prins, Stephen L Archer
Journal: Circulation (2021)

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by cellular remodeling in the pulmonary circulation. Pulmonary vascular obstruction, stiffening and constriction elevate pulmonary artery pressure and right ventricular (RV) afterload leading to failure (RVF). In a model of PAH induced by injection of monocrotaline (MCT, 60mg/kg sc) RV decompensation was confirmed. Then the RV proteome was analyzed using Mass Spectrometry (LC-MSMS). Proteomics revealed 1,277 differentially regulated proteins. Integration of this proteome with our previously published transcriptomic study of RVs harvested from an independent group of rats with MCT-induced PAH revealed 410 common targets, 15 of which were both highly enriched at protein (corrected q -values &lt;0.05) and mRNA level (corrected p-adjust &lt;0.05 ). Most regulated pairs were increased in RVF, including: Atrial natriuretic peptide protein (7.55-fold, transcript = 4.19-fold), Thrombospondin-4 protein (5.56-fold, transcript = 4.4-fold), Periostin (protein = 3.83-fold, transcript = 4.56-fold), Latent transforming growth factor beta binding protein 2 (2.67-fold, transcript = 4.16-fold), Heme oxygenase 1 (4.59-fold, transcript = 2.05-fold), Transforming Growth Factor Beta-1-Induced Transcript 4 Protein (3.82-fold, transcript = 2.1-fold), Transmembrane glycoprotein NMB (3.21-fold, transcript = 2.35-fold), S100 calcium-binding protein A4 (2.43-fold, transcript = 1.93-fold), Collagen XVIII, alpha 1 (2.59-fold, transcript = 1.61-fold), Ankyrin repeat domain 2 (4.04-fold, transcript = 2.49-fold), Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase 1, (6.89-fold, transcript = 2.3-fold), Tenascin-C (5.18-fold, transcript = 2.53-fold). In contrast, ATPase Na+/K+ Transporting Subunit Alpha 2 3.47 (protein = 3.47-fold, transcript = 2.23-fold) and Glutathione S-Transferase Zeta 1 (protein = 1.97-fold, transcript = 2.38-fold) were downregulated in RVF. A functional analysis of this list of regulated protein/transcript pairs revealed enriched functions include mitochondrial metabolism, cellular respiration and purine metabolism. Our integrated multiomic approach is validated by independent datasets and provides a molecular context for RVF in MCT-induced PAH.
Abstract 10410: Human Stem Cell-Derived Endothelial Cells Suppress Automaticity of Stem Cell-Derived Cardiomyocytes
Authors: Jessica C Garbern, Qiang Li, Ren Liu, Estela Mancheno Juncosa, Zuwan Lin, Hannah L Elwell, Junya Aoyama, Sokol K Morgan, Jia Liu, Richard T Lee
Journal: Circulation (2021)

Clinical translation of stem cell therapies for heart disease is limited by a risk of potentially life-threatening ventricular arrhythmias seen following cardiomyocyte delivery in large animal models. Enhancing cardiomyocyte maturation may reduce this arrhythmogenic risk by reducing automaticity of delivered cardiomyocytes. We tested whether human induced pluripotent stem cell (hiPSC)-derived endothelial cells can enhance maturation and suppress automaticity of iPSC-derived cardiomyocytes in vitro. We found that co-culture of hiPSC-derived endothelial cells with hiPSC-derived cardiomyocytes significantly increased protein expression of cardiac troponin T, cardiac troponin I, Kir2.1, connexin 43, and CD36. In addition, using a stretchable mesh nanoelectronics device, we found that hiPSC-derived endothelial cells accelerated electrical maturation of hiPSC-derived cardiomyocytes and progressively suppressed cardiomyocyte automaticity in vitro (Figure). Using single cell RNA-seq, we identified a subpopulation of hiPSC-derived cardiomyocytes that is eliminated upon co-culture with hiPSC-derived endothelial cells. Further work will investigate whether this subpopulation of cardiomyocytes is responsible for automaticity of cardiomyocyte cultures. Figure. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes alone (CM only) or iPSC-derived cardiomyocytes co-cultured with iPSC-derived endothelial cells (CM+EC) were seeded onto a stretchable mesh nanoelectronics device. Unstimulated voltage tracings at day 30 of cardiomyocyte differentiation show cardiomyocytes with a slower beating rate and more narrow action potential when co-cultured with iPSC-derived endothelial cells compared to iPSC-derived cardiomyocytes alone.
Abstract 14247: Myocardial Histopathology In Atrial Cardiomyopathy
Authors: Ilkka Ruohonen, Antti Eranti, Sami Sinisilta, Veikko Lahtinen, Arto Relander, Sirpa Jalkanen, Juhani Airaksinen, Juho M Jalkanen, Jarmo Gunn, Maija Hollmen, Tuomas O Kiviniemi
Journal: Circulation (2021)

