tbuckley/cabot-search huggingface dataset:
Abstract 11792: Low Penetrance Sarcomere Variants Indicate an Additive Genetic Risk Model in Hypertrophic Cardiomyopathy
Authors: Eric Smith, Brynn Elder, Gabriela Chen, Yao-chang Tsan, John Stendahl, Jodie Ingles, Victoria N Parikh, Samuel Wittekind, Steven Colan, Neal K Lakdawala, Anjali T Owens, Daniel L Jacoby, Sharlene Day, Christopher Semsarian, iacopo olivotto, Carolyn Ho, Mark W Russell, Sara Saberi, James S Ware, Adam S Helms
Journal: Circulation (2021)

Introduction: Genetic hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition primarily due to pathogenic variants in sarcomere genes, often with marked clinical variability. We hypothesized that this variability may, in part, be due to additive effects from low penetrance sarcomere variants that would otherwise be dismissed due to high population prevalence. Methods: Low-penetrance HCM-associated sarcomere gene variants were identified by meeting a threshold for enrichment in HCM (ascertained from the Sarcomeric Human Cardiomyopathy Registry, SHaRe) versus the general population (ascertained from the Genome Aggregation Database, gnomAD), defined by an odds ratio (OR) &gt;5, and a population prevalence greater than the most common autosomal dominant pathogenic HCM variant, MYBPC3 R502W (4x10 -5 ). Clinical variables and time-event analyses were performed from SHaRe . Results: A total of 507 unique sarcomere gene variants were present in 6384 individuals with genetic testing. Ten putative low-penetrance variants were identified in the genes MYBPC3 (N=2), TNNT2 (N=1), TNNI3 (N=2), and MYH7 (N=5) with a combined OR of 12.7 (range 5.8 - 28.4). These variants had a population prevalence of 4.02x10 -5 to 3.5x10 -4 . Family members of low-penetrance variant carriers were less likely to have HCM (35/171, 20%) than those of MYBPC3 R502W carriers (44/113, 39%, p&lt;0.005). Age of diagnosis was older in patients with isolated low-penetrance variants than those with pathogenic variants (42 ± 19 vs 37 ± 18, p=0.005). Composite adverse events were less likely in patients with isolated low-penetrance variants than typical pathogenic sarcomere variants, but the risk was additive with both present (see Figure). Conclusions: A subset of low-penetrance sarcomere gene variants are tolerated in the general population at higher than expected proportions for HCM and may exert an additive pathogenic effect. These findings support an oligogenic risk model of HCM.
Abstract 9359: Intrarenal Release of Superoxide Act Synergistically With Interstitial Angiotensin II to Promote Hypertension During Chronic Acidotic Conditions
Authors: Dinesh Aryal, JeanChristophe Chamcheu, Keith E JACKSON
Journal: Circulation (2021)

The capacity of chronic metabolic acidosis (CMA) to evoke hypertension has been previously evaluated. The superoxide mediated oxidative stress and the activation of intrarenal angiotensin II (Ang II), demonstrated a potential role in the pathogenesis of hypertension during CMA involving renal tubular sodium retention leading to volume expansion and strain to blood vessels. The primary focus of the present study was to determine whether the superoxide and the renal angiotensin II acts either synergistically or independently of each other to promote hypertension and the underlying mechanism of superoxide generation. Male Sprague Dawley Rats (100-150gms) were divided into four groups. Chronic acidosis was induced in all 4 groups by providing free access to ammonium chloride solution (0.28M) for 8 weeks in the drinking water. The second, third, and fourth groups were injected daily with captopril (12 mg/kg/day), tempol (100μmol/kg/day) and captopril+tempol respectively. After 8 weeks, blood and urine samples were collected for pH measurements and analyzed for sodium and potassium levels. Rats were anesthetized and in-line mean arterial pressure were determined. The renal cortical tissue homogenates from all four groups were analyzed for superoxide dismutase (SOD) and NADPH oxidase (NOX2) expression. Mean arterial pressure is significantly decreased in fourth group compared to the second and third groups. The serum sodium levels in fourth group were significantly reduced compared to the separately treated second and third groups, which suggested the declined reabsorption of sodium as the cause of decreased blood pressure in the fourth group. On the other hand, there was an increased SOD activity in the fourth group compared to the second and third groups, which implied intrarenal Ang II reduces the release of superoxide by increasing its dismutation. Moreover, our results demonstrated that there were no significant alterations in phagocytic NOX2 protein levels in all four treatment groups, which indicated that the superoxide release could be due to mitochondrial oxidative stress. Overall, blocking the release of intrarenal Ang II along with promoting the superoxide dismutation, showed a potential combined effect to control the observed hypertension.
