tbuckley/cabot-search huggingface dataset:
Abstract P356: Dual Dysfunction Of Kir2.1 Underlies Conduction And Excitation-contraction Coupling Defects Promoting Arrhythmias In A Mouse Model Of Andersen-tawil Syndrome Type 1
Authors: Alvaro Macias, Andrés González-Guerra, Ana I. Moreno-Manuel, Francisco M. Cruz, Nieves García-Quintáns, Lilian K. Gutiérrez, Marta Roche-Molina, Francisco J. Bermúdez-Jiménez, Vicente Andrés, Maria L. Vera-Pedrosa, Isabel Martínez-Carrascoso, Juan A. Bernal, José Jalife
Journal: Circulation Research (2021)

Background: Andersen-Tawil syndrome type 1 (ATS1), caused by trafficking deficient mutations in the gene KCNJ2 coding the inward rectifier K + channel Kir2.1, is associated with life-threatening arrhythmias, which in some patients resemble catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms are poorly understood. We tested the hypothesis that dysfunction of two different populations of mutant Kir2.1 channels, one at the sarcolemma, and the other at the sarcoplasmic reticulum (SR) membrane, directly alters conduction and intracellular calcium dynamics, respectively, to promote the ATS1 phenotype and arrhythmias that resemble CPVT. Methods: We generated a new mouse model of ATS1 by a single i.v. injection of cardiac specific adeno-associated viral (AAV) transduction with Kir2.1 Δ314-315 . In-vivo and cellular, structural and functional analyses of the model were carried out by electrocardiogram (ECG), magnetic resonance imaging (MRI), intracardiac stimulation, patch-clamping, membrane fractionation, western blot, immunolocalization and live calcium imaging. Results: Our mouse model carrying mutant Kir2.1 Δ314-315 recapitulated the ATS1 phenotype without modifying ventricular function. On ECG, Kir2.1 Δ314-315 mice had prolonged PR, QRS and QT intervals and occasional U waves. They showed significantly slower conduction velocities than wildtype mice in response to flecaidine-induced Na + -channel blockade, additional QT prolongation in response to isoproterenol, and increased vulnerability to cardiac fibrillation. Cardiomyocytes from Kir2.1 Δ314-315 mice had significantly reduced inward rectifier K + and Na + inward currents, depolarized resting membrane potential and prolonged action potential duration. Immunolocalization in wildtype cardiomyocytes and skeletal muscle cells revealed a novel SR microdomain of functional Kir2.1 channels contributing to intracellular Ca 2+ homeostasis. Kir2.1 Δ314-315 cardiomyocytes showed defects in SR Kir2.1 localization and function, which contributed to abnormal spontaneous Ca 2+ release events. Conclusions: Cardiac-specific AAV transduction with Kir2.1 Δ314-315 in mice recapitulates the ATS1 phenotype by disrupting localization and function of Kir2.1 channels at the SR, and the Kir2.1-Na V 1.5 channelosome at the sarcolemma. These results reveal a novel dual mechanism of arrhythmogenesis in ATS1 involving defects in Kir2.1 channel trafficking and function at two different microdomains. They also provide the first demonstration at the molecular level of the mechanism underlying the overlap between ATS1 and CPVT associated with defects in intracellular calcium homeostasis.
Abstract 13766: The Use of Echocardiography to Assess Regional Strain Abnormalities in Patients With Chronic Mitral Regurgitation
Authors: Gil Dagan, Ronny Alcalai, David Leibowitz
Journal: Circulation (2021)

Background: Patients with primary mitral regurgitation (MR) secondary to mitral valve prolapse (MVP) have regional LV fibrosis in myocardial segments adjacent to the posterior papillary muscle detected by MRI not seen in other patients with MR.. Echocardiographically determined strain is associated with LV fibrosis. Patients with chronic MR are generally followed by echocardiography, however no study has utilized echocardiography to examine regional strain variations in these patients. The object of this study was to examine regional myocardial strain in patients with chronic MR with and without MVP. Methods: Patients undergoing routine transthoracic echocardiography for the assessment of chronic severe MR were included. Patients with secondary MR, ejection fraction &lt; 50%, other significant primary valve disease, history of cardiomyopathy, ischemic heart disease, previous cardiac surgery or pacemaker implantation were excluded. The primary MR subjects were be divided into MVP or non-MVP cohorts. MVP was defined as displacement of 1 or both mitral leaflets by at least 2 mm below the mitral annulus in parasternal long-axis view. Global and segmental strain analysis in 17 left ventricular segments was performed offline and results of the MVP and non-MVP groups compared. Results: 28 patients (mean age 63 ±14 yrs ; 23F/5M) of whom 11 had MVP and 17 had non-MVP disease were included in the study. Patients in the MVP group were significantly younger (59.2 ± 16 vs 69 ± 11 p = 0.05) then in the non-MVP group. Standard echocardiographic measurements including ejection fraction were similar except for estimated PA pressure which was lower in the MVP group, (31.3 ± 6.9 vs 42.6 ± 11.9 mmHg p-value = 0.008).Global strain was normal and similar in the two groups (-21.3 ± 4.4% vs -19.9 ± 2.9%; p = 0.30). (Patients with MVP had significantly reduced segmental strain in the inferior basal segment ( -11.2 ± 9.7 in the MVP group, -18 ± 2.6 in the non-MVP group, p-value 0.037). No other segments showed significant differences between the MVP and non-MVP groups Conclusions: Our findings suggest that patients with chronic MR and MVP have significantly reduced echocardiographic strain in the inferior base when compared to patients with MR secondary to other causes.
Assessment of Response to a Third Dose of the SARS-CoV-2 BNT162b2 mRNA Vaccine in Patients With Solid Tumors Undergoing Active Treatment
Authors: Yakir Rottenberg, Albert Grinshpun, Iddo Z. Ben-Dov, Esther Oiknine Djian, Dana G. Wolf, Luna Kadouri
Journal: JAMA Oncology (2021)
CTIM-29. CLINICAL EVALUATION OF CHLOROTOXIN-DIRECTED CAR T CELLS FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Christine Brown, M Suzette Blanchard, Maryam Aftabizadeh, Jonathan Hibbard, Ramsinh Dodia, Chetan Raj Lingaraju, Renate Starr, Massimo D'Apuzzo, Stephen J Forman, Jana Portnow, Julie A Ressler, Tracey Stiller, Baishakhi Barva, Julie Kilpatrick, Paige McNamara, Jamie R Wagner, Dongrui Wang, Michael Barish, Behnam Badie
Journal: Neuro-Oncology (2021)

Abstract Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM.
Abstract 11185: Impact of Covid-19 on Acute Myocarditis Hospital Admissions in the National Health Service of England, Uk (2019-2020)
Authors: Amrit S Lota, Devendra Meena, Brian Halliday, Upasana Tayal, Alma Iacob, Daniel Hammersley, Richard Jones, Abbas Dehghan, Ioanna Tzoulaki, James S Ware, John Cleland, Dudley J Pennell, Sanjay K Prasad
Journal: Circulation (2021)

Introduction: Acute myocarditis has been reported in patients infected with COVID-19 in case series and imaging-based studies. We sought to assess this link by evaluating trends in hospital admissions due to acute myocarditis and COVID-19 on a national level during the pandemic. Methods: Data on all NHS England hospital admissions with a primary or secondary diagnosis of acute myocarditis were acquired and curated from the NHS Digital hospital episode statistics dataset from 2019-2020. COVID-19 data was obtained from the UK government daily statistics. Rolling averages over 28-day periods are presented. Results: Across all ages, there were 1,894 hospital admissions due to myocarditis in 2019 compared with 1,610 in 2020 (15% reduction). During the first national lockdown (23 rd Mar-19 th Jun 2020), myocarditis admissions were 32% lower than the same period in 2019. During the second lockdown (5 th Nov-2 nd Dec), myocarditis admissions were 9% greater than in 2019, although this increase was not sustained throughout December despite the subsequent surge in COVID-19 admissions. In general, patients admitted in 2020, compared to 2019, were older (median age 46 years, interquartile range 28-61 vs 41 years, IQR 26-58; p&lt;0.001), but sex (66% men), ethnicity (39% non-Caucasian, 9% unknown) and duration of hospital admission (median 2 days; IQR 1-4) were similar for both years. Discussion: As COVID-19 admissions peaked in early 2020, there was a sharp decline in myocarditis admissions, probably attributed to profound disruptions in healthcare provision, but possibly due to reduced transmission of other viruses during lockdown. Whilst myocarditis admissions increased during the second lockdown, there was no clear association between COVID-19 and myocarditis admission numbers. Further research may identify delayed presentations or sequelae of myocarditis, particularly following the larger COVID-19 peak in January 2021, as well as the impact of the vaccination programme.
Abstract 11383: Automated Measurement of Global Longitudinal Strain by Speckle-Tracking Echocardiography in Cardio-Oncology Patients Using Artificial Intelligence
Authors: Waqas Hanif, Ythan Goldberg, Cynthia C Taub, David A Vorchheimer, Leandro Slipczuk, Edwin Ho, Carlos Rodriguez, Muhammad Farooq, Mario J Garcia, Lili Zhang
Journal: Circulation (2021)

Introduction: Left ventricular (LV) global longitudinal strain (GLS) is a robust LV systolic function measure used to detect subtle chemotherapy cardiotoxicity. However, inter-reader and inter-vendor variabilities compromise the clinical value of longitudinal follow-up of GLS. Artificial intelligence (AI)-based, fully automated measurement of longitudinal strain may be more reliable compared with human interpretation. Methods: We studied 52 transthoracic echocardiographic examinations randomly selected from a Cardio-oncology registry. All subjects received anthracycline-based chemotherapy in 2016-2019. AI-based longitudinal strain was assessed by EchoGo Core using standard 2- and 4-chamber apical views. Two readers verified the myocardium tracing by AI and found no errors. Longitudinal strain results by EchoGo were compared to GLS measured by conventional software (TomTec and Philips QLAB) using standard 3-, 2- and 4-chamber apical views. Results: AI-based longitudinal strain analysis was feasible in 51/52 (98%) transthoracic echocardiographic studies. The mean longitudinal strain was -17.3±3.3% for EchoGo, -16.9±2.4% for TomTec and -17.5±3.1% for QLAB. Bland-Altman analysis showed a bias of -0.4 ± 2.7% and 95% limits of -5.7 to 4.9% between EchoGo longitudinal strain and TomTec GLS (Figure 1A). A bias of 0.2 ± 3.3% and 95% limits of -6.2 to 6.6% between EchoGo longitudinal strain and QLAB GLS (Figure 1B) were seen. The bias between TomTec GLS and QLAB GLS was 0.6 ±2.2% (Figure 1C). The inter-reader correlation coefficients of TomTec GLS and QLAB GLS were 0.57 and 0.71, respectively. Conclusions: This novel AI-based longitudinal strain analysis was feasible in the majority of echocardiograms without any operator input. The bias between EchoGo longitudinal strain and conventional software appears small. AI-based myocardial strain analysis may reduce variabilities and facilitate longitudinal follow-up of GLS in Cardio-oncology patients.
Response Prediction to Isocitrate Dehydrogenase (IDH) Inhibitors in Patients with <i>IDH1</i>- or <i>IDH2</i>-Mutated Acute Myeloid Leukemia Using Clinical and Genomic Data
Authors: Emma C. Scott, Kamil Kural, Sean Smith, Michael Colgan, Alexander J. Ambinder, Gabriel Ghiaur, Nora Holmes, Dickran Kazandjian, Catherine Lai, Colleen McGuire, Lorraine Pelosof, Svetlana Petrovskaya, V. Ashutosh Rao, Amy Rosenberg, Luis Santana-Quintero, Joseph Wynne, Wenming Xiao, Yong Zhang, R. Angelo de Claro, Richard Pazdur, Julia A. Beaver, Kelly J. Norsworthy
Journal: Blood (2021)
Outpatient Based Autologous Hematopoietic Stem Cell Transplantation Is a Feasible Therapeutic Option for Patients with Chronic Inflammatory Demyelinating Polyneuropathy: The Mexican Experience
Authors: Iván Murrieta-Álvarez, Lorena Bojalil-Álvarez, Yahveth Cantero-Fortiz, Elizabeth García-Villaseñor, Andrés A. León-Peña, José Manuel Priesca-Marin, Juan Carlos Olivares-Gazca, Elías González-López, Andres Gomez-De Leon, Guillermo J. Ruiz-Delgado, David Gomez-Almaguer, Guillermo J. Ruiz-Argüelles
Journal: Blood (2021)
The Giant Protein Titin
Authors: Siegfried Labeit, Bernhard Kolmerer, Wolfgang A. Linke
Journal: Circulation Research (1997)

Titin is a giant protein of vertebrate striated muscles (M(r), > or = 3000 kD). Its molecules are of filamentous shape and span from the Z disk to the M line, thereby forming a third filament system of the sarcomere. This filament system is important for both the structural integrity of the myofibril and the passive tension response of a stretched muscle fiber. The determination of the cDNA sequence of human cardiac titin has shown that the cardiac titin filament is formed by a single, giant. 27,000-residue-long polypeptide chain. The titin strand has a modular structure, and different modular arrangements are expressed in different muscle tissue types by differential splicing. In the A band, the titin modules provide regular arrays of binding sites for other sarcomeric proteins, thereby contributing to a precise assembly of myofibrillar proteins in vivo. In the I band, two specific motif families, tandem-immunoglobulin domains and PEVK-rich sequences, confer extensibility to the titin filament. Expression of muscle tissue-specific length variants of the PEVK region by alternative splicing may explain the differences in the passive tension properties between various striated muscle types. Apart from the titin sequences with apparent functions for muscle structure and elasticity, the titin molecule contains a class of unique sequence insertions. Among these sequences are phosphorylation sites, a serine/threonine kinase domain, and binding sites for muscle-specific calpain proteases. Thus, it is likely that the titin filament also plays a role in myofibrillar signal transduction pathways.
Abstract 11608: DOAC Effect on Cardiovascular Outcomes in Patients with Peripheral Arterial Disease
Authors: Lana Matti, Christine Firth, Marlene Girardo, Corbin Rayfield, Olubadewa Fatunde, Michael Apolinario, David Liedl, Paul W Wennberg, Fadi Shamoun
Journal: Circulation (2021)

Introduction: Peripheral arterial disease (PAD) increases cardiovascular (CV) morbidity and mortality, but remains underdiagnosed and undertreated. Several trials support low-dose rivaroxaban in PAD treatment, although this has yet to be widely adopted in clinical practice. The effect of warfarin and direct oral anticoagulants (DOACs) on comprehensive PAD outcomes warrants further study. Hypothesis: Anticoagulant therapy, particularly DOACs, improves CV outcomes in PAD. Methods: We conducted a retrospective study of patients who underwent ankle-brachial index testing (ABI) from 1996 – 2020 at Mayo Clinic. We included patients with PAD defined by abnormal ABI (&lt;1.0 or &gt;/=1.4). Prolonged (&gt;6 months) DOAC or warfarin use was compared to no anticoagulant therapy. Multivariable (MV) regression, controlling for baseline CV risk factors, was used. Results: 21,891 patients had abnormal ABI readings; 3,093 were on warfarin and 267 were on DOAC for any indication. Anticoagulation improved mortality, with DOACs superior to warfarin. DOACs improved critical limb ischemia (CLI)/amputation in univariate analysis, although this was not significant in MV. Patients with poorly compressible vessels (ABI &gt;/=1.4) had increased limb outcomes compared to reduced ABI (&lt;1.0). Ischemic stroke and myocardial infarction occurred more frequently in those on anticoagulation, but the risk was less for DOACs vs. warfarin. Notably, both anticoagulant groups had greater baseline comorbidity than the non-anticoagulant group; the DOAC and warfarin groups were similar. Major bleeding (6.7%) was increased in both anticoagulant groups, but less so with DOACs and this was similar to the bleeding risk seen with aspirin (HR 1.20). Conclusion: Anticoagulant therapy improved mortality in a large cohort of PAD patients. The risk of limb events appears improved in those on DOACs. DOACs showed improved risk profiles compared to warfarin regarding CV and bleeding outcomes.
Validation of the Pyruvate Kinase Deficiency Impact Assessment (PKDIA): A Patient-Reported Outcome Measure for Pyruvate Kinase (PK) Deficiency
Authors: Shayna Egan, Erin Zagadailov, Adrian Jewett, Junlong Li, Feng Tai, Audra Boscoe, David A. Andrae
Journal: Blood (2021)
<i>Notes from the Field:</i> Testing for Nonprescribed Fentanyl and Percentage of Positive Test Results Among Patients with Opioid Use Disorder — United States, 2019–2020
Authors: Justin K. Niles, Jeffrey Gudin, Alana M. Vivolo-Kantor, R. Matthew Gladden, Desiree Mustaquim, Puja Seth, Harvey W. Kaufman
Journal: MMWR Morbidity and Mortality Weekly Report (2021)
Potent and Orally Bioavailable BCL6 PROTAC TM Degraders Demonstrate Efficacy in Pre-Clinical Models of Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Sheryl M Gough, Dan Sherman, Lynn DeCarr, Sarah Eaton, Maja Milanovic, Mark Bookbinder, Jennifer Pizzano, Martha Altieri, John Corradi, Hong Xiao, Felipe Gallego, Leofal Soto, Ram Lingamaneni, Xin Chen, Wei Zhang, Gan Wang, Hanqing Dong, Deborah Chirnomas, Michael Berlin, Keith Hornberger, Lawrence Snyder, Ian Taylor
Journal: Blood (2021)
Abstract 10759: Atp Citrate Lyase: An Attractive Target at the Nexus of Metabolic and Epigenetic Alterations in Pulmonary Arterial Hypertension
Authors: Charlotte Romanet, Alice Bourgeois, Yann Grobs, Tsukasa Shimauchi, Sarah-eve Lemay, Valerie Nadeau, Sandra Breuils Bonnet, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of distal pulmonary arteries (PAs). As in cancer, excessive proliferation and resistance to apoptosis of PA resident cells (especially PA smooth muscle cells, PASMCs), fueled by metabolic aberrations (metabolic shift toward glycolysis) and interconnected global changes in the epigenetic landscape is a pivotal component of severe PA remodeling, for which current pharmacotherapies have limited efficacy. ATP Citrate Lyase (ACLY), a nuclear cytosolic enzyme that converts citrate to Acetyl-CoA, has recently emerged as a key player and therapeutic target in cancer by favoring Warburg effect, lipid synthesis and chromatin remodeling. However, its role in PAH is unknown. We hypothesized that ACLY is upregulated in PAH and supports the abnormal phenotype of PAH-PASMCs. Methods/Results: Increased expression and nuclear localization of ACLY were observed in lungs and isolated PASMCs from PAH patients compared to controls (n=10, p&lt;0.05; immunoblot and immunofluorescence). Similarly, ACLY was upregulated in PAH animal models (Su/Hx rats and mice). We found that pharmacological or molecular (siRNA) inhibition of ACLY impedes PAH-PASMC bioenergetics (as assessed by TMRM, expression of glycolytic enzymes and seahorse) and decreased P300-dependent histone H3 and H4 acetylation. Consistently, inhibition of ACLY was accompanied by 1) a decrease in proliferation (Ki67 labeling, n=8, p&lt;0.05), 2) an increase in apoptosis (Annexin V and TMRM, n=8, p&lt;0.05) and 3) a downregulation of P300-regulated pro-proliferative/anti-apoptotic factors (western blot of PCNA, Survivin, PLK1 and STAT3). In vivo, inhibition of ACLY using ETC-1002 in both male and female Su/Hx-challenged rats with established PAH resulted in a significant improvement in pulmonary vascular remodeling and right ventricular function (RVSP, mPAP, TAPSE, S-Wave, SV by echocardiography and catheterization). Furthermore, we found that inactivation of Acly targeted to smooth muscle cells confers protection in a gene-dosage-dependent manner against Su/Hx-induced PAH in mice. Conclusion: We demonstrated that the inhibition of ACLY is a novel and attractive therapeutic strategy to reverse PAH.