tbuckley/cabot-search huggingface dataset:
CTIM-18. LUMINOS-101: INITIAL SAFETY AND TOLERABILITY OF PVSRIPO AND PEMBROLIZUMAB COMBINATION THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Andrew Sloan, Robin Buerki, Daniel Landi, Annick Desjardins, Allan Friedman, Prakash Ambady, Kevin Becker, Nicholas Butowski, Robert Cavaliere, William Curry, Shirley Ong, Rafael Vega, Patrick Wen, Bruno Bockorny, E Antonio Chiocca, J Bradley Elder, Ketan Bulsara, Mitchel Berger, Elizabeth Gerstner, Eric Sauvageau, Andrea Kelly, Lori Mixson, LeAnn Jackson, Chris Learn, Adam Dickinson, W Garrett Nichols
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Recurrent glioblastoma (rGBM) is rapidly fatal with current therapies. PVSRIPO is an intratumoral immunotherapy targeting CD155 on antigen-presenting and malignant cells of solid tumors. Preclinically, PVSRIPO treatment leads to systemic, tumor antigen-specific, polyfunctional T-cell–mediated anti-tumor response, predominately driven by type I/III interferons. This inflammatory signature generates anti-tumor immunity and upregulates the programmed death (PD)-1 immune checkpoint in the tumor microenvironment. Preclinical models (including GBM) have shown that PVSRIPO+anti-PD-1/L1 therapy was more efficacious than either agent alone, warranting further investigation. METHODS Adults with histologically confirmed rGBM (1-2 prior progressions), Karnofsky performance status (KPS) ≥70, and an active, supratentorial, contrast-enhancing lesion (1-5.5 cm), received PVSRIPO (5x107 TCID50) intratumorally via convection-enhanced delivery (Day 1), followed by 200 mg pembrolizumab IV at week 2, given every 3 weeks for up to 24 months, to evaluate the safety/efficacy of the combination. A safety lead-in period (n=3-6) with a minimum 21–28-day delay before treatment of subsequent patients was planned, with a data safety monitoring board (DSMB) evaluating safety/tolerability prior to expansion (up to N=30). RESULTS The first 3 patients enrolled (ages 55-60, KPS 90-100) all received PVSRIPO followed by pembrolizumab (1-5 cycles), as planned. At cutoff (26-106 days of follow-up), there were no dose-limiting toxicities, treatment-emergent (TE) serious adverse events (SAE), or TEAEs necessitating a delay in initial/subsequent pembrolizumab treatments. All patients experienced a related TEAE, all grade 1 or 2 in severity. One patient experienced an AE of special interest (peritumoral edema, resulting in headache and hemiparesis), successfully managed with low-dose bevacizumab and corticosteroids. The DSMB unanimously recommended the study proceed without modification. CONCLUSIONS Intratumoral PVSRIPO+pembrolizumab was reasonably well tolerated, warranting continued investigation of the safety and efficacy of this combination in patients with rGBM.
Abstract 10043: Disparities in Femoropopliteal Endovascular Intervention and Subsequent Outcomes by Race and Socioeconomic Status
Authors: Anna K Krawisz, Rishi Wadhera, Sahana Natesan, Siyan Chen, Yang Song, Robert W Yeh, Michael R Jaff, Eric A Secemsky
Journal: Circulation (2021)