Abstract 12442: Extracellular Vesicles Engineered to Target Cardiomyocytes Demonstrate Improved Cardioprotection in a Mouse Model of Myocardial Infarction
Authors: Kyle I Mentkowski, Cody A Manzanero, Lisa A Eagler, Jennifer K Lang
Journal: Circulation (2021)

Background: Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following myocardial infarction (MI). While extracellular vesicles (EVs) secreted by cardiosphere-derived cells (CDCs) have shown efficacy in promoting cardiac repair in large animal models of MI, their translational potential is limited by their biodistribution. To improve cardiac uptake, we previously engineered CDC-derived EVs to express a CM-specific binding peptide (CMP) on their surface. CMP-EVs demonstrated improved cardiac retention in vivo and decreased CM apoptosis in vitro when compared with non-targeted EVs. We hypothesized that targeting therapeutic EVs to CMs would result in further reduction of CM cell death in vivo and improvement in cardiac function post-MI. Methods: EVs were isolated from serum-free media as previously described and characterized by established protocols for size, morphology, and protein expression. To determine if CMP-EVs could enhance cardioprotection in vivo , we induced acute MI in adult C57BL/6 mice and randomized them to receive 1) EVs, 2) CMP-EVs or 3) vehicle control by IV and intramyocardial delivery according to approved institutional protocols. LVEF was assessed by echo at 1- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. Results: CMP-EVs demonstrated superior cardiac targeting (IV route) and retention (intramyocardial route) when compared with control EVs 24 hours post MI (fold change of 1.8 ± 0.23 and 4.8 ± 2.3 respectively; n=8-10 mice/group, mean ± SEM, p&lt;0.05, t-test). Intramyocardial administered CDC-derived EVs improved LVEF compared with vehicle control treated animals 4 weeks post-MI (55 ± 2% vs 44 ± 2%). Mice treated with CMP-EVs demonstrated a statistically significant improvement in LVEF (64 ± 5%) compared with non-targeted EVs (n=6-8 mice/group, mean ± SEM, p&lt;0.05, one-way ANOVA). Conclusions: Targeting CMP-EVs to CMs post-MI improved cardiac function compared with control EVs, highlighting the potential importance of CMs as a target cell for CDC-derived EV therapy and demonstrating a strategy to further optimize therapeutic EV delivery to increase efficacy and decease off-target effects.
CTNI-52. RETROSPECTIVE ANALYSIS OF USING RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR CHINESE PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Yang Wang, Jingsong Wu, Zhiyong Qin, Enmin Wang, Yu Yao, Dongxiao Zhuang, Lipin Liang, chunxia Ni, peijiang Lu, Shu Chen, Chao Li
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVES Tumor Treating Fields (TTFields) has been shown to improve the overall survival of newly diagnosed GBM (ndGBM) when combined with Temozolomide (TMZ) in the EF-14 trial. Preclinical studies suggested synergistic effects between TTFields and radiotherapy. This study is aimed to examine the safety and efficacy of combination therapy (chemoradiation concurrent with TTFields treatment) for ndGBM patients in China. METHODS From July 2020 to May 2021, 33 ndGBM patients were treated with combination therapy (radiation target volume following NCCN guidelines). Eight patients had transducer array removed during radiotherapy, others retained transducer array on scalp. All patients had assessment every two months by MRI scan. The adverse reactions and monthly compliance data for TTFields treatment were recorded. RESULTS Twenty-five patients have completed the combination therapy. Three patients retained transducer array during radiotherapy but did not limit the scalp dose (mean: 21.7Gy). As a result, Grade 2 cutaneous adverse reactions developed, and TTFields treatment was suspended. Four patients suspended TTFields treatment due to other adverse reactions. The remaining patients who had limited scalp doses (mean &amp;lt; 20Gy) had no suspension or delay in combination therapy due to cutaneous adverse reactions. The median time of TTFields treatment during radiotherapy is 21.24 hours/day (IQR:19.26,22.08). Two patients had progressive disease, 1 died of pulmonary infection, and 30 had stable disease. The incidence of cutaneous AE was 48.5% (16/33), Grade1: 27.2% (9/33), Grade 2: 21.2% (7/33), and Grade 3: 3% (1/33). CONCLUSIONS The combination therapy was well tolerated in Chinese patients with ndGBM. Removing transducer array during radiotherapy may increase the frequency of array replacement while reducing the patient's daily treatment time. However, retaining transducer array will increase cutaneous adverse reactions. Scalp dose limitation is required yet it allows a maximum duration of TTFields. Further follow-ups are ongoing.
