tbuckley/cabot-search huggingface dataset:
Abstract 11388: Multimorbidity Moderates Changes in Peak Oxygen Uptake in Cardiac Rehabilitation Patients
Authors: Audry Chacin Suarez, Jose R Medina-inojosa, Joshua Smith, Jenna L Taylor, Amanda R Bonikowske, Ray W Squires, Randal J Thomas, Thomas P Olson
Journal: Circulation (2021)

Introduction: Patients undergoing cardiac rehabilitation (CR) exhibit various degrees of illness severity and high prevalence of chronic conditions (CC). Cardiorespiratory fitness (CRF) is a key predictor of outcomes in patients with cardiovascular disease. Participation in CR is associated with increased CRF, reduced future cardiovascular events, and mortality. Peak oxygen uptake (VO 2 ) is the gold-standard method to evaluate CRF; however, the burden of multimorbidity and its impact on CRF improvement has not been extensively studied. Methods: We included 618 patients who were ≥ 18 years old and underwent cardiopulmonary exercise testing prior to and after CR at Mayo Clinic. Using the Rochester Epidemiology Project records- linkage system, we assessed the prevalence of 18 CC defined by the US Department of Health and Human Services. To evaluate changes in peak VO 2 in patients with multimorbidity (categorized as ≥6 CC), we created logistic regression models adjusting for age, sex, and baseline peak VO 2 . Results: Mean age was 61.5 ± 11.0 years and 75.5% were male. Most patients (81.2%) attended ≥18 CR sessions. Half (50.4%) of patients had at least 6 CC (median 6; range 0-13). Overall, peak VO 2 at baseline was 20.7 ± 6.3 mL/kg per min and the percent change in peak VO 2 following CR was 11.4% ± 21.6%, Figure 1A . Multimorbidity was associated with lower improvement in peak VO 2 following CR compared to patients with &lt;6 CC (7.5% vs 11.4%, p=0.0001). Furthermore, across categories of CRF improvement (i.e., 1%, 5%, and 10% percent change in peak VO 2 ) lower multimorbidity was associated with a 1.5-2-fold increase in CRF when compared to those with higher multimorbidity (≥6 CC), Figure 1B . Conclusions: Patients entering CR have a high multimorbidity burden. Our results suggest that multimorbidity in CR patients attenuates improvement in peak VO 2 . Individualized interventions should focus on managing and reducing multimorbidity to minimize the negative impact on CRF improvement.
ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma
Authors: Víctor A. Arrieta, Andrew X. Chen, J. Robert Kane, Seong Jae Kang, Cynthia Kassab, Crismita Dmello, Junfei Zhao, Kirsten B. Burdett, Pavan S. Upadhyayula, Catalina Lee-Chang, Joseph Shilati, Dinesh Jaishankar, Li Chen, Andrew Gould, Daniel Zhang, Jinzhou Yuan, Wenting Zhao, Xiaoyang Ling, Jared K. Burks, Brice Laffleur, Christina Amidei, Jeffrey N. Bruce, Rimas V. Lukas, Jonathan T. Yamaguchi, David Cieremans, Gerson Rothschild, Uttiya Basu, Matthew McCord, Daniel J. Brat, Hui Zhang, Lee A. D. Cooper, Bin Zhang, Peter Sims, Tim F. Cloughesy, Robert Prins, Peter Canoll, Roger Stupp, Amy B. Heimberger, Craig Horbinski, Fabio M. Iwamoto, Raul Rabadan, Adam M. Sonabend
Journal: Nature Cancer (2021)
Abstract 11773: Impact of Race on Incident Atrial Fibrillation in a Large Cohort With Cardiac Implantable Electronic Devices
Authors: Jack A Goergen, Nathan Varberg, Tanvi Nayak, Paul D Ziegler, Dana Soderlund, Rod S Passman
Journal: Circulation (2021)

