tbuckley/cabot-search huggingface dataset:
Abstract 13227: Safety and Effectiveness of Trans-Catheter Mitral Valve Repair in the Elderly and Very Elderly Patients
Authors: Christian Mahnkopf, Steffen Schnupp, Majdi Amami, Mahmoud Oudeh, Hesham Mady, Issameddine Ajmi
Journal: Circulation (2021)

Introduction: Symptomatic mitral regurgitation (MR) is associated with a high mortality rate and high HF-related hospitalization. Symptomatic therapy in the elderly and very elderly patients remains weak in controlling severe MR. Patients with an increased risk of surgical repair of the MR seemed to benefit from MitraClip procedures. Hypothesis: Therefore, we thought to analyze the postprocedural safety and success of the MitraClip in octogenarians and older patients. Methods: Elderly patients with severe and symptomatic MR were presented and evaluated in the heart team. Patients with high surgical risks underwent MitraClip (Abbot, USA) procedure in our center. Post-procedural transthoracic echocardiography (TTE) procedure was performed to determine the MR grade and exclude procedure-related complications. Results: Two hundred eleven consecutive patients, older than 80 years (83.75 ±2.95, 106 Men (83.5±3.06) and 105 Women (84.01±2.83)), who received MitraClip between May 2015 and May 2020 were enrolled. The baseline characteristics are presented in table 1. Procedural success, defined as reducing the MR to grad I-II, was achieved in 93% of the patients (3.11±0.34 vs. 1.25±0.46, P = 0.002). All patients improved in the New York Heart Association functional class (3.04±0.40 vs. 1.92±0.76 one year after the intervention). No procedure-related death was registered. 81% (n=168) survival rate was achieved one year after the intervention. No clip embolization was detected in 3 months echocardiography control, Table 2. Conclusions: Our preliminary results indicate that MitraClip is a safe and effective therapeutic option in Elderly and very elderly patients with severe MR and high surgical risks. Therefore, this therapy should be considered despite age and comorbidities for effective symptomatic treatment in this particular cohort.
Abstract 12078: Pre-Glenn Aorto-Pulmonary Collaterals and Its Impact on Outcomes in Single Ventricle Patients
Authors: Varun Sharma, Laura Carlson, Jesse Esch, Mallika Gopal, Kim Gauvreau, Isaac Wamala, Angelika Muter, Diego Porras, Meena Nathan
Journal: Circulation (2021)

Introduction: In single-ventricle patients undergoing bi-directional Glenn (BDG), 36-59% have angiographically detectable aorto-pulmonary collateral (APC) flow. However, predictors, hemodynamic and clinical outcomes are unknown. Hypothesis: We hypothesize that (a) shunt type, hemodynamic findings at the pre-Glenn catheterization predict pre-BDG APC burden and (b) APC burden at BDG catheterization may predict post BDG death/transplantation, pulmonary artery (PA) or APC intervention. Methods: Retrospective cohort study of patients following Norwood Procedure for single ventricle anatomy. Covariates included demographics; clinical and hemodynamic at Pre-BDG catheterization. APC burden at pre-BDG catheterization was assessed dichotomously by a single reader (moderate/severe vs. none/mild). Logistic regression was used to identify predictors of APC burden and Cox regression for time to clinical outcomes. Results: Among 104 patients, 89.4% (n=93/104) underwent pre-BDG catherization, of which 55% (n=51/93) had APC intervention and 91% (n=85/93) progressed to BDG. Post-BDG, 60% (n=51/85) had no/mild and 40% (n=34/85) had moderate/severe APC burden. Within 36 months, APC intervention occurred in 74% (n=69/63) with no difference between groups (84% vs. 79%, Logrank 0.75). Predictors of APC burden were male sex (OR 3.59; 95% CI 1.18-10.98), older age at BDG (1.02 per year; 1.01-1.04), PA saturations (1.80;1.18-2.75), and Qp:Qs ratio (OR 1.23 per 0.10 unit increase;1.08-1.41). APC burden is not predictive of death/transplantation or future APC intervention but may show a trend towards future PA intervention (HR 2.11, 95% CI 0.98-4.52, p=0.056)(Figure 1). Sano shunt is a predictor of APC intervention following BDG (HR 2.07, 95%CI 1.09-3.90, p=0.03). Conclusions: Moderate or severe APC burden was present in 40% after stage I Norwood and QP:QS is a strong predictor for APC burden; patients with moderate/severe APC’s may be at higher risk of PA interventions.
Abstract 14317: Left Ventricular Free Wall Adaptations in Heart Failure With Preserved Ejection Fraction: Insights From a Murine Model
Authors: Maziyar Keshavarzian, Sunder Neelakantan, Lilly McAlister, Abby Leatherman, Sarinity Frazier, Carl W Tong, Reza Avazmohammadi
Journal: Circulation (2021)