Antibody response after 2 and 3 doses of SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic cell transplant recipients
Authors: Alexis Maillard, Rabah Redjoul, Marion Klemencie, Hélène Labussière Wallet, Amandine Le Bourgeois, Maud D'Aveni, Anne Huynh, Ana Berceanu, Tony Marchand, Sylvain Chantepie, Carmen Botella Garcia, Michael Loschi, Magalie Joris, Cristina Castilla-Llorente, Anne Thiebaut-Bertrand, Sylvie François, Mathieu Leclerc, Patrice Chevallier, Stephanie Nguyen
Journal: Blood (2021)
STEM-23. LncRNA HOTAIR SPONGES miR301a-3p TO PROMOTE GLIOMA’S PROLIFERATION AND INVASION THROUGH THE ACTIVATION OF FosL1
Authors: Pendelton King, Alyssa Guo, Jingwei Wan, Mingli Liu
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Non-coding RNAs, including LncRNAs, function in regulating glioblastomas’ numerous oncogenic phenotypes, such as invasiveness and stemness of glioblastoma stem cells. These LncRNAs contain long non-encoding RNA transcripts &amp;gt;200 nucleotides in length, many of which show cell type-specific expression. In this project, we investigated how TRPM7, a promoter for glioma’s proliferation and invasion, regulates LncRNA and contributes to glioma tumorigenesis. METHODS 1) Total RNA, from either with A172 glioma cells or A172 glioma cells with TRPM7 knocked out (A172 KO), were extracted and then parallelly subjected to Human Cancer Pathway Finder, RT2 LncRNA PCR Array. 2) We then analyzed the prognostic role of LncRNAs using a publicly available bioinformatics data set (www.Oncolanc.org). 3) We examined the effects of TRPM7-regulated LncRNA, and its downstream molecules miR301a-3p and FosL1 oncogene, on the proliferation and invasion of glioma cells in A172 and PDX-L12 cells by either inhibition or activation of the above molecules. RESULTS 1) Data analysis from RT2 data resulted in a list of 10 downregulated and 7 upregulated LncRNAs whose transcripts are statistically significant with fold changes greater than 2.0 by TRPM7 knockout. 2) The results showed that TRPM7 functions as a positive regulator of LncRNA, HOTAIR, which is an unfavorable prognostic factor of 7-year overall survival in glioma patients. 3) In addition, we found that LncRNA HOTAIR sponges miR-301a-3p to promote proliferation, invasion, and stemness of glioma through upregulating the oncogene FosL1. 4) Furthermore, we identified that FosL1 is a novel prognostic marker of glioma patients. CONCLUSION Our results demonstrated the role of TRPM7-regulated LncRNA HOTAIR as a miRNA sponge in glioma, which shed new light on LncRNA-directed therapeutics in glioma.
Abstract 11782: Phenotyping Exercise Intolerance in HFpEF: Which Muscle is Limiting Aerobic Performance?
Authors: James P Macnamara, Satyam Sarma, Bryce Balmain, Christopher Hearon, Andrew Tomlinson, Margot Morris, Sheryl A Livingston, Raksa Moran, Jessica N Alcala, Mitchel Samels, Marcus Payne, Teverick Boyd, Tony Babb, Benjamin D Levine
Journal: Circulation (2021)

Background: Low aerobic power (peak VO 2 ) is common in patients with Heart Failure with preserved Ejection Fraction (HFpEF). Mechanisms for low VO 2 are diverse and vary between patients. We used the cardiac output (Qc) response to VO 2 during exercise to characterize patients with HFpEF into those with primary cardiac or peripheral defects in oxygen uptake. Methods: Patients with HFpEF (n =15, age 69±6 years) underwent invasive cardiopulmonary exercise testing with measures taken at rest, 20W, and peak exercise. A right heart catheter was used to measure end-expiratory PCWP and cardiac output (Qc, direct Fick). Oxygen uptake (VO 2 ) was measured using Douglas bags. Patients were “cardiac limited” if their ΔQc/ΔVO 2 relationship was blunted (&lt;5) or “peripherally limited” if ΔQc/ΔVO 2 was normal or high (≥5). Effect size between groups was determined with Cohen’s d . Results: Seven patients were cardiac limited and eight were peripherally limited. ΔQc/ΔVO 2 slope was lower in cardiac limited patients (4.2±0.7 vs 6.6±1.3, Cohen’s d = 1.52). Cardiac limited patients were younger and more often female (Values and Cohen’s d shown in Table ). Peak PCWP was similar between the groups (C: 34±8 vs P: 33±7 mm Hg, d = 0.09). Peak VO 2 was higher in cardiac limited patients (C: 12.7±4.3 vs P 9.8±1.3 ml/min/kg, d = 0.85). Stroke volume reserve was lower in the cardiac limited patients (C: 9±18% vs P: 37±20%, d = 0.77). Peripheral oxygen extraction (ΔAVO 2 ) during exercise was lower in the peripherally limited patients (C: 13.2±1.7% vs P: 10.8±1.4%, d =1.24). Conclusions: Phenotyping exercise intolerance using the Fick equation can identify HFpEF patients with primary cardiac and peripheral limitations causing low aerobic power. Cardiac limited patients were unable to augment stroke volume, while peripherally limited patients were unable to augment the oxygen extraction from skeletal muscles. Exercise based phenotyping may be a useful strategy to match therapies to patient specific physiology.