Introduction: Prior studies showed lower rates of atrial fibrillation (AF) in African Americans (AA) compared to Caucasians (CC) despite a higher prevalence of AF risk factors. These studies often relied on a clinical diagnosis of AF or limited analyses to Medicare beneficiaries which may bias the results. Our objective is to compare AF-free survival in AA vs CC patients with dual chamber cardiac implantable electronic devices (CIEDs) capable of continuous AF monitoring. Hypothesis: There is no significant difference in incident AF between AA and CC patients with dual chamber CIEDs. Methods: Using the Optum® de-identified Electronic Health Record dataset (01/2007 to 06/2019) linked with the Medtronic CareLink® device database, we identified self-described AA and CC patients with dual chamber CIEDs and no prior AF history. The primary endpoint was time to first AF ≥ 6 minutes. Cox proportional hazards models were used to examine the association between race and AF while adjusting for age, sex, and vascular risk factors in the pacemaker and ICD cohorts. Results: Of the 110,323 patients analyzed, mean age was 69±13 years, 64% were male, 8.9% were AA, and 39% had a pacemaker. CC were older (69.5 vs 63.4 years) and more were male (65% vs 54%). Heart failure, hypertension and diabetes were more common in AA (36% vs 22%; 60% vs 47%; 32% vs 22%, respectively). Over a mean follow-up of 2.3±1.8 years, unadjusted AF-free survival was higher in AA compared to CC in both CIED cohorts (p&lt;0.0001). After adjusting for age, sex and vascular risk factors, CC with pacemakers had a higher risk of incident AF (HR 1.10; 95% CI 1.03-1.17) but a lower risk was observed in CC with ICDs (HR 0.91; 95% CI 0.87-0.94) (Figure 1). Conclusions: In contrast to previous studies, this analysis of 110,323 CIED patients showed that adjusted AF-free survival was higher in AAs with pacemakers but not ICDs. These results challenge our understanding of the interaction between race and incident AF.
Abstract 11516: Quantification of Regurgitation Through Dual Orifices: Pulsatile <i>in Vitro</i> Analysis with Echocardiography and MRI Assessment
Authors: Erik Wu, Jeesoo Lee, Oneil R Mason, Michael Markl, James D Thomas
Journal: Circulation (2021)

Introduction: Proximal Isovelocity Surface Area (PISA) measurement is widely accepted to quantify mitral regurgitant volume (RVol), but flow convergence (FC) zones are complicated with dual orifices, seen with mitral clipping. This study seeks to investigate how flow through one orifice affects PISA measurement across the other to better quantify RVol in dual orifice conditions. Methods: 3D-printed dual circular orifice models with varying relative areas were integrated into a pulsatile flow phantom simulating left heart flow. One orifice (A) was standardized at 19.6 mm 2 while the other (B) was 1X, 2X, and 3X the area of A in three models. Inter-orifice distance was 5 mm to emulate mitral clipping. Continuous wave doppler echocardiography measured peak velocity and velocity time integral. PISA was performed at four aliasing velocities normalized to peak velocity (V a /V peak ) (10%, 8%, 4%, 2%) to compute RVol with 2D phase contrast MRI as reference. In each model, PISA RVol and percent error was calculated to see how varying the area of B impacts PISA accuracy of A. 4D flow MRI FC data was also collected to visualize the 3D formation of FC zones. Results: Using a high V a /V peak to create distinct FC zones provides a better RVol estimation with PISA, as low V a /V peak will merge the FC zones, overestimating flow across individual orifices. Single factor analysis of variance (ANOVA) of percent error of A across the three models showed no significant difference at high V a /V peak (8%: p=0.80, 10%: p=0.23), but significant difference at low V a /V peak (2%: p=0.010, 4%: p=0.005). High V a /V peak FC zones of orifices are independent from each other; PISA can be measured with standard practices and added together for an accurate total RVol. At low V a /V peak , FC orifice zones overlap with overestimation error increasing with larger B area. This finding suggests that resolving two separate FC zones to minimize flow interference is important for accurate RVol estimate in a dual orifice setting.
Regulation of Heterochromatin Landscape in T-Cell Acute Lymphoblastic Leukemia
Authors: Yali Ding, Bing He, Jonathon Payne, Dhimant Desai, Arati Sharma, Daniel Bogush, Elanora Dovat, Joseph Schramm, Melanie Ehudin, Diwakar Bastihalli Tukaramrao, Chandrika Gowda, Sinisa Dovat
Journal: Blood (2021)
Abstract 10614: An Automated View Identification Model for Pediatric Echocardiography Using Artificial Intelligence
Authors: Addison Gearhart, Shinichi Goto, Andrew J Powell, Rahul C Deo
Journal: Circulation (2021)