Background: Atrial cardiomyopathy (ACM) is characterized by multiple histopathological features but the entity lacks systematic validation. Objectives: We sought to correlate atrial histopathology with clinical characteristics of patients with ACM and AF and outcomes following cardiac surgery. Methods: The pathological findings of the atrial myocardial biopsies from 178 patients who underwent any cardiac surgery between 2016-2018. Atrial cell nuclear structure and morphology, myocyte hypertrophy and interstitial fibrosis were graded and analyzed quantitatively. Study population was divided in three groups based on preoperative ECG: 1) patients in sinus rhythm with no signs of ACM (P wave duration &lt;120ms)(SRn); 2) patients in sinus rhythm and ACM (P&gt;=120 or biphasic waves in inferior leads)(SRa); and 3) atrial fibrillation (AF). Results: SRa patients had decreased number of nuclei/area and smaller total cardiomyocyte area compared to SRn patients (p=0.04 forboth). Patients with AF had bigger, less solid and circular nuclei compared to SRn patients (p&lt;0.01 for all). AF patients had increased area of interstitial fibrosis (p&lt;0.01) compared to SRn patients. Conclusions: Histopathological characteristics of ACM include changes in nuclear chromatin structure.
CSIG-05. DISSOCIATION OF THE INTRAMOLECULARLY CLEAVED N- AND C-TERMINAL FRAGMENTS OF ADHESION G PROTEIN-COUPLED RECEPTOR GPR133 (ADGRD1) INCREASES ITS CANONICAL SIGNALING IN GLIOBLASTOMA
Authors: Joshua Frenster, Gabriele Stephan, Niklas Ravn-Boess, Devin Bready, Jordan Wilcox, Ines Liebscher, Torsten Schöneberg, Dimitris Placantonakis
Journal: Neuro-Oncology (2021)

Abstract We previously demonstrated that GPR133 (ADGRD1), an adhesion GPCR that signals via cytosolic cAMP increase, is de novo expressed in glioblastoma (GBM) and enriched in patient-derived glioblastoma stem cells. Knockdown of GPR133 reduces GBM cell proliferation and tumorsphere formation, and abolishes orthotopic xenograft initiation in vivo. GPR133’s requirement for GBM growth and its absence in non-malignant brain suggest its therapeutic potential, yet its mechanisms of action and activation remained unclear. Here, we demonstrate in patient-derived GBM cultures and HEK293T cells that GPR133 gets intramolecularly cleaved into N-terminal and C-terminal fragments (NTF and CTF) right after synthesis in the endoplasmic reticulum. The resulting NTF and CTF remain non-covalently bound to each other, until the mature receptor reaches the plasma membrane, where we observe dissociation of the extracellular NTF from the transmembrane-spanning CTF. While cleavage is not required for correct subcellular trafficking, the cleaved wild-type GPR133 generates significantly higher cytosolic cAMP levels than an uncleavable point mutant GPR133 (H543R), suggesting that cleavage and dissociation are involved in receptor activation. To test this hypothesis in a more controllable proxy system, we generated a fusion of the CTF of GPR133 and the N-terminus of human protease-activated receptor 1 (hPAR1). Indeed, acute thrombin-induced cleavage and shedding of the hPAR1 NTF increases intracellular cAMP levels generated by the GPR133 CTF. These results support a model wherein dissociation of the NTF from the CTF at the plasma membrane promotes GPR133 activation and downstream signaling. To test whether extracellular binding proteins could influence NTF shedding and/or GPR133 signaling activation, we conducted ligand discovery screens and indeed found a new GPR133 binding protein in GBM cells, which is capable of influencing receptor signaling. Together, these findings provide critical insights into GPR133’s mechanism of activation, that will guide future approaches of therapeutic targeting of GPR133 in GBM.
Abstract 14241: Cigarette Smoke Causes Atrial Fibrillation via PiP2 Signaling
Authors: Bojjibabu Chidipi, Mengmeng Chang, Obada Abu-Assail, Michelle Reiser, Zhi Tian, Diane Allen-Gipson, Sami F Noujaim
Journal: Circulation (2021)

Introduction: Cigarette smoking (CS) is a major cause of cardiovascular diseases. Smokers are at a significantly higher risk for developing atrial fibrillation (AF), a dangerous and abnormal heart rhythm. In the US, 15.5% of adults are current smokers, and it is becoming clear that CS is an independent risk factor for AF, but a detailed mechanistic understanding of how CS contributes to the molecular patho-electrophysiology of AF remains elusive. We investigated if CS related AF is in part mediated through a mechanism that depends on the cardiac acetylcholine activated inward rectifier potassium current (I KACh ). Hypothesis: We tested the hypothesis that CS stimulates phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K) signaling, leading to increased cellular phosphatidylinositol 4,5- bisphosphate (PiP2) levels, and subsequent I KACh activation and AF perpetuation. Methods: We used patch clamp in HEK293 cells expressing Kir3.1 and Kir3.4, the molecular correlates of IKACh, cultured in the presence of 5% CS extracts. In vivo inducibility of AF was assessed in mice exposed to CS for 8 weeks. Results: In HEK293 cells, 24 h incubation with CSE increased the cellular PiP2 levels, and increased I KACh . Addition of 5 uM ISA, an inhibitor of PIP5K, abrogated the CS effects on I KACh, indicating that CS activates PIP5K. Finally, intrajugular injection of tertiapinQ, an I KACh blocker, terminated atrial fibrillation in mice exposed to CS for 8 weeks. Conclusions: Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through I KACh activation by increasing the cellular levels of PiP2.
Abstract 10744: Efficacy of Remote Pulmonary Artery Hemodynamic Monitoring in Reducing Heart Failure Readmissions Among Patients with Obstructive Sleep Apnea of Varying Severity
Authors: Mansi Oberoi, Naveen Rajpurohit, Marian Petrasko, Adam Stys, Tom Stys, Deborah Vicinsky, Orvar Jonsson
Journal: Circulation (2021)

