tbuckley/cabot-search huggingface dataset:
Abstract MP239: Hippo Signaling Pathway Maintains Homeostasis Of The Cardiac Conduction System
Authors: Mingjie Zheng, Jun Wang
Journal: Circulation Research (2021)

The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. The fundamental Hippo signaling pathway plays critical roles in the heart, yet its role in the CCS remains largely unknown. Here, we found that conditional knockout (CKO) of Hippo signaling kinases Lats1 and Lats2 in the CCS using Hcn4 CreERT2 , led to cardiac arrhythmias in adult mice. Compared with controls, Lats1/2 CKO mutant mice had disrupted calcium homeostasis, increased fibrosis and more fibroblast proliferation in the sinoatrial node. Deletion of the Hippo signaling effectors Yap and Taz in the CCS rescued phenotypes caused by Lats1/2 deletion, and these mice had rescued sinus rhythm and reduced fibrosis, which indicated that Lats1/2 function through Yap and Taz in CCS. Our Cleavage Under Targets and Tagmentation (CUT&amp;Tag)-sequencing using Yap antibody followed by RNA-Seq revealed that Yap directly regulates calcium homeostasis genes such as Ryr2 and fibrosis induction genes such as TGF-β family. Further, we discovered that miR-17-92 represses Hippo signaling by directly suppressing Lats2 expression. miR-17-92 CKO in the CCS led to increased Hippo signaling activity and cardiac arrhythmias, indicating that a fine-tuned level of Hippo signaling is critical for CCS homeostasis. Together, our findings reveal the critical role of a miR-Hippo-Yap genetic pathway in maintaining CCS homeostasis.
Abstract 14244: SCD-HeFT Reanalyzed - A Need for Multimorbidity Risk-Stratified Trial Evaluations for Clinical Interventions
Authors: Emma Hegwood, Gerald Naccarelli, Eric Schaefer, Andrew Foy
Journal: Circulation (2021)

Introduction: Patients with multiple chronic conditions (i.e., multimorbidity) are under-represented in clinical trials. This represents a challenge to the external validity of clinical trials since multimorbidity may associate with treatment effect heterogeneity (HTE). In this analysis, we sought to determine the distribution of multimorbidity scores in patients enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and looked for an association between such scores and HTE for the outcome of all-cause mortality. Methods: A modified version of the Charlson Comorbidity Index (mCCI) was created using enrollment data. For the subgroup analysis, we fit a Cox model that included comorbidity index, randomized group, and their interaction. The interaction term allows the effect of randomized group to differ by level of comorbidity index, and is the primary effect of interest. The comorbidity index was modeled using quartiles. Following the same analysis framework as the original manuscript Amiodarone or ICD was compared to placebo in separate models. Results: The majority of patients had a mCCI score ≤ 5 (75.4%) and mortality risk was strongly associated with increased score. Interaction testing across subgroups suggested HTE for Amiodarone ( p = 0.07 ) or ICD ( p = 0.08 ) vs placebo as scores increased. For Amiodarone, the Q1 and Q4 HRs were 0.78 (0.43-1.39) and 1.50 (1.03-2.18), respectively. For ICD, the Q1 and Q4 HRs were 0.42 (0.20-0.84) and 0.99 (0.67-1.47), respectively (see Figure). Conclusions: Increasing multimorbidity may be associated with HTE for all-cause mortality when comparing Amiodarone and ICD to placebo in the SCD-HeFT trial. Our results highlight the importance of enrolling patients with advanced multimorbidity when considering interventions. As statistical power remains challenging in trial sub analysis, consideration should be given to performing separate trials for patients with more advanced multimorbidity.