A Quantitative Systems Pharmacology (QSP) Model to Compare the Non-Clinical Biodistribution and Efficacy between Recombinant Factor IX (rIX) Therapies
Authors: Sabine Pestel, Douglas Chung, Alireza Rezvani-Sharif, Ineke Muir, Sivarmurthy Krupa, Markus Brechmann, Anne Verhagen, Steve Dower, Piet H. van der Graaf, Eva Herzog, Oliver Ghobrial
Journal: Blood (2021)
Abstract 10725: Prevalence and Impact of Recurrent Rejection on Graft Loss in Pediatric Heart Transplant Recipients: A Pediatric Heart Transplant Society Multi-Institutional Analysis
Authors: Shahnawaz Amdani, James K Kirklin, Ryan Cantor, Devin Koehl, Ashwin K Lal, Peter Chau, Valerie Curren, Jonathan Edelson, John J Parent, Hannah Bostdorff, Ali L BURNETTE, Jacqueline M Lamour
Journal: Circulation (2021)

Introduction: Rejection remains a significant cause of graft loss after heart transplantation. The current prevalence of recurrent rejection and its impact on graft loss after pediatric heart transplantation is unknown. Methods: All pediatric heart transplants between 1/2000-6/2020 in the Pediatric Heart Transplant Society database were included. Rejection was defined as a clinical event determined by biopsy, echocardiogram or clinical findings that resulted in augmentation of immunosuppression. Recurrent rejection was defined as ≥ 2 episodes of rejection after heart transplant. Freedom from recurrent rejection in the early (2000-2009) and current (2010-2020) era were compared. Multiphase parametric hazard modeling was utilized to understand the effects of each additional episode of rejection on graft loss in addition to identifying other risk factors. Results: Of 6342 heart transplants during the study period, 3921 (62%) had 0, 1386 (21%) had 1 and 1035 (17%) had ≥2 rejection episodes. In the current era, recurrent rejection is less frequent [468/4206 (11.1%) vs. 567/2136 (26.5%); p&lt;0.001] (Figure A). Recurrent rejection increased probability of graft loss in both the unadjusted and multivariate adjusted analysis (HR 1.68; 95% CI 1.61-1.75, p&lt;0.001) (Figure B and Table). Other risk factors for graft loss after pediatric HT are outlined in the Table. Conclusions: Currently, recurrent rejection is experienced by 1 in 10 pediatric HT recipients. Each additional episode of rejection post-HT confers an increasing risk for graft loss. Identifying risk factors for recurrent rejection is paramount to improving graft longevity.
Efficacy and safety of risankizumab for active psoriatic arthritis: 24-week results from the randomised, double-blind, phase 3 KEEPsAKE 2 trial
Authors: Andrew Östör, Filip Van den Bosch, Kim Papp, Cecilia Asnal, Ricardo Blanco, Jacob Aelion, Gabriela Alperovich, Wenjing Lu, Zailong Wang, Ahmed M Soliman, Ann Eldred, Lisa Barcomb, Alan Kivitz
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Risankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to ≤2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here. Methods Adults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved ≥20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes. Results A total of 444 patients (median age 53 years, range 23–84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p&lt;0.001) and all secondary endpoints (p&lt;0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively. Conclusion Treatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR. Trial registration number NCT03671148 .
