tbuckley/cabot-search huggingface dataset:
Abstract 11362: Revisiting Gender Equality in Mortality After MitraClip Implantation: A Systematic Review and Meta-Analysis
Authors: Sanjana Nagraj, ISRAEL SAFIRIYU, Sheetal Vasundara Mathai, Leena B.s, Robert Faillace
Journal: Circulation (2021)

Introduction: The presence of gender disparities in outcomes after non-coronary cardiac interventions is well-recognized, but conflicting data have been reported regarding the impact of gender on mortality after MitraClip (MC) implantation. Identification of sex differences in outcomes is important for effective risk stratification in patients with severe mitral regurgitation, who are at high risk for surgery. Hypothesis: We hypothesized that there are no gender-based differences in all-cause mortality after MC procedure. Methods: We searched electronic databases PubMed, Embase, and Web of Science from inception up to May 2021 for studies evaluating patient outcomes after MC implantation. The primary outcome of interest was late all-cause mortality ≥ 1 year after MC procedure. Secondary outcome of interest was in-hospital mortality. A random-effects model meta-analysis was conducted, and heterogeneity was assessed using I-squared test. Results: Seventeen studies comprising 21,549 patients were included. Women constituted 45.2% of the cohort. Male and female genders were not found to be independent predictors of late all-cause mortality ≥ 1 year after MC procedure (male, Hazard Ratio: 1.08; 95% CI: 0.92-1.26; I 2 = 15% and female, Odds Ratio (OR): 0.91; 95% CI: 0.73-1.14; I 2 = 0%, respectively) (Figure 1). There were no differences in in-hospital mortality between women and men after the index procedure (female, OR: 1.06; 95% CI: 0.61-1.85; I 2 = 29%) (Figure 2). Conclusions: There is no gender disparity in mortality with MitraClip implantation, both in-hospital and during long-term follow-up.
Abstract P402: Caveolin-1 Upregulation Leads To Decreased Erg And Stress-induced Ventricular Tachycardia In Cystic Fibrosis Hearts
Authors: Dao-Fu Dai
Journal: Circulation Research (2021)