Abstract 13764: Prognostic Value of a Novel Echocardiographic Risk Score for Long-Term Clinical Outcomes in Patients With Ischemic Heart Failure
Authors: Peter Nordbeck, Dan Liu, kai hu
Journal: Circulation (2021)

Introduction: Two-dimensional-echocardiography (2DE) derived global longitudinal strain (GLS) could predict outcome in patients with heart failure. Mitral annular plane systolic excursion (MAPSE) derived from M-mode echocardiography is a classical indicator of clinical outcome in heart failure patients. Hypothesis: This study aimed to compare the prognostic performance of GLS and MAPSE as well as a new echocardiographic risk score for the prediction of mortality and cardiovascular (CV) rehospitalization risk in ischemic heart failure (IHF) patients with reduced left ventricular ejection fraction (LVEF). Methods: This retrospective observational study comprised 1277 IHF patients with reduced LVEF (&lt;50%) receiving echocardiography including GLS. All patients completed at least one-year clinical follow-up by telephone interview or clinical visit. The primary endpoints included all-cause death, heart transplantation, CV death, or rehospitalization. Measures were used to develop a novel risk score for clinical outcome. Results: After adjusted for age, sex, and other clinical risk factors, lower LVEF (≤30% vs. &gt;30%, HR=1.39 and 1.53, P=0.005 and 0.002), lower MAPSE (≤7 vs. &gt;7mm, HR=1.35 and 1.35, P=0.007 and P=0.021), or lower GLS (≤8.4% vs. &gt;8.4%, HR=1.31 and 1.51, P=0.012 and 0.001) remained as independent predictors for overall and CV mortality, but not for CV rehospitalization. Prediction efficacy of a new echocardiographic risk score including multiple echocardiographic parameters, including systolic dysfunction (LVEF, MAPSE, or GLS), diastolic dysfunction, LV remodeling, and right-side cardiac dysfunction (right ventricular diameter and systolic pulmonary artery pressure) was tested stratifying low, intermediate, and high risk. Patients with high-risk score faced both significantly higher risk of overall mortality (HR=1.99 or 1.42) CV mortality (HR=2.15 or 1.60), and CV rehospitalization risk (HR=2.01 or 1.43) as compared patients with low or intermediate risk score (all P&lt;0.05). Conclusions: The new echocardiographic risk score derived from multiple echocardiographic indicators is associated with satisfactory prognostic performance on both mortality and CV rehospitalization.
Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
Authors: Evandro D. Bezerra, Reona Sakemura, James Girsch, Carli M. Stewart, Gunjan A Awatramani, Claudia Manriquez-Roman, Kendall J. Schick, Ismail Can, Ekene J. Ogbodo, Erin E. Tapper, Elizabeth L. Siegler, Mohamad M. Adada, Lionel A. Kankeu Fonkoua, Mehrdad Hefazi, Michael W. Ruff, Susan L. Slager, Sameer A. Parikh, Neil E. Kay, Cameron Durrant, Omar Ahmed, Dale Chappell, Michelle J. Cox, Saad S. Kenderian
Journal: Blood (2021)
Establishment of patient-derived organoid models of lower-grade glioma
Authors: Kalil G Abdullah, Cylaina E Bird, Joseph D Buehler, Lauren C Gattie, Milan R Savani, Alex C Sternisha, Yi Xiao, Michael M Levitt, William H Hicks, Wenhao Li, Denise M O Ramirez, Toral Patel, Tomas Garzon-Muvdi, Samuel Barnett, Gao Zhang, David M Ashley, Kimmo J Hatanpaa, Timothy E Richardson, Samuel K McBrayer
Journal: Neuro-Oncology (2021)

Abstract Background Historically, creating patient-derived models of lower-grade glioma (LGG) has been challenging, contributing to few experimental platforms that support laboratory-based investigations of this disease. Although organoid modeling approaches have recently been employed to create in vitro models of high-grade glioma (HGG), it is unknown whether this approach can be successfully applied to LGG. Methods In this study, we developed an optimized protocol for the establishment of organoids from LGG primary tissue samples by utilizing physiologic (5%) oxygenation conditions and employed it to produce the first known suite of these models. To assess their fidelity, we surveyed key biological features of patient-derived organoids using metabolic, genomic, histologic, and lineage marker gene expression assays. Results Organoid models were created with a success rate of 91% (n = 20/22) from primary tumor samples across glioma histological subtypes and tumor grades (WHO Grades 1–4), and a success rate of 87% (13/15) for WHO Grade 1–3 tumors. Patient-derived organoids recapitulated stemness, proliferative, and tumor-stromal composition profiles of their respective parental tumor specimens. Cytoarchitectural, mutational, and metabolic traits of parental tumors were also conserved. Importantly, LGG organoids were maintained in vitro for weeks to months and reanimated after biobanking without loss of integrity. Conclusions We report an efficient method for producing faithful in vitro models of LGG. New experimental platforms generated through this approach are well positioned to support preclinical studies of this disease, particularly those related to tumor immunology, tumor-stroma interactions, identification of novel drug targets, and personalized assessments of treatment response profiles.
Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant
Authors: Mateo Mejia Saldarriaga, Yassine Tahri, Sangmin Lee, Zhengming Chen, Tsiporah B. Shore, Danielle Guarneri, Sebastian A. Mayer, Adrienne A. Phillips, Alexandra Gomez-Arteaga, Pinkal Desai, Ellen Ritchie, Michael B. Samuel, Gail J. Roboz, Koen van Besien, Jingmei Hsu
Journal: Blood (2021)
Abstract 12257: The Utility of PREDICT-HF Score in High-Risk Asian Heart Failure Patients Receiving Sacubitril/Valsartan Treatment
Authors: Chien-Yi Hsu, Hung-Yu Chang, Ying-Hsiang Lee
Journal: Circulation (2021)

Introduction: Although the efficacy and safety of sacubitril/valsartan (Sac/val) for treating patients with heart failure and reduced ejection fraction (HFrEF) have been shown in global clinical trials, long-term tolerability and effectiveness data from Asian patients are limited. Hypothesis: The aim of this study was to investigate the effectiveness and tolerability of Sac/val in clinical practice and the utility of PREDICT-HF score for outcome prediction in Asian heart failure patients with difference risk profiles. Methods: The TAROT-HF study was a multicenter, single-arm, observational study. Totally 1,187 outpatients with HFrEF treated with Sac/val were enrolled and categorized by: (1) high-risk group with one or more of the following three risk factors: old age (≥80 years), low baseline systolic blood pressure (&lt;100mmHg), and renal impairment (eGFR &lt;30ml/min/1.73 m2), and (2) standard-risk group, those who did not have any risk factors. Clinical outcomes were assessed using the PREDICT-HF risk model. Results: A total of 305 (25.7%) patients matched the criteria for the high-risk group. The event rates of cardiovascular death or first unplanned heart failure hospitalization (HFH) among the overall population, high-risk, and standard-risk groups were 13.7, 24.9, and 10.8 events per 100 patient-years, respectively. The C statistics for the PREDICT-HF model in the overall cohort and high-risk group for cardiovascular death or first unplanned HFH at 2 years were 0.73 (95% CI 0.70-0.76) and 0.71 (95% CI 0.65-0.76), respectively. Conclusions: Real-world outcomes of the TAROT-HF study showed good tolerability of Sac/val. Although the current study enrolled high-risk patients not included in the PARADIGM-HF trial, the PREDICT-HF model performed well in real-world Asian HFrEF patients. Three easily detected clinical profiles of age, renal function, and systolic BP could help to identify patients at risk before initiating Sac/val therapy.
NIMG-19. SYNTHETIC ISOCITRATE DEHYDROGENASE-MUTANT GLIOBLASTOMAS FROM GENERATIVE ADVERSARIAL NETWORK PROVIDE MORPHOLOGIC VARIABILITY AND DIAGNOSTIC PERFORMANCE SIMILAR TO REAL DATA: DEVELOPMENT AND VALIDATION
Authors: Ji Eun Park, Ho Sung Kim, Dain Eun
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Generative adversarial network (GAN) creates synthetic MRI data that may provide morphologic variability to assess molecular characteristics of glioblastomas. PURPOSE To investigate the ability of GAN-based generation of isocitrate dehydrogenase (IDH)-mutant glioblastomas to provide morphologic variability and improve molecular prediction. METHODS GAN was retrospectively trained on 110 IDH-mutant high-grade gliomas. Paired contrast-enhanced T1-weighted and FLAIR synthetic MRI data were generated. Diagnostic models were developed from 80 IDH-wild type glioblastomas and 38 IDH-mutant patients, (real model), 38 IDH-mutant GAN-generated synthetic data (synthetic model), or both combined (augmented model). Two neuroradiologists independently assessed real and morphologic characteristics of contrast-enhancement patterns, the presence of necrosis, and margins and type of non-enhancing region. Significant predictors of IDH mutation were selected from multivariable logistic regression, and diagnostic performance was validated in 44 separate patients, 33 with IDH-wild type and 11 with IDH-mutant glioblastomas. RESULTS Synthetic IDH-mutant glioblastomas were similar to real tumors on Turing tests, with an area under the curve (AUC) of 0.67–0.71. Significant predictors of a more frontal or insular location (odds ratio [OR], 1.34 vs. 1.52; highest P = .04) and distinct non-enhancing tumor margins (OR, 2.68 vs. 3.88; P &amp;lt; .001) were similar for the real and synthetic models, with the synthetic (AUC, 0.958) and augmented (AUC, 0.899) models having higher diagnostic performance than the real model (AUC, 0.864) in the training set. The diagnostic accuracy was higher for the synthetic and augmented models (90.9% [40/44] each for both observers) than for the real model (84.1% [37/44] for one observer and 86.4% [38/44] for the other). CONCLUSIONS The GAN-based synthetic images yield morphologically variable IDH-mutant glioblastomas and may be useful as realistic training sets.