Abstract 13303: Identification of Critical Six Transcriptional Factors for Reprogramming of Mouse Adipose-Derived Regenerative Cells Toward Cardiomyocytes and Its Therapeutic Effect
Authors: Shingo Narita, Kazumasa Unno, Rei Shibata, Kazuhisa Kondo, Yuuki Shimizu, katsuhiro kato, Yusuke Fujikawa, Toyoaki Murohara
Journal: Circulation (2021)

Background: Adipose-derived regenerative cells (ADRCs) are promising stem cells for regenerative medicine that are easy to harvest from adipose tissues and can expand in vitro . While ADRCs can differentiate into mesodermal lineage cells including adipocytes, osteocytes, and chondrocytes, little is known about differentiating adult ADRCs into mature cardiomyocytes. Objective: The aim of this study was to explore how to differentiate adult mouse ADRCs into cardiomyocytes efficiently and test their effect on the myocardial infarction mouse model in vivo . Method and Results: We performed differential expression analysis to identify transcriptional factors which were upregulated in developing mice heart (E11.5) compared with ADRCs. We systemically screened the combinations of the required transcription factors in ADRCs derived from αMHC-EGFP reporter mice. Here, we identified the following six genes; Baf60c , Gata4 , Gata6 , Klf15 , Mef2a , Myocd , not more or less, as the best combination to efficiently induce αMHC in ADRCs. Fluorescence-activated cell sorting analysis showed that 3.0±0.61% (n=3) ADRCs were positive for αMHC after introducing these six factors. In addition, quantitative PCR demonstrated that several other marker genes of mature cardiomyocytes, including Actc1 , Tnnt2 , Ttn , Fhod3 , were confirmed to be upregulated by six factors. Immunocytochemical staining showed that most of the induced ADRCs had fibrous conformation of sarcomeric α-actin. Moreover, the gene expression pattern of the cells showed upregulation of genes associated with cardiac muscle cell differentiation. Finally, injection of the induced ADRCs into acute myocardial infarction lesions in vivo resulted in the improvement of survival rate (p=0.028, n=32), fractional shortening (p=0.012, n=7, 15), and the reduction of infarction scar area compared to the injection of ADRCs without induction (p=0.029, n=7). The induced ADRCs could survive in situ and continued to express the cardiac troponin T protein for four weeks after injection. Conclusions: The combination of six transcriptional factors could induce cardiomyocyte-like gene expression patterns on adult ADRCs. The induced ADRCs could have a therapeutic effect on an experimental ischemic heart model in vivo .
Abstract 12453: Smooth Muscle-Specific Latexin Deficiency Prevents Platelet-Derived Growth Factor-Mediated Vascular Smooth Muscle Cell Phenotypic Switch and Neointimal Formation
Authors: Kyosuke Kazama, Wennan Liu, Chen Zhang, Xiaobo Sun, Jianxin Sun
Journal: Circulation (2021)

Introduction: Vascular smooth muscle cell (SMC) phenotypic switch from a contractile to a synthetic phenotype plays a significant role in vascular pathologies, including atherosclerosis, restenosis, and aneurysm. Latexin (LXN) is a novel inflammatory protein that is highly expressed in SMCs; the role of LXN in SMCs biology, however, remains largely unknown. Methods: Both global and SMC-specific LXN-knockout mice were generated to determine the in vivo function of LXN in SMC remolding. Neointimal formation induced by mouse carotid artery ligation was assessed by HE staining. Mouse SMCs were isolated from thoracic aortas and used for biological and functional assays. Western blot (WB), immunohistochemistry (IHC), RNA-seq, and quantitative polymerase chain reaction (qPCR) were used to assess protein and gene expression. BrdU incorporation assay and Boyden’s chamber assay were used to assess SMC proliferation and migration. Results: The expression of contractile SMC markers were down-regulated, while synthetic SMC markers were up-regulated in the mouse model of carotid artery ligation. LXN expression was significantly increased in mouse carotid arteries after ligation-induced injury. Furthermore, we found that both global and SMC-specific deletion of LXN significantly attenuated neointimal formation after injury, implicating an essential role of LXN in the modulation of SMC phenotype. Our ex vivo and in vitro functional assays showed that LXN deficiency attenuates SMC proliferation and migration, which is consistent with our RNA-seq data showing that the expression of cell proliferation-related genes was down-regulated in LXN deficient mouse SMCs. Mechanistically, we identified platelet-derived growth factor receptor alpha as a critical mediator involved in regulating SMC phenotypic switch by LXN. Conclusions: Our results for the first time identify LXN as a critical mediator in regulating SMC phenotypic switch and suggest that inhibition of LXN may represent a novel therapeutic strategy for the treatment of proliferative vascular diseases such as atherosclerosis and restenosis.