Introduction: Heart failure with preserved ejection fraction has heterogeneous causes. Understanding the cause of diastolic dysfunction can help with pairing correct treatment. Hypothesis: We hypothesize that one can elucidate the underlying cause using echocardiography. Methods: We performed echocardiography on hearts of cardiac myosin binding protein-C phosphorylation deficient mouse t3SA vs. its control tWT at 3 months of age with both sexes (n=6 for each group). Left ventricular free wall (LVFW) specimens were harvested and biaxially stretched along circumferential and longitudinal directions, followed by picrosirius red staining. Fiber architecture was quantified by analyzing histology images. Results: t3SA hearts demonstrated hypertrophy (see Fig. 1a-b for representative mice) and diastolic dysfunction (slowed e’ and increased E/e’ ratio; see Table 1). t3SA LVFW specimens showed increased longitudinal stiffness (p&lt;0.05 for strains &gt;0.25; Fig. 1c-d). Consistent with this stiffening, t3SA specimens exhibited pronounced fiber orientation towards the longitudinal direction (see Fig. 1e-f for representative mice). The smaller e’+S showed that t3SA mice had slowed cross-bridge cycling rates. Biomechanical analyses indicated that LVFW myocardial adaptations contributed to diastolic dysfunction. Conclusions: Echocardiography indices can be used to noninvasively infer underlying remodeling events contributing to diastolic dysfunction facilitating remodeling-targeted therapy selection.
Abstract 10566: Echocardiographic Predictors of Successful Transcatheter Mitral Valve Repair with the Mitraclip System
Authors: Sandra Hadjadj, Afonso Freitas-Ferraz, Amelie Paquin, mathieu bernier, Kim O’Connor, Erwan Salaun, Philippe Pibarot, Marie-annick Clavel, Josep Rodes-Cabau, Jean-Michel Paradis, Jonathan Beaudoin
Journal: Circulation (2021)

