tbuckley/cabot-search huggingface dataset:
Abstract 12140: <i>SCN1B</i> Expression Modulates Sodium Influx in Cardiomyocytes and Diastolic Function in the Adult Heart
Authors: Daniel O Cervantes, Emanuele Pizzo, Samantha Tang, Eleonora Cianflone, Govindaiah Vinukonda, Jason Jacobson, Sudhir Jain, Marcello Rota
Journal: Circulation (2021)

Voltage-gated sodium channels (VGSCs) are macromolecular complexes composed of a number of proteins regulating channel biophysical properties. VGSCs generate Na + current (I Na ) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na . Variants in the gene SCN1B , encoding the VGSC β1 and β1B subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knock-out, cKO) were studied. Myocytes from cKO mice had decreased levels of Scn1b transcripts (-85%) and increased densities of fast- (+20%) and slow-inactivating (+140%) components of I Na , with respect to cells from corresponding control (Ctrl) animals. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were preserved in both male and female cKO mice, with respect to sex- and age-matched Ctrl animals. However, by transmitral flow Doppler echocardiography, cKO mice presented reduced velocity of the passive filling wave (-~20%), attenuated ratio of the passive-to-active filling velocity waves (-~20%), and prolonged isovolumic relaxation time (+~16%). Moreover, by pressure-volume (PV) loop assessment, cKO mice had steeper slope of the LV end diastolic PV relation and prolonged LV relaxation tau, suggesting impairment of diastolic function. Importantly, inhibition of late I Na with GS967 (0.5 mg/kg body weight) normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice, but had no consequences in Ctrl animals. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients decay and cell shortening with respect to Ctrl myocytes. These defects were partly corrected by inhibition of the late I Na . Collectively, these results document that VGSC β1/β1B subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.
Abstract 10819: Eosinophilic Myocarditis Due to Idiopathic Hypereosinophilic Syndrome
Authors: Paul M Bourdillon, Fima Macheret, Haodong Xu, David C Chhieng, Song Li
Journal: Circulation (2021)

Background: Idiopathic Hypereosinophilic Syndrome (iHES) is a rare disease with varied clinical presentations including acute heart failure. Case: A 44-year-old man who had been treated for asthma 9 months ago was admitted with worsening exertional dyspnea. EKG demonstrated sinus tachycardia with anterolateral ST depressions. Labs revealed troponin-I 44.95 ng/ml, BNP 405 pg/mL, and white blood cell count 21.2k with 50% eosinophils. Transthoracic echocardiogram showed normal left ventricular size with globally reduced ejection fraction (30-35%). Coronary angiography found normal coronary arteries. An extensive infectious and auto-immune workup was unrevealing, and bone marrow biopsy was negative for monoclonal proliferation (Fig 1A). He received 1 gram of IV methylprednisolone for 2 days lowering eosinophil count to zero and was discharged on heart failure GDMT. Two weeks later, he was readmitted from clinic for ventricular tachycardia (VT) near 120bpm (Fig 1B). Cardiac MRI and endomyocardial biopsy confirmed active eosinophilic myocarditis (Fig 1C/D). Patient was diagnosed with iHES and treated with IV methylprednisolone (500mg BID x 3 days) with an oral prednisone taper. Amiodarone and lidocaine infusions were temporarily needed to suppress his VT and an ICD was placed. After clinical stabilization and immunology consultation, an interleukin-5 inhibitor was used for further treatment of iHES. Discussion: Only 6% of patients with iHES present with cardiac symptoms, however one in five eventually develop cardiac manifestations that are often rapidly progressive. Prompt treatment with glucocorticoids is indicated for severe presentations, and subsequent use of targeted therapies can dramatically reduce morbidity and mortality. Recognition of severe peripheral eosinophilia should prompt a broad hematologic, infectious, and auto-immune workup to guide treatment and prevent end-organ damage.
Abstract 12150: Incorporation of Natriuretic Peptides With Clinical Risk-Scores to Predict Heart Failure Among Individuals With Dysglycemia
Authors: Matthew W Segar, Mohammad S Khan, Kershaw Patel, Muthiah Vaduganathan, Vaishnavi Kannan, Duwayne Willett, Eric D Peterson, Wai Hong W Tang, Javed Butler, Brendan M Everett, Gregg C Fonarow, Thomas J Wang, Darren K McGuire, Ambarish Pandey
Journal: Circulation (2021)

Introduction: The WATCH-DM score can predict risk of heart failure (HF) in patients with diabetes. Hypothesis: Addition of natriuretic peptide (NP) levels will improve WATCH-DM performance in individuals with dysglycemia. Methods: Adults with diabetes/pre-diabetes free of HF at baseline from 4 cohort studies (ARIC, CHS, FHS, and MESA) were included. The integer- [WATCH-DM(i)] and machine learning-based [WATCH-DM(ml)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP-levels was assessed by C-index, Brier score, and continuous net reclassification improvement (NRI). Results: Of the 8,938 participants included, 3,554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5-years. Among 5,384 (60.2%) participants with pre-diabetes, 647 (12.0%) developed incident HF. The WATCH-DM(ml) and (i) scores demonstrated high discrimination for predicting HF risk in diabetes (C-indices=0.76 and 0.69), pre-diabetes (0.83 and 0.72), and overall cohort (0.80 and 0.71), respectively, with no evidence of miscalibration (GND=P &gt;0.10). A greater improvement in C-index was observed with the addition of NP-levels at lower WATCH-DM(i) scores with degradation of risk discrimination at higher scores (Fig. A). Calibration was also improved with addition of NP-levels at lower compared to higher WATCH-DM(i) scores (Fig. B). A greater improvement in reclassification was observed by combing WATCH-DM(i) score with selected NP-levels assessment in low (score&lt;13) vs. high-risk (≥13) participants (NRI=0.45 vs. 0.17; p-value&lt;0.001). Conclusions: The WATCH-DM risk score can accurately predict incident HF risk in community-based individuals with dysglycemia. The addition of NP-levels improves risk prediction among adults with low/intermediate but not high HF risk.
Abstract 14148: Transcatheter Mitral Valve Replacement: A Single Center Tertiary Care Experience
Authors: Kirtivardhan Vashistha, Amel Tobaa, Adee Elhamdani, Adnan Khalif, Mark Doyle, ramzi khalil
Journal: Circulation (2021)

Background: Transcatheter mitral valve replacement (TMVR) using transcatheter aortic valves is considered an advanced structural heart procedure performed at comprehensive valve centers in patients with degenerated mitral valve prostheses. We present our single-center experience of patients undergoing Valve in Valve (ViV) and Valve in Ring (ViR) TMVR. Methods: We identified patients who underwent the TMVR procedure at our center from 1/1/2017 to 12/31/2020. We analyzed baseline characteristics, STS-PROM score, functional status (NYHA and KCCQ), baseline laboratory values, echocardiographic parameters (including LVEF, MV area, gradient, grading of MS and MR was collected. Follow-up data on functional status, echocardiographic parameters, and mortality were collected at 30 days and 1-year post-procedure. Results: A total of 32 patients were identified during this time period. 70.5 % were females, 96.8 % Caucasian. Mean NYHA class was 3.25, STS-PROM was 6.25% (5.56-9.43), and KCCQ score of 38.04 (SD 19.9). 94 % (30) of patients had a previous history of MV replacement and 6 % (2) of them had a history of MV repair. Baseline mean LVEF was 57% (46.5-67), at 30 days 55% (47.5-64.5) at 1 year 53.5% (46.5-58.25). NYHA decreased from 3.25 (1-4) to 2 (1-2) at 30 days and 2 (1.5-2) at 1 year with KCCQ following a similar trend. MV area at baseline was 1.2 (0.66-1.63) which increased to 1.45 (SD 0.44) at 30 days and 1.63 (SD 0.4) at 1 year. MV mean gradient decreased from 12.43 (SD 5.2) to 8 (7-10) at 30 days and remained stable at 9 (6-11) at 1 year. MR gradient decreased from severe MR in 11 patients (35.48 5 at baseline) to 6 (18.75 %) and 0 at 1 year. TR gradients followed the trend. The mortality rate at 30 days was 6.25 % (2) and 15.62% (5) at 1 year. Conclusion: TMVR offers acceptable outcomes in patients with symptomatic bioprosthetic mitral valve dysfunction. Follow-up data at 30 days and 1 year demonstrates improvement in functional status and sustained decrease in mitral valve gradients.
Abstract 14178: Artificial Intelligence (AI)-ECG Derived Biological Age Identifies Accelerated Aging in the Lamin A/C Gene (LMNA) Mutations
Authors: Shahar Shelly, Margherita Milone, Audry Chacin-Suarez, Michal Cohen-Shelly, Jose Medina-inojosa, Suraj Kapa, Zachi Attia, Anwar Chahal, Virend K Somers, Paul Friedman, Francisco Lopez-Jimenez
Journal: Circulation (2021)

Introduction: LMNA encodes the nuclear envelope proteins lamin A/C that are involved in ageing processes. Mutations in LMNA cause a spectrum of phenotypes which include muscular dystrophy, arrhythm...
CBIO-20. HIGH LEVELS OF TERT CONFER SENSITIVITY TO THE DNA HYPOMETHYLATING AGENT DECITABINE (DAC) IN GLIOMAS
Authors: Jong-Whi Park, Felix Sahm, Bianca Steffl, Isabel Arrillaga-Romany, Daniel Cahill, Michelle Monje, Christel Herold-Mende, Wolfgang Wick, Sevin Turcan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Decitabine (DAC)-incorporated DNA binds DNMT1 enzyme and subsequently triggers DNMT1 degradation. Previously, we showed that DAC can mediate the anti-tumor effect in a preclinical model of IDH-mutant gliomas. Here, we further investigate molecular determinants of response to DAC in gliomas. METHODS DAC response was assessed by soft agar anchorage independent growth assays and cell proliferation measurements. Patient-derived IDH-mutant chromosome 1p/19q codeleted (codel) and non-codel glioma lines upon vehicle and DAC treatment were used for RNA sequencing and Gene Set Enrichment Analysis (GSEA). RESULTS We found that DAC treatment is effective in high TERT-expressing gliomas including IDH-mutant and IDH-wildtype glioma lines. In contrast, pharmacological inhibition of TERT reduces DAC response in glioma lines. Interestingly, transcriptomic profiling showed that DAC reduces the expression of TERT, along with increased CDKN1A/p21 expression. We experimentally validated that TERT expression depends on CDKN1A/p21. Furthermore, p53 is required for DAC-mediated CDKN1A/p21 induction. Importantly, DAC-mediated proliferation defects in TERT-proficient glioma cells are abolished by DNMT1 knockdown, indicative of an expected DAC mechanism. CONCLUSIONS DAC could elicit the pronounced anti-tumor response in IDH-mutant codel oligodendroglioma and IDH-wildtype glioblastoma with TERT activating mutations.
Abstract 12942: A Randomized Trial of Low-Dose Aspirin to Reduce Vascular Endothelial Inflammation in Psoriasis
Authors: Michael S Garshick, Michael Tawil, Tessa Barrett, Angela Lee, Andrea Neimann, Jose Scher, Stuart D Katz, Sanja Jelic, Edward A Fisher, James Krueger, Jeffrey S Berger
Journal: Circulation (2019)

Introduction: Psoriasis (PsO) is a chronic inflammatory skin disease associated with increased CV risk. Randomized clinical trials evaluating CV risk reduction strategies in PsO are lacking. Prior ...
Abstract 13113: Fragility of Functional/Symptomatic Endpoints to Assess the Efficacy of Drugs for Pulmonary Arterial Hypertension
Authors: Luca Barca, Vincenzo De Marzo, Matteo Toma, Giulia Guglielmi, Gabriele Crimi, Italo Porto, Pietro Ameri
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) drugs have historically been evaluated for the effects on functional capacity and symptoms. However, these assessments are approximate and the ensuing therapeutic choices may be aleatory. Methods: We reviewed the articles describing phase 3 PAH randomized controlled trials (RCTs) and calculated the fragility index (FI) for the outcomes exploring functional capacity and symptoms. For RCTs with a significantly different outcome rate between the investigational drug (ID) and placebo/comparator arms, the FI corresponded to the number of events that needed to be added to the arm with the smallest number of events to made the RCT result non-significant. For RCTs with non-significant results (neutral), the FI was the number of events that needed to be removed from the ID group to reach a p value &lt;0.05. In general, the lower the FI, the fragile the RCT with respect to the endpoint examined. When possible, we also computed the FI for PAH hospitalization. Results: Data about the rate of functional/symptomatic improvement were available for 22 RCTs (Table). The ID was superior to placebo/comparator with p &lt;0.05 in 10 (45%) of these studies. The median FI was 2 (IQR 6.5), with 4 RCTs having a FI = 1 and only 2 a FI &gt;10. For the 12 RCTs in which the effect of the ID was neutral, the median FI was 6 (IQR 4.25). No correlation was found between FI and sample size or year of publication for either significant (R = 0.57, p = 0.08 and R = 0.23, p = 0.52, respectively) or neutral (R = 0.51, p = 0.09 and R = -0.18, p = 0.58) RCTs. The hospitalization FI was determined for 17 (77%) of the 22 RCTs and was overall higher than the one for functional/symptomatic outcomes (median 6, IQR 8) (Table). Conclusions: Very few events in one arm could have flipped the results of PAH RCTs from non-significant to significant or, more remarkably, from significant to non-significant. The evidence supporting the reduction of PAH hospitalizations as a treatment goal appears to be more robust.
Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma, a Real-World Experience
Authors: Malin Hultcrantz, Jennifer Orozco, Tim J Peterson, Andriy Derkach, Hani Hassoun, Neha Korde, Sydney X. Lu, Sham Mailankody, Dhwani Patel, Urvi A Shah, Carlyn Tan, Kylee H Maclachlan, David J. Chung, Heather J Landau, Gunjan L Shah, Oscar B Lahoud, Michael Scordo, Ola Landgren, Sergio Giralt, Alexander Lesokhin
Journal: Blood (2021)
Abstract P433: A Pharmacological Model Predicts Drug Activity In Cardiomyocyte Hypertrophy
Authors: Taylor Eggertsen, Jeffrey J Saucerman
Journal: Circulation Research (2021)

Introduction: Cardiomyocyte (CM) hypertrophy is predictive of heart failure, however there are no clinical therapies that target its intracellular pathways. Hypertrophy is a complex process involving numerous neurohormonal and cytokine inputs, resulting in context-dependent responses that determine CM growth. In the face of this complexity, it is critical that computational models are developed. Accurate predictions of drug activity in CM hypertrophy will require a pharmacological model that is developed with and validated against experimental data. Hypothesis: We test the hypothesis that our in silico pharmacological model accurately predicts drugs that inhibit cardiac hypertrophy as well as the context-dependent mechanisms by which they work. Methods: Here we employ a previously published computational model of cardiac hypertrophy signaling. This model utilizes logic-based ordinary differential equations to simulate a network of 106 nodes. Using the DrugBank database, we constructed a pipeline for simulating FDA-approved drugs within this hypertrophy network under multiple environmental contexts. The predicted outcomes of the model were then compared to measured phenotypes from experimental findings in literature. Results: Predicted outcomes of our model were successfully validated against 29 out of 36 distinct experiments described in literature. These simulations identify the optimal drug types that inhibit hypertrophy for each of 17 different stimuli. Sensitivity analyses performed by simulating knockdowns in our model reveals context-dependent mechanisms predicted for 51 drug types. These predictions confirmed, for example, the role of celecoxib in inhibiting CM hypertrophy induced by isoproterenol. Mechanistic analysis suggests celecoxib prevents protein kinase B (Akt) inhibition of glycogen synthase kinase 3 beta (GSK3β), consistent with literature. Conclusions: Our pharmacological model accurately predicts FDA-approved drugs that show in vitro inhibition of CM hypertrophy.
INNV-03. DEVELOPMENT OF A NOVEL DUAL-MODALITY BALLOON IMPLANT FOR SIMULTANEOUS HIGH-DOSE-RATE BRACHYTHERAPY AND MAGNETIC NANOPARTICLE HYPERTHERMIA OF BRAIN TUMOR RESECTION CAVITIES
Authors: Shuying Wan, Dario Rodrigues, Paul Stauffer, Janet Kwiatkowski, Omaditya Khanna, Kevin Judy, Yan Yu, Wenyin Shi, Mark Hurwitz
Journal: Neuro-Oncology (2021)

Abstract PURPOSE To develop a novel thermobrachytherapy (TBT) balloon implant that delivers hyperthermia and radiation simultaneously, with three specific aims: 1) to fabricate a prototype TBT balloon device; 2) to verify compatibility of all heating and radiation delivery components and evaluate heat and radiation dosimetry in full size skull/brain phantom models; and 3) to characterize in vivo heating patterns in pig brain. METHODS Five 3cm diameter TBT balloons were fabricated. Each balloon has two layers: an inner layer to be filled with saline to expand the resection cavity, and an outer layer to be filled with magnetic nanoparticle (MNP) solution to absorb energy from an external magnetic field hence generate heat. The balloon shaft houses 4 ports to fill inner and outer layers, insert a high-dose-rate brachytherapy source into the balloon center, and a fiber optic sensor into the outer layer to monitor and control balloon temperature. A 3D-printed skull phantom was filled with brain tissue-equivalent gel for in-phantom measurements of heating around a TBT balloon. Optically stimulated luminescent dosimeters and Gafchromic film were used to measure radiation dose; while motorized temperature probes placed in catheters were inserted in surrounding gel for thermal mapping. For in vivo experiments, a 1cm balloon was specifically fabricated for pigs 40-50 kg. RESULTS The presence of MNP, magnetic field, and 43-55°C heating did not affect radiation dose significantly. Thermal mapping demonstrated spherically symmetric heating in both phantom and in vivo brain tissue, where a higher concentration of MNP and stronger magnetic field of 1.6-4.5 kA/m at 133 kHz was used to achieve temperatures of 55°C in the much smaller balloon. CONCLUSION Novel dual-modality balloons have been fabricated and tested successfully in the lab and in vivo, hence providing crucial information to validate thermal modeling for combined heat and radiation treatment of brain tumor resection cavities.
EXTH-24. TUMOR PHARMACOKINETICS, PHARMACODYNAMICS AND RADIATION SENSITIZATION IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE SECOND-GENERATION HDAC INHIBITOR, QUISINOSTAT
Authors: Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna Melendez, James McNamara, William Knight, Sarah Himes, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Class I Histone deacetylases (HDACs) are highly expressed in glioblastoma (GBM) and are considered promising therapeutic targets for cancer treatment. Quisinostat is a class I HDAC inhibitor with high specificity for HDAC1 and 2. In this study, we evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and radiation sensitization properties of quisinostat in orthotopic and flank human glioma models of GBM. METHODS In vitro drug-uptake and PK-PD correlation experiments were conducted in patient-derived glioma stem cell (GSC) lines. Pilot PK studies were performed in mice to optimize the dosing regimen and administration route (subcutaneous (s.q.), intraperitoneal (i.p.) and oral gavage). Athymic mice with intracranial or flank tumors were treated with the most optimized treatment schedule to evaluate plasma PK profile and brain/tumor distribution of quisinostat. The drug levels in plasma, normal brain, and tumor-tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Western blot analysis and immunocytochemistry were performed to assess changes in acetylated histone, Ki67 (proliferation) and cleaved caspase 3 (cell death) levels. Tumor-bearing mice were randomized to four cohorts – vehicle, radiotherapy, quisinostat monotherapy, and quisinostat plus radiotherapy. RESULTS Quisinostat exhibited potent growth inhibition in multiple GSC lines (IC50 ~60 nM), radiosensitization, increased histone acetylation, and decreased expression of key stem cell markers. Significant toxicity was observed at 10 mg/kg s.q. dosing while the same dosing via i.p. route was tolerated relatively well. The unbound concentration of quisinostat was 19 nmol/L, 0.03 nmol/kg and 0.03 nmol/kg in plasma, tumor, and brain tissue, respectively, at 2 hours post-dose. Pharmacodynamic changes were observed in flank but not in intracranial tumors. CONCLUSION Our data indicate low free quisinostat levels in the brain primarily due to drug instability.
TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut
Authors: Anastazja M. Gorecki, Chidozie C. Anyaegbu, Ryan S. Anderton
Journal: Translational Neurodegeneration (2021)

Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.