Background: Cardiac manifestations of cystic fibrosis are classically accepted as cor pulmonale, yet emerging evidence supports that cardiac abnormalities can develop early when respiratory function is preserved. Myocardial cystic fibrosis transmembrane regulator (CFTR) channels, inactive in normal conditions, are activated in response to catecholamine stress. Methods and Results: In multiple mouse models of homozygous CFTR mutations (S489X or F508d), we demonstrate increased susceptibility to ventricular tachycardia (VT) in response to epinephrine, and this is associated with prolongation of QTc intervals (repolarization). Despite having normal left ventricular ejection fraction and histology, CF S489X mut/mut hearts showed 460 proteins significantly altered compared with WT hearts by tandem mass tag (TMT) proteomics. The Ingenuity Pathway Analysis of proteomics data revealed mitochondrial dysfunction and increased caveolin-1 signaling among the top pathways affected in CF S489X mut/mut hearts. In mouse hearts and human induced pluripotent stem cells derived cardiomyocytes (iPS-CM) with CFTR mutations, we observed increased ER stress and caveolin-1 (cav-1). These changes are concomitant with reduced levels of the ERG channel, a K+ channel contributing to phase 3 repolarization, mutations of which cause long QT syndrome II and VT. Patch clamp analysis showed decreased phase 2-3 repolarization current (including hERG current) in CF F508d iPS-CM compared with control iPS-CM, consistent with the findings of decreased membranous hERG and elevated Cav-1. Suppression of Cav-1 successfully restores membranous hERG in two separate lines of mutant iPS-CM generated from CF patients with F508d mutation. In F508d mut/mut mice, suppression of cardiac Cav-1 upregulation by reducing ER stress using TUDCA or crossing with heterozygous Cav-1 +/- abolished the stress-induced VT. Our analysis of a large-scale real-world clinical database from TriNetX, including 4520 CF men, 3510 CF women and the same number of well-matched controls demonstrated novel findings of increased risk for QT prolongation and VT in CF patients. Retrospective analysis of 126 CF patients with available EKG in our hospital revealed significant QTc prolongation in CF patients compared with matched controls, for both males (CF 447.8±4.5 vs cont. 429.2±2.5) and females (CF 454.0±3.5 vs cont.437.5±2.4). The QTc interval is not affected by lung function (%predicted FEV1) and is an independent predictor of survival in CF patients. Conclusions: In mice and iPS-CM models of CF, we demonstrated impaired repolarization and increased susceptibility to stress-induced VT. This is mediated by ER-stress-induced upregulation of Cav-1, which leads to internalization of ERG and subsequent decrease in repolarization current.
CTIM-09. PHASE I STUDY OF PD-L1 INHIBITION WITH AVELUMAB AND LASER INTERSTITIAL THERMAL THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Adilia Hormigo, Daniel Chiu, Mary Hahn, Jingjing Qi, Brian Lee, John Mandeli, Saadi Ghatan, Constantinos Hadjipanayis, Raymund Yong, Isabelle Germano, Sacha Gnjatic, Seunghee Kim-Schulze
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The treatment of glioblastoma (GBM) poses many challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by a low mutational burden and low infiltration by T cells. The combination of ICI with other treatment modalities may improve efficacy. METHODS Patients with recurrent GBM were treated with 800 mg avelumab, a human IgG1 antibody directed against PD-L1, either alone (in part A) or within a week after MRI-guided laser interstitial thermal therapy (LITT, in part B) and by-weekly thereafter (NCT03341806). To spare steroid use, bevacizumab was allowed to be combined with avelumab. The primary objective was to characterize the tolerability and safety of the regimen. The secondary objectives included overall survival, progression-free survival, and signature of plasma analytes. RESULTS A total of 12 patients (median age 64, range 37 - 73) enrolled from June 2018 to November 2019, 5 in part A and 7 in part B. Three serious adverse events (SAE) occurred in the same patient, not leading to death. There were 94 AEs reported, 5 grade 3, 28 grade 2, and 61 grade 1. The median PFS was 16.7 weeks (range 7.4-56.7) for patients in Part A and 30.9 weeks (range 8.5-77.7) for patients in Part B. The median survival for patients in part A was 11 months and 13.5 months for part B. The risk ratio of death by combining bevacizumab was 0.573 (p=0.258) with significantly decreased levels of peripheral blood plasma inflammatory markers such as EGF, CXCL5, VEGFA, LAP.TGβ1, ANGPT2 in women. CONCLUSIONS Avelumab was generally well-tolerated, and the combination with LITT had a manageable safety profile and increased survival in a subset of patients. The addition of bevacizumab may increase survival by lowering cytokine expression in a gender-dependent manner. These results warrant further investigation in the next phase study.
NCOG-33. GROWTH DYNAMICS OF INCIDENTAL MENINGIOMAS - A 10-YEAR PROSPECTIVE STUDY
Authors: Torbjørn Austveg Strømsnes, Morten Lund-Johansen, Geir Olve Skeie, Bente Sandvei Skeie
Journal: Neuro-Oncology (2021)

Abstract There is no consensus for the management of incidental meningiomas. To evaluate the natural history, we assessed tumour growth dynamics during 10 years of active monitoring of 62 patients (45 female and mean age 63.9) harbouring 68 tumours. Radiological and clinical data was obtained was obtained biannually for two years, then annually the following eight. Thirty-six patients (38 tumours) were referred to treatment and/or died of unrelated causes (n=5) within 5 years. The remaining were monitored for up to 10 years. Mean overall survival was at 128 months (95% CI: 118.8-136.7). Median progression free survival was 34 months (95% CI: 14.7-53.3). Median time for growth requiring intervention was 46 months (95% CI: 23.5-68.5). All tumours with self-limiting growth at 5 years (57.9 %) were still stable or reducing in size at 10 years. Mean growth rate decreased from 0.27 cm3/year (95% CI: 0.10-0.43) during the early observation period (0-5 years) to 0.09 cm3/year (95% CI: -0.02-0.21) in the late observation period. No tumours were referred to treatment during the late observation period. Two patients, both with verified WHO2 grade meningiomas succumbed to the disease, seven and eight years after diagnosis. No other patients developed symptoms and none other of the 18 total mortalities were meningioma related. Most clinical and radiological events occur within 5 years after diagnosis. Our findings suggests that if tumour growth slows down during the first 5 years of monitoring, this trend will continue. Clinical follow-up should be sufficient when a self-limiting growth pattern has been established.
Social overcrowding impacts gut microbiota, promoting stress, inflammation, and dysglycemia
Authors: Delaroque Clara, Mélissa Chervy, Andrew T Gewirtz, Benoit Chassaing
Journal: Gut Microbes (2021)