Introduction: Residual mitral regurgitation (rMR) and elevated transmitral gradients (TMG) are associated with worse outcomes after percutaneous mitral repair. This study aims to assess if pre-intervention MR jet width and its relation to the mitral commissural length (MCL) are able to predict post-procedure rMR and TMG. Methods: Preprocedural echocardiographic images were retrospectively reviewed in 74 patients who underwent an edge-to-edge repair (2014-2018). Maximal MR jet width and MCL were measured from a bi-commissural view. Complete follow-up echocardiographic examination was performed at 1-3 months. Left ventricle (LV) and left atrial (LA) severe dilation were defined as LV end-diastolic diameter ≥6.5 cm and LA indexed volume ≥48 ml/m 2 . Presence of rMR ≥moderate, combination of rMR and TMG &gt;5 mmHg (rMR+TMG), and all-cause mortality within 1-year follow-up were examined. Results: Of 74 patients, 25 (34%) had rMR [17/25 moderate and 8/25 severe)] and 39 (53%) had either rMR or elevated TMG. Both MR jet width and its ratio with MCL were good predictors for the implantation of &gt;2 clips (p&lt;0.01 for both). Patients with rMR had a significantly larger pre-procedural jet width versus those without MR (1.63±0.54 cm vs 1.29±0.53 cm; p=0.01); without significant difference for the ratio of jet width/MCL (p=0.07). However, this ratio was higher in patients having rMR+TMG (41.05±13.15 % vs 34.26±12.64 %; p=0.03). In univariate analysis, MR jet width was a good predictor of rMR (OR: 3.35, 95%CI: 1.09-10.48; p=0.03) and severe post-intervention LV (OR: 6.43, 95%CI: 1.35-45.01; p=0.03) and LA dilation (OR: 3.02, 95%CI: 1.16-8.69; p=0.03); whereas the ratio was a good predictor of rMR+TMG (OR: 1.69, 95%CI: 1.12-2.70; p=0.02). Patients with rMR and rMR+TMG tended to be at higher risk of mortality at one year, without reaching statistical significance in this small population (24% vs 14%, p=0.17 and 23% vs 11%, p=0.14 respectively). Conclusion: MR jet width and its ratio with MCL are respectively associated to rMR or combined rMR+TMG after percutaneous mitral repair. MR jet width was also useful to identify patients who remained with severe LV and LA dilatation post-intervention.
Abstract 10832: Transient Receptor Potential Melastatin 7 (TRPM7) Contributes to Myocardial Ischemic Injury
Authors: Lixia Yue, jianlin feng, Zhichao Yue, Lixia Yue
Journal: Circulation (2021)

Introduction: Ischemic heart disease is the leading cause of death in the USA. Despite the progress of interventional coronary reperfusion strategies, myocardial ischemia reperfusion (I/R) injury remains a substantial challenge for treatment. TRPM7 is a Ca 2+ -permeable nonselective channel which plays an important role in cardiogenesis and atrial fibrillation. However the role of TRPM7 in pathogenesis of myocardial I/R is unknown. Hypothesis: TRPM7 contributes to myocardial I/R injury. Methods: TRPM7 knockout mice (M7KO) and Cre - control littermates (WT) mice were exposed to 45 min ischemia or sham procedure followed by 24 hrs of reperfusion (n=8 to 12/group). Heart function was evaluated by echocardiograph, and in vitro assays were used for mechanistic investigation. Results: We found that TRPM7 expression was upregulated in I/R injury WT mouse hearts. Global M7KO (gM7KO) improved heart performance via increasing the ejection fraction and fraction shortening by 29.1 ± 4.2 % and 10.8 ± 3.0 % respectively (p&lt;0.05). Trpm7 deletion also reduced the infarct size by 31.1 ± 1.2 % in comparison with WT mice (P&lt;0.05). Myocytes specific knockout (mM7KO) exhibited similar protective effect against I/R injury. Moreover, deletion of Trpm7 significantly reduced tunnel positive cells, suggesting that upregulated TRPM7 in WT mice contributed to myocyte apoptosis in I/R injury. Interestingly, deletion of Trpm7 also significantly reduced the protein level of NLRP3, cleaved-caspase-1 and mature IL-1β after I/R injury (p&lt;0.05), indicating that TRPM7 contributed to pyroptosis during I/R injury. Consistent with the increased IL-1β level induced by I/R injury in WT mice, the cleaved N-terminal Gasdermin D (N-GSDMD) level was also increased in WT I/R injury hearts versus sham control hearts. Deletion of Trpm7 significantly attenuated the increase of the cleaved N-GSDMD level induced by I/R injury (p&lt;0.05). Conclusions: Trpm7 deletion in cardiac myocytes protects mice against myocardial ischemic injury. This is the first study to demonstrate the important role of TRPM7 in I/R injury through the mechanisms of activation of both apoptosis and pyroptosis. Our results suggest that TRPM7 may serve as a novel therapeutic target for myocardial ischemia/reperfusion injury.
TMOD-24. PATIENT-DERIVED ORGANOIDS TO MODEL AND CHARACTERIZE TUMORAL HETEROGENEITY OF PEDIATRIC BRAIN CANCERS
Authors: Chiara Lago, Claudio Ballabio, Evelina Miele, Luca Tiberi
Journal: Neuro-Oncology (2021)

Abstract Central nervous system (CNS) tumors are the most common solid tumors in the pediatric population and the main cause of death among childhood cancers. They present common features related to the development and produce symptoms based on their location, rate of tumor growth and age of the child. Tumors of embryonal origin, such as medulloblastoma or primitive neuroectodermal tumor, have a higher incidence in younger patients, whereas older ones tend to present tumors of glial origin. Most of CNS-embryonal tumors are highly malignant and consequently leading to poor prognoses. Despite the understanding of the underlying molecular landscape of these tumors that has helped in clinical advances to improve life expectancies of the patients, there is still an emerging need to minimize morbidity and manage the long-term therapy effects. Developing new models to better understand the heterogeneity of these tumors and to test personalized treatment strategies remains a clinical challenge. We are trying to answer to this medical need with Patient-Derived Organoids (PDOs) established through the direct in vitro culture of primary tumors and patient derived xenograft (PDX)-derived tumors. We have developed a method for generating PDOs from a variety of pediatric brain cancers that recapitulates the cellular heterogeneity, histological features and mutational profiles of the corresponding parental tumors. We have obtained promising results from the DNA methylation profile analysis, nowadays used for an accurate routine CNS tumors diagnosis. Through this new model, we confirmed the action of some clinically used drugs, obtaining a proof of concept of their possible application as a reliable tool for drug screening. Another interesting application derives from the enrichment of PDOs culture media for possible tumor-specific antigens: their identification could be of pivotal importance for the definition of tumor markers identifiable with diagnostic tests or as candidates for new therapies.
Abstract 13589: The Mechano-Signaling Roles of the Adaptor Protein Nck1 in Atherogenic Endothelial Activation
Authors: Mabruka Alfaidi, Milla Reddick, Xinggui Shen, A. Wayne Orr
Journal: Circulation (2021)

Rational: Alterations in hemodynamic shear stress (SS) at atherosclerosis-prone sites promotes endothelial activation, characterized by nuclear factor-κB (NF-κB)-driven expression of cell adhesion molecules that mediate leukocyte homing. In addition, proinflammatory cytokines (e.g. IL-1β) promote NF-κB-dependent endothelial activation. While the recent CANTOS trial using an IL-1β antagonist highlights the potential for treating atherogenic inflammation beyond lipid lowering therapies alone, our understanding of how endothelial activation contributes to this effect remains limited. Methodology &amp; Results: We identified the signaling adaptor Nck1 as a critical regulator of atherogenic endothelial activation. Endothelial cells deficient in Nck1 lack SS-induced NF-κB activation and proinflammatory gene expression. Additionally, we demonstrated an interaction between Nck1 and IL-1β signaling in response to SS, showing that SS activates the IL-1β receptor (IL1R1) signaling partner IRAK-1 in a Nck1-dependent manner both in vitro and in vivo . IRAK-1 depletion inhibited the proinflammatory response to SS. Mechanistically, point mutation analysis suggest a critical role for the Nck1 SH2 domain (phosphotyrosine binding domain) in mediating these effects. Consistent with our cell culture studies, Global Nck1 knockout mice show reduced atherosclerosis characterized by diminished macrophage and smooth muscle incorporation and bone marrow chimeras suggest non-hematopoietic Nck1 mediates this response. Conclusions: A recent GWAS analysis linked Nck1 to coronary artery disease, underscoring its importance to human disease. Therefore, our data suggest that Nck1 mediates the formation of IL-1-related signaling complexes to induce atherogenic endothelial activation, and selective inhibition of Nck1 or its critical domains will allow efficient inhibition of atherosclerosis in humans.
Abstract 9360: Increasing Mass Transfer Flux of Low-Density Lipoproteins-Cholesterol or Apolipoprotein B at the Endothelium of Atherogenic Sites as a Primary Target of Atherosclerotic Cardiovascular Disease
Authors: XING F WANG
Journal: Circulation (2021)

Major pathological evidences indicate that subendothelial low-density lipoproteins-cholesterol (LDL-c) accumulations at atherogenic sites cause atheroscleroticcardiovascular disease (ACD). As such, current guidelines focus on LDL-c as aprimary target of ACD. Accumulating data from clinical trials have suggested thata shift from LDL-c to apolipoprotein B (Apo B) may improve target accuracy. Inthis study, we assess the hypothesis that focuses on increasing mass transfer flux ofLDL-c or Apo B from the disturbed blood flow to the endothelium of atherogenicsites as a primary target of ACD. A set of multidisciplinary analysis models areused to describe dynamic behaviors of LDL-c or Apo B particles and create amultibiomarker analysis formula (MAF) for the assessment, prevention andtreatment of ACD. The models reveal that individuals’ atheroscleroticmultibiomarker such as elevated LDL-c levels or increasing Apo B, hypertension,rising heart rate and increasing atrial stiffness contribute to an increase in LDL-c orApo B mass transfer flux at the endothelium of atherogenic sites and the increasingLDL-c flux then directly triggers subendothelial LDL-c accumulations at the sites.Excitingly, we show that the individual ACD risks assessed by MAF correspondrobustly to the 2013 ACC/AHA Guideline. In conclusion, LDL-c or Apo B masstransfer flux at the endothelium of atherogenic sites is a primary target of ACD andthe flux combines the contributions of different biomarkers to ACD. MAFencompasses a multibiomarker approach that has been utilized to analyzescreening data from over 95,000 patients conducted by the Cleveland Heart Laband MDVIP, Inc., which highlights the potential to prevent ACD and savehundreds of millions of dollars in healthcare costs.
Abstract P392: The Effect Of Cell Sex On Magnetic Nanoparticle Uptake Of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Morteza Mahmoudi, Vahid Serpooshan, Phillip C Yang, Mahyar Heydarpour
Journal: Circulation Research (2021)

Introduction: It is well understood that the occurrence, progress, and treatment of heart failure, which is a leading cause of death worldwide, is sex-specific. Over the past decade, the majority of efforts in myocardial regeneration have been centered on cell-based cardiac repair. A promising cell source for these efforts is patient-specific human cardiomyocytes (CMs) differentiated from human inducible pluripotent stem cells (hiPSCs). However, successful use of hiPSC-CMs faces a major limitation, the poor engraftment and electromechanical coupling of transplanted cells with the host myocardial tissue. Magnetic nanoparticles (NPs) demonstrate great potential to address this challenge for treating heart failure via cell therapies. In particular, superparamagnetic iron oxide NPs (SPIONs) have been used to label hiPSC-CMs and, with the aid of external magnetic field, improve their engraftment and electromechanical coupling in the heart tissue. However, the critical role of cell sex in the uptake and labeling efficacy of NPs has not been evaluated. Hypothesis: Significant differences in the molecular and structural (e.g., actin structures and distribution) characteristics of male and female hiPSC-CMs affect their labeling efficacy with SPIONs. Methods and Results: To test our hypothesis, we first performed RNA-Seq analysis on three male and three female (healthy) hiPSC-CM lines. The normalized outcomes were analyzed by edgeR package. We next calculated gene-expression differential between male and female CMs. The results revealed 58 genes with significant differences between the male and female cells (p-value &lt; 0.01). The highest observed sex-specific variation in genes was related to tophit gene (MEG3: logFC = 7.32, P-value = 5.63e -06 ), which is the maternally expressed imprinted gene with a great role in cardiac angiogenesis. Among the identified genes, a number of those were related to the cellular cytoskeletal structures including actin. We probed possible structural differences between actin filaments organization and distribution of male and female hiPSC-CMs using the stochastic optical reconstruction microscopy (STORM) technique. The results demonstrated substantial differences in organization, distribution, and morphology of actin filaments between male and female CMs. Incubation of SPIONs with male and female hiPSC-CMs revealed higher uptake of NPs (~ 3 folds) in female cells as compared to the male cells. The significant differences in the uptake of SPIONs by male vs. female cells could be attributed to the distinct organization, distribution, and morphology of actin in male vs. female cells. Conclusions: Our results indicate that male and female hiPSCs-CMs respond differently to the labeling SPIONs.
Abstract 12593: A Disordered Linker Regulates the Dynamics and Activity of the Protease Domain of the Urokinase-Type Plasminogen Activator
Authors: Constanza Torres Paris, Elizabeth A Komives
Journal: Circulation (2021)

Introduction: The urokinase-type Plasminogen Activator (uPA) catalyzes the rate-limiting step in the fibrinolysis pathway. How the activity of uPA is regulated is not well characterized and its understanding could unravel alternative ways of tuning fibrinolysis. The uPA has three domains: an EGF-like and a Kringle domain linked through a disordered linker to a serine protease domain. The linker binds to the protease domain through a disulfide bond that is located 22.7 Å away from the catalytic triad. There is no crystal structure available for full-length uPA and it is unknown if these domains interact among themselves. We recently showed that full-length uPA is more active than the protease domain by itself. Hydrogen Deuterium Exchange Mass Spectrometry (HDXMS) revealed that the protease domain was less dynamic in the presence of the EGF and Kringle domains, however, our data did not show any interface between the domains. We hypothesize that the linker is allosterically regulating the protease domain. Methods: We mutated two residues in the linker of full-length uPA (S138D and P141A) and measured their activity using a small substrate analog and the endogenous substrate Plasminogen. In addition, changes in dynamics of the protease domain were evaluated using HDXMS. Results: The S138D mutation decreased the activity of the enzyme towards both substrates, while the P141A mutation increased the activity towards the small chromogenic substrate and did not alter the activity towards Plasminogen. HDXMS revealed how the dynamics of different loops in the protease domain were affected by the mutations. The 220s loop was less dynamic in the P141A mutant, however the 110s loop, the activation loop and the β9 strand were more dynamic on this mutant compared to the wildtype. The 110s, 170s and 140s loops together with the activation loop and the β9 strand were more dynamic in the S138D mutant. Interestingly, all these loops are between 20 to 40 Å away from the cysteine that connects the linker to the protease domain, as measured from PDB: 1C5W. Conclusions: Our results support the hypothesis that the long-range dynamic allostery in full-length uPA is mediated by the disordered linker. In addition, this allostery regulates the activity and dynamics of the protease domain of uPA.
From “Ought” to “Is”: Surfacing Values in Patient and Family Advocacy in Rare Diseases
Authors: Meghan C. Halley
Journal: The American Journal of Bioethics (2021)

This article refers to:Helpful Lessons and Cautionary Tales: How Should COVID-19 Drug Development and Access Inform Approaches to Non-Pandemic Diseases?Physician Responsibility to Discuss Palliative Unproven Therapies With Out-of-Option PatientsDecisions on Innovation or Research for Devastating DiseaseAnother Cautionary Lesson from COVID Research
Dose Escalation Study of GCC19CART CoupledCAR ® Technology for Patients with Relapsed or Refractory Colorectal Cancer
Authors: Naifei Chen, Chengfei Pu, Lingling Zhao, Chang Wang, Ruihong Zhu, Tingting Liang, Xi Huang, Haiyang Tang, Yizhuo Wang, Beibei Jia, Dongqi Chen, Eugene Kennedy, Zhao Wu, Lei Xiao, Jiuwei Cui
Journal: Blood (2021)