Introduction: A fully automated artificial intelligence driven pipeline to perform cardiac structural and functional measurements and disease detection requires accurate identification of individual echocardiographic views. However, there are no view classification algorithms for pediatric echocardiograms where there is a broader range in body size, anatomy, view types, and sweep length than in adult studies. Hypothesis: To develop and test a machine learning model to automatically perform view classification on individual pediatric echocardiogram images. Methods: Using a derivation dataset of 12,067 echocardiogram cine and still images from patients 0 to 19 years of age, a convolutional neural network (CNN) model was trained and evaluated for the automated identification of 28 pre-selected standard pediatric echocardiogram views that included anatomic sweeps, color Doppler, and Doppler tracings. The model was validated using an additional 6,197 images and trained for 150 epochs. Classification accuracy was evaluated using a test dataset composed of 9,684 images obtained from 100 different patients equally distributed across the age range. The model was subsequently deployed on studies of 524 children with leukemia to identify 6 pre-selected views pertinent to left ventricular function. Results: The model identified the 28 preselected views with 90% accuracy. Accuracy was comparable across age groups (89% for 0-4 yr, 91% for 4-9 yr, 90% for 9-14 yr, and 91% for 14-19 yr). Accuracy was 91% for the sweeps with color Doppler, 83% for sweeps without color Doppler, and 91% for Doppler tracings. Among the leukemia cohort, the model identified the 6 preselected views on a per study basis with a positive predictive value of 99% and an accuracy of 81-97%. A second pass of the model with a threshold prioritizing sensitivity achieved 100% detection of the missing views. Conclusions: We constructed a CNN model for view classification of pediatric echocardiograms that was accurate across the age spectrum and for cine images, anatomic sweeps, color Doppler images, and Doppler traces. This model lays the groundwork for automated quantitative analysis and diagnostic support to promote more efficient, accurate, and scalable analysis of pediatric echocardiograms.
Abstract P347: Transcriptional Features Of Biological Age Maintained In Cultured Cardiac Interstitial Cells
Authors: Oscar E Echeagaray, Taeyong Kim, Alex Casillas, Megan M Monsanto, Mark A Sussman
Journal: Circulation Research (2021)