An array of chronic inflammatory diseases, including metabolic diseases such as obesity and diabetes, are thought to be promoted by disturbance of the intestinal microbiota. Such diseases disproportionately impact low-income communities, which are frequently afflicted by chronic stress and increased density housing. Hence, we hypothesized that overcrowded housing might promote stress, microbiota dysbiosis, inflammation, and, consequently, metabolic diseases. We tested this hypothesis in a tractable murine model of social overcrowding (SOC), in which mice were housed at twice normal density. SOC moderately impacted behavior in some widely used assays (Open Field, Elevated Plus Maze and Light/Dark tests) and resulted in a stark increase in corticosterone levels. Such indices of stress were associated with mild chronic gut inflammation, hyperglycemia, elevations in colonic cytokines, and alterations in gut microbiota composition. All of these consequences of SOC were eliminated by broad spectrum antibiotics, while some (inflammation and hyperglycemia) were transmitted by microbiota transplantation from SOC mice to germfree mice housed at normal density. Altogether, these results suggest a central role for intestinal microbiota in driving stress, inflammation, and chronic diseases that are promoted by overcrowded housing.
Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells
Authors: Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love
Journal: Journal of Clinical Investigation (2021)

Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper-like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.
Abstract 12130: Statin Use is Associated With Lower Risk of New Onset Dementia in Patients With Heart Failure: A Population-Based Study
Authors: Qingwen Ren, Tse Yi Kei Stephanie, Si-Yeung Yu, Hang Long Li, Wong Pui Fai, Wu mei zhen, Kai Hang Yiu
Journal: Circulation (2021)

Introduction: Increasing number of heart failure (HF) patients diagnosed with dementia due to improved treatment and aging population. Data relating to the association of statin use on the risk of dementia incidence among patients with HF are sparse. Hypothesis: The use of statin is associated with lower risk of new- onset dementia in HF population. Methods: Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (N=241,995) from 1996 to 2019. Propensity score matching was used to balance baseline covariates between statin nonusers (167,738 patients) with statin users (74,257 patients). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of incident dementia associated with statin use. Results: Of all eligible subjects, the mean age was 76.5±13.0 years, 115,371(47.7%) was male. Over a median follow-up of 2.7 years (interquartile range [IQR]: 0.6 to 6.7), 13,482 (5.6%) patients were diagnosed with dementia including Alzheimer's disease (N=5,253), senile dementia uncomplicated (N=4,273), arteriosclerotic dementia (N=3,262), and others (N=694). Statin use (vs. none) was associated with a 58% lower risk of dementia incidence (multivariable-adjusted sub-distribution hazard ratio [SHR]=0.42; 95% Confidence Interval [CI], 0.38 to 0.46) after accounting for death as a competing risk. Moreover, the male gender was associated with a 51% lower risk of dementia incidence (multivariable-adjusted SHR=0.59; 95%CI (0.54-0.65) compared with females. Conclusions: Our study suggests that there is substantial sex difference in the incidence of dementia among HF patients. Moreover, statin use is associated with a significantly lower risk of incident dementia in HF.
Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats
Authors: Yu-Feng Hu, An-Sheng Lee, Shih-Lin Chang, Shien-Fong Lin, Ching-Hui Weng, Hsin-Yu Lo, Pei-Chun Chou, Yung-Nan Tsai, Yen-Ling Sung, Chien-Chang Chen, Ruey-Bing Yang, Yuh-Charn Lin, Terry B. J. Kuo, Cheng-Han Wu, Jin-Dian Liu, Tze-Wen Chung, Shih-Ann Chen
Journal: Nature Biomedical Engineering (2021)
Abstract 13306: Predictors of All-Cause Mortality in Heart Transplant Recipients With COVID-19
Authors: Sovik De Sirkar, Mingxi Yu
Journal: Circulation (2021)