Abstract 11270: Including the Patient’s Perspective in the Planning of Data Collection in the Recurrent Pericarditis Registry, RESONANCE
Authors: Sushil A Luis, Paul Cremer, Michael A Portman, ajit raisinghani, Alexandra Malinowski, Lora Marden, Alison Reid, Dana Martin
Journal: Circulation (2021)

Introduction: In conjunction with pericardial disease physician specialists, industry experts, and recurrent pericarditis (RP) patients the RESONANCE Registry was designed to collect retrospective and prospective, longitudinal, observational data in real-world clinical practice across the United States (US). We aimed to collect data that were complete and meaningful in terms of patient experience and health related quality of life (HRQoL). Herein, we describe a novel patient-centric research approach to obtain feedback on evaluation tools for incorporation in the RESONANCE Registry (NCT04687358). Methods: Ten adult patients with a self-reported duration of disease ranging from 8 months to 25 years participated in an advisory board during which they provided feedback through a virtual platform. Their feedback informed development of multiple registry aspects. These included selection of patient reported outcomes measures (PROMs), to be collected every three months at prospective data collection timepoints, and design of several questionnaires, including evaluation of specific RP episode characteristics. Results: Prior to finalization, registry case report forms were optimized based on feedback provided by patients. Areas of data-capture informed by patient input included selection of PROMs to be assessed and patient-centric tools used for self-assessment of disease experience and HRQoL. For example, sections of a patient questionnaire were modified to include documentation of the presenting symptom, breathlessness, fear of episodes, and patient management of each episode. Conclusions: This patient-centered research collaboration resulted in enhancements to the RESONANCE Registry that enabled capture of information meaningful to patients’ daily experiences, preferences, and expectations. Patient participation in tangible aspects of research, including registry tools and design, can increase engagement with the communities that have a vested interest in improving patient care. In addition, patient involvement can help to ensure research efforts reflect the needs of not only the healthcare community but of patients alike, with an ultimate goal of improving clinical outcomes.
CSIG-29. TRIBBLES-1 (TRIB1) INCREASES TUMOR FORMATION IN AN ORTHOTOPIC MOUSE MODELS BY PROMOTING SURVIVAL OF GBM CELLS AND TREATMENT RESISTANCE
Authors: Karnika Singh, Chunhua Han, Jessica Fleming, Joseph McElroy, Ashok Kumar, Ebin Sebastian, Erica Bell, Pierre Robe, Jahar Haque, Arnab Chakravarti
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive CNS tumor with an average survival of about 15 months after diagnosis. The current gold standard therapy comprises radiation therapy (RT) and concurrent and adjuvant temozolamide (TMZ). Due to poor prognosis, novel therapeutic targets need to be identified for drug development. To this end, we identified TRIB1 through correlative studies using patient derived methylation data from an institutional cohort as a novel therapeutic target. TRIB1 is a Ser/Thr pseudokinase that functions as a scaffold for the degradation of its substrates and activates Akt and MEK oncogenic pathways. In this study, we show that TRIB1 promoted GBM progression by upregulating survival pathways and reducing RT/TMZ-induced cell death. MATERIALS AND METHODS In vitro functional validation was performed by overexpression and knockdown approaches. GBM patient derived (PDX) cell lines overexpressing the TRIB1 transgene were used to create an orthotopic tumor model for in vivo studies. Mice were monitored for changes in tumor volume and overall survival. Stable cell lines were generated by puromycin selection. Western blotting was utilized to detect protein levels. RESULTS Mice inoculated with PDX cells overexpressing TRIB1 transgene had increased tumor volume and worse overall survival compared to the empty vector control. We also observed that TRIB1 overexpression caused decreased apoptosis of PDX cell lines after RT/TMZ treatment. Additionally, an increase in the phosphorylation of ERK and Akt was also noted after TRIB1 overexpression. Consistent with these observations, TRIB1 knockdown sensitized the cells towards radiation and caused decreased Akt phosphorylation/activation as well. CONCLUSION TRIB1 overexpression decreases overall survival of xenograft bearing mice and promotes GBM cell survival by upregulating survival signaling pathways. This compromises the effects of RT/TMZ therapy, which is reversed after TRIB1 knockdown. Targeting of TRIB1 may reduce oncogenic signaling in GBM cells and therefore would sensitize them towards RT/TMZ therapy.