Introduction: Ex vivo expansion of cells is necessary in regenerative medicine to generate large populations for therapeutic use. Adaptation to culture conditions prompt an increase in transcriptome diversity and decreased population heterogeneity in cKit+ cardiac interstitial cells (cCICs). The “transcriptional memory” influenced by cellular origin remains unexplored and is likely to differ between neonatal versus senescent input cells undergoing culture expansion. Approach: cCICs isolated from neonatal and adult cardiac tissue (Left Ventricular Assist Device; LVAD). Single cell libraries from in vitro expanded cells were prepared following five passages as previously demonstrated by our group to promote transcriptional homogeneity. “Transcriptional memory” was surveyed via bioinformatic analysis including unsupervised clustering, differential expression analysis, gene ontology and pathway analysis. Transitional states were assessed through pseudotime analysis. Results: Cell cycle imprint associated with biological age after culture was observed in Neonatal cCICs via upregulation of G2M genes. LVAD derived cCICs retained a widespread senescent profile, in particular high expression of interleukins and elements of the senescence associated secretory phenotype (SASP). Nuclear pore complex TPR and UBC9 and translation initiation factors, displayed age-associated downregulation of elements in the RNA transport and processing pathway. Pathway and co-expression analysis of fibroblast markers Ddr2, Tcf21, Vimentin, Periostin and Collagen deposition markers indicated a primed fibrotic phenotype in senescent cells. A small subset of cCICs exist in a transcriptional continuum between “youthful” phenotype and the damaged microenvironment of adult tissue in which they were embedded. Conclusion: The influence of age, pathology and the cellular stress associated to the in vivo tissue microenvironment persist after culture adaptation, influencing targets of 1) cell cycle, 2) senescence associated secretory phenotype (SASP), 3) RNA transport, and 4) ECM-receptor/fibrosis. The connate transcriptional phenotypes offer fundamental biological insight and highlights cellular input as a consideration in culture expansion and adoptive transfer protocols.
Abstract 13094: Pharmacokinetics and Therapeutic Efficacy of Drpitor1a, a Novel Dynamin-Related Protein 1 Inhibitor, in a Preclinical Model of Pulmonary Arterial Hypertension
Authors: Danchen Wu, Ross D Jansen-van Vuuren, Asish Das Gupta, Kuang-Huieh Chen, Ruaa Al-qazazi, Jeffrey D Mewburn, Patricia D Lima, Oliver Jones, Yuan Yuan Zhao, Gopinath Sutendra, Michael Wells, Stephen L Archer
Journal: Circulation (2021)

Introduction: Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission contributes to the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the pharmacokinetic characteristics of Drpitor1a, a novel, small molecule, ellipticine Drp1 inhibitor (prepared in-house), and tested its therapeutic efficacy in a pilot study using the rat monocrotaline (MCT)-PAH model. Methods: A single dose of Drpitor1a (5mg/kg) was administered IV or PO to male and female rats (n=3/sex). Blood was collected at 0, 5 and 30 minutes, and at 1, 2, 4, 6, 8 and 24 hours post drug administration. Plasma, lung and right ventricle (RV) were collected and tissue concentration of Drpitor1a was measured using HPLC coupled with mass spectrometry. The effects of Drpitor1a on mitochondrial fission and cell proliferation were assessed in human PAH pulmonary artery smooth muscle cells (PASMC). In an MCT-PAH model, a catheter was implanted in the left jugular vein on day 14 post-MCT injection. Drpitor1a (1mg/kg) was administered by IV every 48 hours from day 17 to day 27. On day 28, RV function and pulmonary hemodynamics were assessed. Results: Drpitor1a’s half-life varies by sex (9.9±5.3 hours and 24.3±21.4 hours in male and female rats respectively). Oral bioavailability of Drpitor1a was similar in males (21.1%) and females (19.7%). Lung concentration of Drpitor1a was similar between males and females (0.441±0.015 nM/mg and 0.444±0.581 nM/mg, respectively). In the RV, Drpitor1a level was higher in females (0.102±0.053 nM/mg) than males (0.055±0.015 nM/mg). Drpitor1a inhibited mitochondrial fission and cell proliferation in human PAH PASMC. In addition, Drpitor1a regressed pulmonary artery medial thickening (25.5% vs 34.9%), inhibited RV hypertrophy (Fulton index: 0.33 vs 0.39) and improved RV function (TAPSE: 2.2mm vs 1.8mm) in female MCT-PAH rats. Conclusion: Drpitor1a is a potential therapeutic agent for preclinical PAH and may be more effective in females.
Abstract 10241: Single-Cell RNA-Sequencing Reveals Hyperacute NK Cell and Monocyte Cell States Correlating with Poor Neurological Outcomes After Cardiac Arrest
Authors: Tomoyoshi Tamura, Changde Cheng, Alexandra Weissman, Mayra Pinilla-Vera, Louis Merriam, Jack Varon, Sam Saliba, Peter Hou, Raghu Seethala, Patrick R Lawler, William M Oldham, Jiyoung Choi, Kohei Ikeda, Kei Hayashida, Yohannes Tesfaigzi, Katherine Berg, Erin Bohula, David Morrow, Rebecca Baron, Michael Donnino, Fumito Ichinose, Xiang Chen, Edy Kim
Journal: Circulation (2021)

Background: Lymphopenia and elevated cytokine levels suggest a role for the systemic immune response after cardiac arrest (CA). However, little is known about the phenotypes and interactions of immune cells after CA. This study aimed to investigate the immunological network after CA and identify cell states correlating with poor neurological outcomes. Methods: Peripheral mononuclear blood cells of 11 post-out-of-hospital CA patients and 3 healthy subjects were analyzed by single-cell RNA-sequencing (scRNA-seq), with validation by flow cytometry, bulk RNA-seq of sorted cell subsets, plasma levels of cytokines, and the murine model of CA. Good and poor neurological outcomes at hospital discharge were defined by Cerebral Performance Category 1-2 and 3-5, respectively. Results: The scRNA-seq analysis of 96,179 cells revealed 6 major cell lineages with several subclusters. At 6h post-CA, cells of patients with good outcomes co-clustered with healthy subjects, while patients with poor outcomes formed distinct transcriptomic clusters. This distinction was lost by 48h post-CA. At 6h post-CA, we identified pro-inflammatory and hypoxia-responsive Tim-3 + NK cell and Nectin-2 + monocyte cell states specific to poor outcomes. In a validation cohort of post-CA patients, Tim-3 + NK cells and Nectin-2 + monocyte cell states were validated by flow cytometry. Bulk RNA-seq analysis of these sorted cells reproduced the transcriptomic profile determined by scRNA-seq. Interactome analysis identified NK cell-monocyte axes in poor outcomes, including IFNG-IFNGR2. Measurement of plasma cytokine levels revealed increased IFNγ levels at 6h post-CA that were associated with poor outcomes, but both poor and good outcomes had similarIFNγ levels by 48h. A murine model of CA demonstrated that IFNγ drives poor outcomes and mortality after CA. Conclusions: In clinical CA, transcriptomic analysis at single-cell resolution revealed hyperacute cell states of NK cells and monocytes associated with poor neurological outcomes. These hyperacute cell states interact by IFNγ-IFNγR2 axis, which is pathogenic in the murine model of CA. The immunophenotypes that distinguish patients with poor or good neurological outcomes are present at 6h but are no longer detectable by 48h post-CA.
Plans for same day emergency care are stalling from lack of investment, leaders warn
Authors: Elisabeth Mahase
Journal: BMJ (2021)

An NHS England scheme to provide urgent care to patients without admitting them to hospital is stalling because of inappropriate use and a lack of investment, the Society for Acute Medicine (SAM) has warned.

NHS England announced in March 2019 that every major hospital would provide same day emergency care (SDEC)—also known as ambulatory emergency care—by the end of that year to prevent around half a million unnecessary overnight stays in 2020. But an audit by SAM has found the units are often being inappropriately used as overflow for admitted patients.1