Introduction: Disparities in the diagnosis, treatment, and outcomes of patients with peripheral artery disease are well-established. It is not known whether race or wealth-based disparities exist in the use of or outcomes following femoropopliteal endovascular intervention (PVI). Hypothesis: Black and lower socioeconomic status (SES) patients are treated with PVI more frequently and have worse outcomes following PVI. Methods: All fee-for-service Medicare beneficiaries ≥66 years of age from 2016 to 2018 were evaluated to determine the population-level use of PVI by race (Black/White/Other) and dual Medicaid enrollment (DE) status standardized by age and sex. Separately, age and sex standardized risks for the composite of death and amputation within 1 year after PVI were examined by race and DE status. Subgroup analyses were performed by indication for PVI (claudication/critical limb ischemia/other). Results: 215,320 patients underwent PVI. Black beneficiaries underwent 928 PVIs per 100,000 Black beneficiaries compared with 530 PVIs per 100,000 White beneficiaries and 469 PVIs per 100,000 beneficiaries of Other races (risk ratio [RR] = 1.75 for Black vs. White, 95% CI 1.73-1.77, p&lt;0.01; RR = 0.89 for Other vs. White, 95% CI 0.87-0.90, p&lt;0.01). DE patients underwent 999 PVIs per 100,000 DE beneficiaries compared with 495 PVIs per 100,000 non-Medicaid beneficiaries (RR = 2.02, 95% CI 2.00-2.04 p&lt;0.01). 17.6% of Black patients who underwent PVI suffered amputation or death by 1 year vs. 15.2% of White patients (RR = 1.16, 95% CI 1.12-1.20, p&lt;0.01). This association persisted after adjustment by DE status. 19.3% of DE patients experienced amputation or death by 1 year vs. 14.4% of patients with Medicare alone (RR = 1.34, 95% CI 1.31-1.38, p&lt;0.01). These findings persisted after adjustment by race. All analyses demonstrated consistent findings across indications for PVI. Conclusions: Among Medicare beneficiaries, Black patients underwent more PVIs than White patients and patients of other races and experienced greater rates of subsequent amputation and death. Patients with lower SES underwent more PVIs than patients with higher SES and had higher rates of subsequent amputation and death. Findings persisted after adjustment for age, sex, and race or SES.
Abstract 12381: Clinical Implications of SCN5A and SCN10A Loss of Function Variants in 169,610 Exomes Representing the General Population
Authors: Christian Paludan-Mueller, Simon Larsen, Gustav Ahlberg, Laura Andreasen, Jesper Hastrup H Svendsen, Jorgen K Kanters, Morten S Olesen
Journal: Circulation (2021)

Background: Genetic variation in the genes SCN5A and SCN10A has previously been associated with cardiac disease and conduction velocity through genome-wide association studies (GWAS) and rare varia...
Abstract 11955: Heart Disease as a Risk Factor for Dementia Has Higher Association in Women Than in Men
Authors: Dongshan Zhu, wenting Hao, Chunying Fu
Journal: Circulation (2021)

Introduction: Cardiovascular diseases (CVD) have been linked to cognitive impairment and dementia. However, whether the association of CVD events and dementia differed by sex remains unclear. Hypothesis: We hypothesized that there might be a sex difference in the association between CVD events and dementia, and the effect of CVD on the risk of dementia might be greater in women than in men. Methods: We used cohort data from UK Biobank, a large population-based prospective cohort study that recruited 502 649 individuals ages 40- 69, between 2006 and 2010. Cox proportional hazards models were used to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (including coronary heart diseases (CHD), stroke and heart failure) and incident dementia (including all-cause dementia, Alzheimer's Disease (AD), vascular dementia and dementias in other diseases classified elsewhere). Results: Overall, 482 185 (54.6% women) people with no prevalent dementia were included. After 10 (median) years follow-up, 5330 participants (46.9% women) developed dementia. The crude incidence rates were 10.1 for women and 13.8 for men, per 10,000 person-years. The HRs (95%CI) between any CVD events, un-overlapped CHD, stroke, heart failure and all-cause dementia in women were higher than the estimates in men, with an RHR (95%CI) of 1.25 (1.17, 1.34), 1.37 (1.23, 1.51), 1.15 (1.00, 1.34) and 1.16 (1.03, 1.31) respectively. Also, the HRs for AD of CHD and heart failure in women were higher than the estimates in men, with an RHR (95%CI) of 1.73 (1.48, 2.02) and 1.40 (1.14, 1.72) respectively. Nevertheless, the HRs (95% CI) between stroke and vascular dementia was higher in men (5.35, 4.07-7.04) than that in women (3.24, 2.14-4.92) (Table 1). Conclusions: There was a sex difference in the association between CVD events and dementia. The risk of CHD and heart failure for dementia was greater in women than in men.
Hypomethylating Agents As Maintenance Treatment Following Allogeneic Hematopoietic Transplant in Children's Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Single Center Study
Authors: Yongsheng Ruan, Danfeng Xie, Xuan Liu, Qiujun Liu, Chunfu Li, Xuedong Wu, Yuelin He, Xiaoqin Feng
Journal: Blood (2021)
Abstract 11533: Genetic Prediction Tool Using <i>LPA</i> Haplotypes Improves Identification of Patients with Elevated Lipoprotein(a)
Authors: Deepak Atri, Ronen E Mukamel, Po-ru Loh, Ron Blankstein, