tbuckley/cabot-search huggingface dataset:
Abstract 9907: High-Power Short-Duration versus Standard-Power Standard-Duration Settings for Repeat Atrial Fibrillation Ablation
Authors: Joey Junarta, Sean Dikdan, Naman Upadhyay, Sairamya Bodempudi, Michael Y Yakobi, Daniel R Frisch
Journal: Circulation (2021)

Introduction: High-power short-duration (HPSD) ablation is a novel strategy using contact force-sensing catheters optimized for radiofrequency ablation for atrial fibrillation (AF). No study has directly compared HPSD versus standard-power standard-duration (SPSD) settings in patients presenting for repeat ablation with AF recurrence after initial ablation. Methods: We studied consecutive cases of patients with AF undergoing repeat ablation with SPSD or HPSD settings after their initial pulmonary vein isolation (PVI) with temperature controlled non-contact force, SPSD or HPSD settings between 6/23/14 to 3/4/20. Procedural data collected included radiofrequency ablation delivery time (RADT). Clinical data collected include sinus rhythm maintenance post-procedure. Results: A total of 61 patients were studied (36 SPSD, 25 HPSD). A total of 51 patients (83.6%) were found to have pulmonary vein reconnections necessitating repeat isolation, 10 patients (16.4%) had durable PVI and ablation targeted non-PV sources. RADT was shorter when comparing repeat ablation using HPSD compared to SPSD (22 vs 35 min; p=0.01). There was no difference in sinus rhythm maintenance by Kaplan-Meier survival analysis (log rank test p = 0.87), after 3 or 12-months between groups overall, and when stratified by AF type, left atrial volume index, CHA 2 DS 2 -VASc score, or left ventricular ejection fraction. Conclusion: We demonstrated that repeat AF ablation with HPSD reduced procedure times with similar sinus rhythm maintenance compared to SPSD in those presenting for repeat ablation.
Dual Targeting PAK4 and NAMPT As a Novel Therapeutic Approach for Aggressive Non-Hodgkin's Lymphoma
Authors: Suresh Kumar Balasubramanian, Husain Khan, Md. Hafiz Uddin, Amro Aboukameel, Yiwei Li, Jeffrey A. Zonder, William T. Senapedis, Erkan Baloglu, Ramzi Mohammad, Jatin J. Shah, Yosef Landesman, Sharon Shacham, Michael G. Kauffman, Asfar Sohail Azmi
Journal: Blood (2021)
Abstract 9599: Rechommend: An Ecg-Based Machine-Learning Approach for Identifying Patients at High-Risk of Undiagnosed Structural Heart Disease Detectable by Echocardiography
Authors: Alvaro Ulloa Cerna, Linyuan Jing, John Pfeifer, Sushravya Raghunath, Jeffrey Ruhl, Daniel Rocha, Joseph Leader, Noah Zimmerman, Steven R Steinhubl, Greg Lee, Christopher Good, Christopher M Haggerty, Brandon Fornwalt, Ruijun Chen
Journal: Circulation (2021)

Introduction: Timely diagnosis of structural heart disease improves patient outcomes, yet millions remain undiagnosed. ECG-based prediction models can help identify high-risk patients for targeted screening, but existing individual disease models often have low positive predictive values (PPV) and limited clinical utility. Hypothesis: An ECG-based composite model can predict one of multiple, actionable structural heart conditions and yield higher prevalence and PPVs than individual models. Methods: Using 2,141,366 ECGs linked to echocardiography and EHR records from 461,466 adults from 1984-2021, we trained machine learning models to predict any of 7 echocardiography-confirmed diseases within 1 year. This composite label included: moderate or severe valvular disease (aortic stenosis or regurgitation, mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction of &amp;lt;50%, or interventricular septal thickness &amp;gt;15mm. We tested various combinations of inputs and evaluated model performance with 1) cross-validation and 2) a simulated retrospective deployment. We measured area under the receiver operating characteristic curve (AUROC) and precision-recall curve (AUPRC), and PPV at 90% sensitivity. Results: Our composite "rECHOmmend" model using age, sex and ECG traces had an AUROC of 0.91, AUPRC of 0.78, and PPV of 52% at 90% sensitivity and 23% disease prevalence. Individual disease models had similar AUROCs (0.88-0.93), but lower AUPRCs (0.07-0.71) and PPVs (2%-41%; Figure). Across inputs, model AUROCs ranged from 0.85 to 0.93. Our simulated deployment model classified 22% of at-risk patients in 2010 as high-risk, of whom 40% developed true, echo-confirmed disease within 1 year. Conclusions: An ECG-based machine learning model using a composite endpoint can predict undiagnosed structural heart disease, outperforming single disease models with higher PPVs to facilitate targeted screening with echocardiography.
STEM-22. TARGETING REPLICATION STRESS RESPONSE FOR GLIOMA STEM CELL SPECIFIC CYTOTOXICITY
Authors: Emily Clough, Tracy Ballinger, Colin Semple, Karen Strathdee, ross carruthers
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Evidence suggests treatment resistant glioma stem cells (GSCs) drive glioblastoma (GBM) recurrence. Current treatments fail to eradicate GSC and novel GSC targeting therapies are a priority. GSC exhibit elevated DNA replication stress (RS) versus non GSC tumour cells driving constitutive DNA damage response (DDR) activation and efficient DNA repair. We previously demonstrated that targeting RS response with combined ATR and PARP inhibition (CAiPi) (VE821 and Olaparib) provides potent GSC specific cytotoxicity. In this study we investigated the underlying DDR phenotype which determines this vulnerability. RESULTS Paired GSC enriched (‘GSC’) and GSC depleted, differentiated (‘bulk’) populations were cultured from GBM specimens in neurobasal media with growth factors or serum containing media respectively. GSC exhibited reduced survival following exposure to CAiPi versus bulk. CAiPi significantly increased 53BP1 G1 phase nuclear bodies (53BP1NBs) in GSC, which are known to shield under-replicated DNA in actively transcribed genes. Mapping the genomic distribution of endogenously occurring replication dependent DNA double strand breaks via Breaks Ligation In Situ Sequencing (BLISS), revealed reduced intragenic DSB in long actively transcribed genes in GSC versus bulk at baseline, suggesting a reliance upon transcription coupled DSB repair in GSC. RNA seq demonstrated CAiPi-induced transcriptomic alterations in GSC including replication regulation and initiation. DNA fibre assay showed that CAiPi increased GSC new origin firing which correlated with PARP trapping. GSCs were rescued from CAiPi by roscovitine induced inhibition of excess origin firing. CAiPi is potently radiosensitizing by clonogenic assay and we demonstrated murine blood brain barrier penetration of CAiPi utilising VE822 and pamiparib in vivo. CONCLUSION Dysregulation of origin firing by CAiPi exposes a GSC specific vulnerability which results in DNA under-replication and abrogation of proficient DNA repair seen at long actively transcribed genes and has potential to be clinically translated as a GSC specific cytotoxic therapy.
Abstract 123: Study Of The Role Of Myosin-binding Protein C In The Structure-function Of Intact Cardiac Muscles Through The Use Of A Sarcomere Activation Biosensor
Authors: Ashley A Martin, Brian R Thompson, Joseph M Metzger
Journal: Circulation Research (2021)

Cardiomyopathies affect as many as 1 in 500 adults, with hypertrophic cardiomyopathy (HCM) being the most commonly inherited heart disease. Although there are various genetic mutations which cause HCM, 40-50% of mutations identified in patients with this disease are found in the cardiac myosin-binding protein C (MyBP-C) gene. Thus, understanding this protein's role in sarcomere activation is critical for the development of effective therapeutic strategies. Previous work has identified MyBP-C as a key modulator of the sarcomere through inter-myofilament signaling. Although these studies have provided valuable information on the function of MyBP-C protein, the bulk of this work has been done with either in vitro protein recombination or permeabilized muscle. Unfortunately, these systems lack significant physiological features of muscle, such as load and intact excitation-contraction coupling mechanisms. Therefore, a large gap exists in the ability to monitor muscle sarcomere activation in an intact system in real time. In order to further advance the study of sarcomere activation in HCM disease models, specifically those targeting MyBP-C, a cardiac specific myofilament-targeted FRET based biosensor has been designed and validated. This new sarcomere activation biosensor reports real-time myofilament dynamics during physiological twitch contractions in live cardiac muscle. This allows for the in vivo biophysical tracking of FRET-detected conformation changes in TnC, which reflect the ensemble of regulatory events which lead to sarcomere activation. Currently, the biosensor is being utilized to investigate changes in sarcomere activation in MyBP-C knockout mice. We find that intact cardiac muscle under load shows slowed isometric twitch relaxation kinetics in MyBP-C knockout mice versus controls. In concert with thin and thick filament modifying small molecules, this biosensor system will be used to investigate sarcomere-based mechanisms of intact cardiac muscle performance in health and disease.
Abstract 14111: Feasibility of Therapeutic Ultrasound Delivery for the Treatment of Mitral Stenosis
Authors: Patricia Rodriguez Lozano, Austin A Robinson, Andrew Thim, Feifei Zhao, Yanjun Xie, Tehan Dassanayaka, Paige Miller, Alexander L Klibanov, Christopher M Kramer, John A Hossack
Journal: Circulation (2021)

Introduction: Currently, the only disease-modifying therapy for degenerative mitral stenosis (DMS) due to mitral annular calcification (MAC) is open surgical valve repair or replacement, but it is technically challenging, and patients with DMS are often at elevated risk of surgical complications. As such, there is an unmet need for less-invasive strategies to treat DMS. Given the ability of shock-wave grade therapeutic ultrasound to disrupt calcifications, we set out to determine whether therapeutic ultrasound may be a possible treatment strategy for DMS. Hypothesis: This study aimed to evaluate whether ex vivo histotripsy can produce internal disruption of calcified nodules in the mitral annulus, a precursor to improving valve function in DMS. Methods: All experiments were performed on a formalin-fixed human cadaveric heart with severe MAC (Figure 1 A). Histotripsy cavitation was directed at calcified nodules utilizing a sonic concepts HIFUPlex Focused 128 element,1.1MHz array therapy transducer (Figure 1 E). B-mode ultrasound imaging was used to guide therapy. Transducer settings were PRF: 60 Hz, Duty cycle: 8x10^-4, transmit frequency: 1.1 MHz, HIFU Voltage: 60 V, resulting in an estimated pressure output of 34.6 MPa_pk. Results: A total of three histotripsy experiments were performed on the primary dominant calcium nodule. Visual assessment of treatment X-ray microtomography (Micro-CT) revealed qualitative fracturing of the calcified nodule from baseline (Figure 1 B), after the first treatment (Figure 1 C), and after three treatments (Figure 1 D). Gross visual inspection and Micro-CT demonstrated no changes to the surrounding fibrous annulus. Conclusions: In a feasibility study involving a fixed cadaveric heart, histotripsy therapeutic ultrasound demonstrated the potential to internally disrupt a MAC nodule without injuring the mitral annulus. Further studies are needed to address the ability of histotripsy to improve valve function in DMS.
Abstract P354: Circulating Interleukin 17 A In Patients With Acute And Chronic Coronary Syndrome
Authors: Dinaldo C Oliveira, Edivaldo Mendes Filho, Mariana Barros, Carolina Oliveira, Joao Vitor Cabral, Esmeralci Ferreira
Journal: Circulation Research (2021)

Introduction: Interleukin L-17 is produced by Th 17 cells and other cells. There is a debate if IL 17 is atherogenic or atheroprotective. The true role of this interleukin during the development and progression of the coronary artery disease is not known. Objective: To evaluate if there are differences between the IL17 A serum levels according to clinical presentation of the coronary artery disease. Methods: This is a cross sectional study which enrolled 101 patients with acute coronary syndrome (ACS), 100 patients with chronic coronary syndrome (CCS) and 100 healthy volunteers. Blood samples were taken from patients ( at admission) and controls to analysis the level of IL17A. Clinical characteristics were collected through questionnaires. This research was approved by ethical committee. Results: Comparisons of the clinical characteristics between patients with ACS and CCS revealed: mean age ( 62 ± 12.4 vs 63.3 ± 9.8, p = 0.4 ), male (63.4% vs 58%, p = 0.4) hypertension (85.1% vs 79%, p = 0.1) , disyipidemia (48% vs 31%, p =0.01), Diabetes Mellitus (47.5% vs 41%, p = 0.3), previous myocardial infarction (57.4% vs 40%, p = 0,01), smoking (29.7% vs 38%, p = 1). The peripheral concentrations of IL17A according to ACS, CCS and controls were: 5.36 ± 8.83 vs 6.69 ± 17.92 vs 6.26 ± 11.13, p = 0.6. Besides, the comparison between ACS and CCS showed: 5.36 ± 8.83 vs 6.69 ± 17.92, p = 0.3. Conclusion: The main finding os this study was that the circulating IL 17 concentrations were similar in patients with ACS, CCS and healthy volunteers). Besides, there was no difference between patients with ACS and CCS. Therefore, our hypothesis is that in patients with ACS and CCS the circulating IL 17 A concentrations are low or undetectable.
TAMI-51. HORIZONTAL MITOCHONDRIAL TRANSFER FROM THE TUMOR MICROENVIRONMENT TO GLIOBLASTOMA INCREASES TUMORIGENICITY
Authors: Dionysios Watson, Defne Bayik, Justin Lathia
Journal: Neuro-Oncology (2021)

Abstract Communication between glioblastoma (GBM) and its microenvironment facilitates tumor growth and therapeutic resistance, and is facilitated through a variety of mechanisms. Organelle transfer between cells was recently observed, including mitochondria transfer from astrocytes to neurons after ischemic stroke. Given the dependence of GBM on microenvironmental interactions, we hypothesized that mitochondria transfer from tumor microenvironment to GBM cells could occur and affect metabolism and tumorigenicity. We interrogated this in vivo by establishing intracranial GBM tumors in mito::mKate2 mice (with trackable fluorescent mitochondria) using syngeneic GFP-expressing tumor cells (SB28 and GL261 models). We also cultured stromal cell types from mito::mKate2 mice with tumor cells, enabling sorting of tumor cells with and without exogenous mitochondria. Confocal microscopy revealed horizontal transfer of mKate2+ mitochondria from mouse cells to implanted GBM cells in vivo and was confirmed by flow cytometry where 20-40% of GBM cells acquired exogenous mitochondria. Transfer was negligible in wildtype mice transplanted with mito::mKate2 bone marrow cells, suggesting that brain-resident cells were the main donors. In vitro, astrocytes and microglia exhibited 5 to 10-fold higher mitochondrial transfer rate than bone-marrow derived macrophages. Seahorse metabolic profiling revealed that GBM cells with mKate2+ mitochondria had 40% lower respiratory reserve compared to cells without exogenous mitochondria. Median survival of mice implanted with SB28 that acquired mitochondria was significantly shorter and in vivo limiting dilution confirmed the frequency of tumor-initiating cells was 3-fold higher in SB28 cells with exogenous mitochondria. Our data indicate that horizontal mitochondrial transfer from brain-resident glia to mouse GBM tumors alters tumor cell metabolism and increases their tumorigenicity. Ongoing studies are assessing gene expression in GBM cells acquiring exogenous mitochondria; validating findings in human specimens; and screening for transfer inhibitor drugs. Horizontal mitochondrial transfer represents a foundational tumor microenvironment interaction contributing to glioblastoma plasticity, and is likely to inform next-generation treatment strategies.
CBIO-19. GENOME SHREDDING ENABLES CRISPR-MEDIATED GLIOBLASTOMA ONCOLYSIS
Authors: Christof Fellmann, I-Li Tan, Alexendar Perez, Rachel Lew, Karen Zhu, Mitchel Berger, Jennifer Doudna
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults 1. Despite multimodal treatment regimens including surgical resection, radio- and chemotherapy, the growth of residual tumor often results in therapy resistance and ultimately death. GBMs are highly diffuse and exhibit extensive intratumoral heterogeneity 2,3, confounding diagnostic efforts and presenting opportunities for therapy evasion. Therefore, innovative treatment paradigms that can efficiently eliminate GBM cells irrespective of their mutational and epigenetic profile are urgently needed. CRISPR technologies have revolutionized medicine by enabling targeted genome editing through RNA-guided introduction of DNA double-strand breaks 4,5. Here, we show that CRISPR-Cas9 mediated genome fragmentation through targeting of highly repetitive loci, termed “genome shredding”, enables rapid and robust elimination of GBM cells. We characterized genome shredding across mammalian and vertebrate cells, and identified optimal repetitive pan-vertebrate and species-specific loci. Genome shredding is equally effective in temozolomide (TMZ)-sensitive and -resistant GBM cells, and multi-cycle treatment regimens are feasible. Importantly, when deployed in intracerebral GBM xenografts through local delivery, CRISPR-Cas9 genome shredding efficiently eliminated all targeted cells. Together, genome shredding enables the rapid and efficient fragmentation of a target cell’s genome and subsequent DNA damage-induced cell death. This provides an innovative treatment paradigm that is independent of a tumor’s mutational and epigenetic profile and leverages CRISPR-Cas9 as a breakthrough therapeutic modality for GBM.
Abstract P491: Myosin-7 E848G Mutation Induces P53-associated Cell Death That Leads To Impaired Tissue Contractility In Patient-derived Induced Pluripotent Stem Cell Model Of Hypertrophic Cardiomyopathy
Authors: Alexander Loiben, Clayton Friedman, Wei-Ming Chen, Benjamin Chung, Kai-chun Yang
Journal: Circulation Research (2021)

Introduction: Familial hypertrophic cardiomyopathy (HCM), affecting 1 in 500 adults, is characterized by idiopathic thickening of the heart and occasional impaired systolic function. Mechanisms through which cardiac sarcomeric mutations manifest in HCM are poorly understood. Hypothesis: We previously identified a novel MYH7 E848G mutation associated with HCM. We hypothesize E848G induces cell death that results in impaired tissue contractility in a dose-dependent manner. Methods: We created MYH7 expressing CMs with WT/WT, E848G/WT, or E848G/E848G alleles by CRISPR/Cas9 gene-editing patient-specific induced pluripotent stem cells (hiPSCs). hiPSC-derived cardiomyocytes were metabolically purified and cocultured with stromal cells on PDMS posts to create 3D engineered heart tissues (EHTs) or cultured as a monolayer. Results: Day 65 monolayer E848G/E848G CMs had 48.5% effective cell number relative to WT/WT. p53 (2.80 ± .11-fold), p21 (7.24 ± .18-fold), and BAX (1.64 ± 0.14-fold) mRNA transcripts were upregulated in day 60 monolayer E848G/E848G relative to WT/WT. E848G/E848G EHTs (n = 12) exhibited lower maximum active twitch force (104.6 ± 18.2 μN) and smaller 2D projected area (5.31 ± 0.22 mm 2 ) at day 14 relative to WT/WT (n = 15; 238.0 ± 20.4 μN; 6.87 ± 0.26 mm 2 ). E848G/WT EHTs (n = 7) had intermediate twitch force (168.7 ± 12.2 μN) and 2D area (6.18 ± 0.36 mm 2 ). Conclusion: These results suggest the MYH7 E848G mutation induces p53-associated cell death that leads to reduced tissue contractility. Ongoing studies will elucidate the molecular mechanism through which E848G activates cell death pathways. Figure: Representative EHTs. L-R: WT/WT, E848G/WT, E848G/E848G.
Abstract 12119: Silencing of Notch Signaling Tempers the Occurrence of Arrhythmic Events in the Post-Infarcted Heart
Authors: Emanuele Pizzo, Daniel O Cervantes, Sudhir Jain, Jason Jacobson, Marcello Rota
Journal: Circulation (2021)

Notch1 receptor signaling is active during cardiac development and is upregulated in the adult myocardium following ischemic damage. We previously documented that Notch1 signaling modulates the electrical activity of myocytes, but whether activation of the Notch receptor system contributes to the functional properties of the injured heart remains to be clarified. In the current study, we assessed the consequences of silencing of Notch1 signaling on electrical activity and arrhythmogenic behavior of the mouse heart, in physiological condition and following myocardial infarction (MI). For this purpose, mice with cardiac-restricted, inducible deletion of Notch1 gene (conditional knock-out, cKO) and corresponding control (Ctrl) mice were studied at baseline and up to one month after permanent coronary artery ligation. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were comparable in both male and female naïve cKO and Ctrl mice. At ~2 and ~4 weeks after MI, chamber dilation occurred and ejection fraction was equally reduced in cKO and Ctrl animals. By electrocardiographic recordings in the conscious state over a period of 10 minutes, no arrhythmic events were observed in naïve Ctrl and cKO mice. In contrast, at one day after MI, a large fraction of Ctrl mice developed premature ventricular complexes (PVCs, 72%, n=18) and ventricular tachycardia (VT, 28%), but the fraction of cKO mice with PVCs was substantially reduced (31%, n=32) and VT was not observed. From 3-~30 days after MI, arrhythmic events occurred sporadically and no major differences were detected between the two groups of mice. Following euthanasia at 30 days after MI, infarcted hearts were perfused in a Langendorff system and monophasic action potential and pseudo-ECGs collected. Spontaneous VT were found in both Ctrl (18%, n=11) and cKO (7% n=14) hearts in sinus rhythm. Importantly, programmed electrical stimulation (S1-S2 protocol) induced PVCs and/or VT in 55% of Ctrl infarcted hearts (n=11), but only in 23% of cKO organs (n=13). Collectively, these findings support the possibility that Notch1 signaling modulates the electrical activity of the injured heart and its propensity to develop arrhythmias.