The Society for Acute Medicine benchmarking audit (SAMBA) took place …
DDRE-29. EGFR INHIBITION DOWNREGULATES MGMT AND SENSITIZES GBM CELLS TO TMZ
Authors: Amyn Habib, Jann Sarkaria, Ke Gong, Gao Guo
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is a highly malignant type of adult brain tumor with a poor prognosis. Temozolomide (TMZ), a DNA alkylating agent, has been widely used as an effective first-line chemotherapeutic agent for the treatment of GBM patients. The efficacy of TMZ in GBM depends on the absence of the DNA repair protein MGMT which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression and increased responsiveness to TMZ. TMZ is less effective in MGMT unmethylated GBMs. We propose that EGFR inhibition downregulates MGMT and sensitizes glioma cells to TMZ and a combination of pretreatment with erlotinib followed by TMZ could be a useful therapeutic approach in MGMT expressing GBMs. As our experimental model, we used multiple MGMT unmethylated lines from the Mayo Clinic patient derived xenografts (PDXs) panel. Our data demonstrate that exposure of cells to erlotinib for 48h results in downregulation of MGMT at the mRNA and protein level. Additionally, EGFR inhibition activates the AP-1 transcription factor, and overexpression of AP-1 components Fos and Jun results in decreased MGMT expression in TMZ resistant PDXs, suggesting that AP-1 acts as a transcriptional repressor of MGMT. We further identified that the mice implanted with TMZ resistant PDXs pretreated with afatinib followed by TMZ treatment survived longer compared to those treated with TMZ alone. Thus, the use of EGFR inhibition may enhance the sensitivity of MGMT unmethylated GBMs to TMZ.
IMMU-45. COMBINATION OF EGFRVIII CAR T-CELL THERAPY AND PARACRINE GAM MODULATION FOR THE TREATMENT OF GBM
Authors: Tomás A Martins, Marie-Françoise Ritz, Tala Shekarian, Philip Schmassmann, Deniz Kaymak, Valentina Bicvic, Gregor Hutter
Journal: Neuro-Oncology (2021)

Abstract The GBM immune tumor microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). We have previously shown that blockade of CD47, a ‘don't eat me’-signal overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, monotherapy with CD47 blockade has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local CAR T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. We generated humanized EGFRvIII CAR T-cells by lentiviral transduction of healthy donor human T-cells and engineered them to constitutively release a soluble SIRPγ-related protein (SGRP) with high affinity towards CD47. Tumor viability and CAR T-cell proliferation were assessed by timelapse imaging analysis in co-cultures with endogenous EGFRvIII-expressing BS153 cells. Tumor-induced CAR T-cell activation and degranulation were confirmed by flow cytometry. CAR T-cell secretomes were analyzed by liquid chromatography-mass spectrometry. Immunocompromised mice were orthotopically implanted with EGFRvIII+ BS153 cells and treated intratumorally with a single CAR T-cell injection. EGFRvIII and EGFRvIII-SGRP CAR T-cells killed tumor cells in a dose-dependent manner (72h-timepoint; complete cytotoxicity at effector-target ratio 1:1) compared to CD19 controls. CAR T-cells proliferated and specifically co-expressed CD25 and CD107a in the presence of tumor antigen (24h-timepoint; EGFRvIII: 59.3±3.00%, EGFRvIII-SGRP: 52.6±1.42%, CD19: 0.1±0.07%). Differential expression analysis of CAR T-cell secretomes identified SGRP from EGFRvIII-SGRP CAR T-cell supernatants (-Log10qValue/Log2fold-change= 3.84/6.15). Consistent with studies of systemic EGFRvIII CAR T-cell therapy, our data suggest that intratumoral EGFRvIII CAR T-cells were insufficient to eliminate BS153 tumors with homogeneous EGFRvIII expression in mice (Overall survival; EGFRvIII-treated: 20%, CD19-treated: 0%, n= 5 per group). Our current work focuses on the functional characterization of SGRP binding, SGRP-mediated phagocytosis, and on the development of a translational preclinical model of heterogeneous EGFRvIII expression to investigate an additive effect of CAR T-cell therapy and GAM modulation.
Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells
Authors: Yannan Jia, Qi Zhang, Weiguo Zhang, Michael Andreeff, Nitin Jain, Peiyi Zhang, Guangrong Zheng, Daohong Zhou, Marina Konopleva
Journal: Blood (2021)