Introduction: Heart transplant recipients are among the most vulnerable to suffer complications from Covid-19, yet there remains no standard of treatment. The primary objective of this study was to identify predictors of all-cause mortality in heart transplant recipients infected with Covid-19 to better tailor management for these medically complex patients. Methods: A retrospective analysis of 28 heart transplant recipients with Covid-19 infections was performed at Loyola University Medical Center, a large tertiary care academic center located in the Chicago metropolitan area. Numerical data was assessed using two-tailed t-tests and bivariate logistical regression. Categorical variables were analyzed using chi-squared tests. Statistical analysis was performed using JMP Pro 15. Results: Between March 1, 2020 and April 30, 2021, 28 heart transplant recipients with Covid-19 sought care at our hospital. The inpatient cohort consisted of 19 patients, 10 (53%) of whom met the primary endpoint of all-cause mortality. Those in the mortality arm (mean age 58.7 ± 21.5 vs 54.3 ± 13.1 in survival arm, p=0.58) were more likely to present closer to symptom onset with an elevated RR, INR, lower MAP, cough, or ESRD. Patients admitted to an ICU with superimposed infections or shock, requiring antibiotics, vasopressors, dialysis, or convalescent plasma were more likely to meet the primary endpoint. Azathioprine appeared protective against all-cause mortality. Conclusions: This is the only known study to assess clinical outcomes in heart transplant recipients based in the American Midwest, a region with a high infection burden but equipped with commensurate clinical resources and access to evolving Covid-directed therapies. Our study demonstrated a considerably high mortality rate (53%) among heart transplant recipients with Covid-19 despite these measures. Further studies are warranted to identify key predictors of mortality in this population to guide management.
Abstract 13136: Immune Cell Mitochondrial Function and Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Natalie J Bohmke, Domenico A Chavez, Moriah C Carper, Hayley E Billingsley, Marco G Del Buono, Roshanak Markley, Salvatore Carbone, Antonio Abbate, Danielle L Kirkman
Journal: Circulation (2021)