Abstract 14182: Diverse microRNA Cargo is Essential for the Cardioprotective Effects of Therapeutic Extracellular Vesicles
Authors: Lindsey M Euscher, Kyle I Mentkowski, Isabella Julian, Lisa A Eagler, Jennifer K Lang
Journal: Circulation (2021)

Background: Extracellular vesicles (EVs) deliver their protein and RNA cargo across the plasma membrane of target cells to exert a functional response. Injection of cardiosphere-derived cell (CDC) EVs have been shown to reduce cardiomyocyte (CM) cell death and improve cardiac function in large and small animal models of myocardial infarction (MI) and ischemia-reperfusion. While several EV miRNAs (miRs) have been identified to play a role in cardioprotection, it has not yet been established whether miR cargo is necessary for the therapeutic benefit of EVs. We hypothesized that miRNA cargo is essential in CDC-EV mediated cardioprotection post-MI. Methods: CDCs were transfected with siRNA against Drosha, the initial endonuclease in the miR biogenesis pathway. EVs were isolated from serum-free media and characterized by size, morphology, and protein/miR expression as previously described. We examined the role of EV miRNA on target cell apoptosis, proliferation, angiogenesis, and gene expression using a series of in vitro assays. To determine if miR cargo is essential for the therapeutic efficacy of CDC-EVs in vivo , we induced acute MI in adult C57BL/6 mice and randomized them to receive 1) EVs, 2) miR depleted EVs or 3) vehicle control. LVEF was assessed by echo at 1- and 28-days post-MI and tissue samples processed for assessment of histological endpoints. Results: Transfection of CDCs with siRNA against Drosha reduces miRNA in CDCs and their EVs by 81±5% and 65±4%, respectively (mean ± SEM, t-test, p&lt;0.001). miR depleted EVs failed to recapitulate the reduction in cardiomyocyte apoptosis, decrease in fibroblast proliferation, and enhancement in angiogenesis seen with control EVs. Furthermore, while intramyocardial administered CDC-derived EVs improved LVEF compared with vehicle control treated animals 28 days post-MI (62 ± 4% vs 44 ± 4%), mice treated with miR-depleted EVs demonstrated no significant difference in LVEF (42 ± 6%) compared with vehicle control (n=8 mice/group, mean ± SEM, p&lt;0.05, one-way ANOVA). Conclusions: miR deficient human CDC-EVs are unable to recapitulate the cardioprotective effects seen with control extracellular vesicles, providing important insight into the mechanism of action of therapeutic EVs.
Abstract 12155: Detecting Peripheral Arterial Stenosis and Monitoring Atherosclerosis Severity
Authors: Tomer Heitner, Amit Livneh, Martha Vargas, Jonathan Lorber, Ron Karmeli, Amir Landesberg
Journal: Circulation (2021)

Background: The AHA guidelines recommend measuring the Ankle-Brachial Index (ABI) for assessing the severity of atherosclerosis. There is also an unmet need for early detection of peripheral artery stenosis to reduce morbidity and tissue loss. However, the sensitivity of ABI in detecting arterial stenosis is limited in the presence of arterial stiffening (arteriosclerosis), especially in diabetic and elderly patients, since arteriosclerosis yields fictitious higher ABI. We hypothesize that non-invasive quantification of the peripheral perfusion dynamics, instead of a single pressure point, can improve the diagnosis and differentiate between focal stenosis and general arteriosclerosis. Methods: Impedance plethysmography (IPG) were measured from the calf of patients that underwent peripheral revascularization, before and shortly after the interventions. The characteristic perfusion dynamics curves were derived from the cardiac complexes of the IPG that were recorded over at least 3 minutes. Successful interventions were defined according to the guidelines as a post-operational ABI increase of at least 0.15. Results: Twenty-four patients (60.9±9.3 years old, 16 (66.6 %) diabetics) that underwent above-knee revascularization were analyzed. The perfusion upstroke consisted of two characteristic phases: an initial slow phase followed by a fast vigorous rise. Improvement in the perfusion after the revascularization appeared only in the initial slow duration, denoted as the ‘Perfusion Deficit Index` (PDI). Of those, 15 (62%) had a successful intervention and the PDI decreased from 115±48 ms to 22±10 ms (p&lt;0.0001) while the ABI increased from 0.53±0.26 to 0.94±0.22. In 9 limbs (37%) with unsuccessful interventions, there were no significant changes in PDI and ABI (from 143±31 ms to 117±40 ms and from 0.38±0.11 to 0.48±0.11, respectively). There was no significant change in the pulse transit time (p=0.19), a well-known index of arteriosclerosis, before and after the interventions. Conclusions: The PDI is a novel sensitive index for detection of focal arterial stenosis and it is independent of the severity of arteriosclerosis. This simple to use method can be used for monitoring atherosclerosis severity.