Introduction: Obstructive sleep apnea (OSA) and heart failure (HF) often co-exist. Remote pulmonary artery (PA) hemodynamic monitoring has shown to decrease HF readmissions. However, there is limited data regarding its efficacy in patients with OSA of varying severity. Hypothesis: Outcomes of remote PA hemodynamic monitoring using CardioMEMS device in reducing HF hospitalization in patients with mild [apnea-hypopnea index (AHI)=5-14], moderate (AHI=15-30) and severe OSA (AHI&gt;30). Methods: Retrospective data was collected for HF patients who had CardioMEMS device implanted based on FDA indications from April 2015 to August 2020. Number of hospitalizations, emergency department (ED) and HF clinic visits data was collected for 1-year pre and 1-year post-implantation. Mortality data was collected at 1-year post-implantation. Severity of OSA was based on AHI documented in the sleep study. Analysis was done using Kruskal-Wallis test for comparison between OSA groups. Mortality was compared with Pearson’s chi-squared test. Results: CardioMEMS device was implanted in 177 patients during the study period. Of this, 108(61%) patients had OSA diagnosed at the time of implantation. Among OSA patients, 52(48%) had severe OSA. There was a statistically significant decrease in overall mean HF admissions from 1.80(± 1.55) to 0.62(± 1.07), 65.6%, p&lt;0.001 and mean HF ED visits from 1.37(± 1.50) to 0.5(± 0.95), 63.5%, p&lt;0.001 in 1-year pre-and post-implantation among all OSA patients. When comparing different OSA groups, there was no statistically significant difference between them in all-cause admissions, HF admissions, ED visits, ED HF visits, and HF clinic visits 1-year pre and post-implantation. No statistically significant difference was observed in mortality. Conclusions: PA hemodynamic monitoring using CardioMEMS device had a net benefit in reducing HF admissions and HF ED visits in OSA patients and this benefit remained unchanged across different OSA groups.
Publisher Correction: Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab
Authors: Estefanía García-Guerrero, Ralph Götz, Sören Doose, Markus Sauer, Alfonso Rodríguez-Gil, Thomas Nerreter, K. Martin Kortüm, José A. Pérez-Simón, Hermann Einsele, Michael Hudecek, Sophia Danhof
Journal: Leukemia (2021)
Abstract 10625: A RE-AIM Evaluation of Lay Advisor Interventions to Improve Hypertension Outcomes - A Systematic Review
Authors: Sonal Patil, Vishwa Bhayani, Yilin Yoshida, Gwendolyn Wilson, Kurt Stange, Robert Saper
Journal: Circulation (2021)

Context: Lay advisor interventions improve hypertension outcomes, especially in vulnerable populations. However, the incremental benefit of adding these interventions, and factors that could inform their widespread implementation, are unknown. Objective: Inform real-world choices about implementation of lay advisor hypertension interventions. Methods: We systematically searched several databases, including Medline, CINAHL, SCOPUS, from January 1, 1980 to December 2020. We included all study designs of hypertension interventions delivered solely by a lay advisor. Search terms for lay advisors included peers, community health workers, barbers, and faith-based activists. Studies of lay advisor interventions combined with other health professional interventions were excluded. Two independent reviewers coded eligible articles using a validated data extraction tool based on the Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM) framework. Results: Of 5986 unique citations, 21 were eligible for inclusion. Most studies showed improvements in hypertension outcomes, but outcomes predominantly were measured shortly after intervention completion. Inclusion/exclusion criteria and lay advisor recruitment and training were usually well-described, and primary outcomes were reported. Participation rates were infrequently reported. None reported adverse outcomes. Only 14% (3 of 21) of studies reported qualitative assessments. External validity domains of adoption, implementation, and maintenance were rarely reported. In the adoption domain, no study reported comparisons of delivery and non-delivery settings or staff representativeness. Presence of previous lay advisor programs in the community improved adoption and implementation. One study mentioned costs of implementation for maintenance. Conclusion: Few studies have examined the incremental effectiveness of adding a lay advisor intervention for hypertension outcomes, most show improvement. Indicators of external validity of lay advisor interventions are not well-reported. Future research designs should improve reporting across RE-AIM dimensions, particularly indicators of external validity, including qualitative assessments.