Background: Systemic, multimorbidity-driven inflammation may promote diastolic dysfunction in HFpEF. In this regard, anti-inflammatory therapies have been an attractive treatment strategy in clinical trials of HFpEF. Metabolic reprogramming of immune cells that alter the mitochondrial bioenergetic profile may be an upstream mediator of inflammation. Our aim was to investigate the relationship between the immune cell bioenergetic profile and diastolic function in HFpEF. Methods: Nine female patients with a diagnosis of HFpEF (4 Black, 5 White; Median [IQR]: Age 60 [46-67] yrs; BMI 37 [34-42] kg/m 2 ) were enrolled. The mitochondrial bioenergetic profile was assessed in isolated peripheral blood mononuclear cells by respirometry coupled with modulators of cellular respiration to obtain basal respiration, ATP-linked respiration, maximal respiration and non-mitochondrial respiration. Transthoracic echocardiographic Doppler measures of diastolic function were performed and included mitral inflow velocities (E wave) and early diastolic mitral annular velocity (e’). Results: Diastolic function, represented by E/e’ (Median [IQR]: 10 [8-10] was inversely associated with basal respiration ( r =-0.78, p=0.01), maximal respiration ( r =-0.87, p =0.002), ATP linked respiration (54 [40-105] pmol/min, r =-0.75, p =0.02), non-mitochondrial oxygen consumption (24 [20-35] pmol/min, r =-0.82, p =0.007) and spare respiratory capacity (r=-0.82, p=0.007) as shown in Figure 1. Conclusion: There is a strong negative association between the immune cell mitochondrial bioenergetic profile and diastolic function in HFpEF. Patients with greater impairment in diastolic function, as shown by higher E/e’ ratios, have lower immune cell respiration and reduced respiratory reserve. The relationship between immune cell mitochondrial function, inflammation and diastolic function in HFpEF patients warrants further investigation.
DDRE-33. PRECLINICAL THERAPEUTIC EFFICACY OF THE NOVEL BLOOD BRAIN BARRIER PENETRANT ATR INHIBITOR LR02 IN GLIOBLASTOMA
Authors: Dimpy Koul, Veerakumar Balasubramaniyan, Xiaolong Li, Sabbir Khan, Davide Guggi, Thomas Mehrling, John DeGroot
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months despite radiation and alkylating temozolomide (TMZ) chemotherapy. DNA damage response (DDR) pathways are among the most important key players of oncogenic mutations associated with resistance to both chemotherapy and radiation in GBM. The high frequency of alterations in DDR pathways in GBM suggests that its inhibition by DDR inhibitors may render GBM cells more susceptible to DNA damaging interventions. Here, we report the preclinical in vitro and in vivo activity of a novel, orally bioavailable Ataxia-telangiectasia mutated serine/threonine protein kinase and Rad3-related (ATR) inhibitor LR02 (Laevoroc Oncology) in a panel of 15 well-characterized glioma stem-like cells (GSCs). Effects on cell proliferation, survival and tumor formation were analyzed following treatment with LR02. Growth inhibition was time- and dose-dependent with a 3-day exposure resulting in a growth inhibitory IC50 (gIC50) in the low nM range in all the glioblastoma cell lines tested. LR02 inhibited growth of GSCs at IC50 values ranging from 500nmol/L to-~2umol/L. Additional studies showed that temozolomide sensitized GSC to LR02. Importantly, we demonstrate that MGMT promotor methylation status was associated with cellular response to LR02 treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. LR02 showed efficacy and survival benefit in a GSC262 (MGMT methylated) orthotopic model of GBM. Further administration of LR02 further enhanced the in vivo antitumor efficacy of temozolomide (TMZ) against GBM using the GSC262 model demonstrating that ATR inhibitor LR02 may enhance alkylating agent-mediated cytotoxicity and provide a novel treatment combination for GBM patients. Our present findings establish that the ATR inhibitor LR02 can specifically be used in tumors with MGMT deficiency when combined with alkylating chemotherapy. Further studies are ongoing to evaluate the potential of LR02 to overcome radiation and chemotherapy resistance in glioblastoma.
Cancer Risks Associated With <i>BRCA1</i> and <i>BRCA2</i> Pathogenic Variants
Authors: Shuai Li, Valentina Silvestri, Goska Leslie, Timothy R. Rebbeck, Susan L. Neuhausen, John L. Hopper, Henriette Roed Nielsen, Andrew Lee, Xin Yang, Lesley McGuffog, Michael T. Parsons, Irene L. Andrulis, Norbert Arnold, Muriel Belotti, Åke Borg, Bruno Buecher, Saundra S. Buys, Sandrine M. Caputo, Wendy K. Chung, Chrystelle Colas, Sarah V. Colonna, Jackie Cook, Mary B. Daly, Miguel de la Hoya, Antoine de Pauw, Hélène Delhomelle, Jacqueline Eason, Christoph Engel, D. Gareth Evans, Ulrike Faust, Tanja N. Fehm, Florentia Fostira, George Fountzilas, Megan Frone, Vanesa Garcia-Barberan, Pilar Garre, Marion Gauthier-Villars, Andrea Gehrig, Gord Glendon, David E. Goldgar, Lisa Golmard, Mark H. Greene, Eric Hahnen, Ute Hamann, Helen Hanson, Tiara Hassan, Julia Hentschel, Judit Horvath, Louise Izatt, Ramunas Janavicius, Yue Jiao, Esther M. John, Beth Y. Karlan, Sung-Won Kim, Irene Konstantopoulou, Ava Kwong, Anthony Laugé, Jong Won Lee, Fabienne Lesueur, Noura Mebirouk, Alfons Meindl, Emmanuelle Mouret-Fourme, Hannah Musgrave, Joanne Ngeow Yuen Yie, Dieter Niederacher, Sue K. Park, Inge Sokilde Pedersen, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Muhammad U. Rashid, Florian Reichl, Julia Ritter, Andreas Rump, Marta Santamariña, Claire Saule, Gunnar Schmidt, Rita K. Schmutzler, Leigha Senter, Saba Shariff, Christian F. Singer, Melissa C. Southey, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Tan, Soo Hwang Teo, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Ana Vega, Sebastian A. Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H. F. Weber, Drakoulis Yannoukakos, Amanda B. Spurdle, Douglas F. Easton, Georgia Chenevix-Trench, Laura Ottini, Antonis C. Antoniou
Journal: Journal of Clinical Oncology (2022)

To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in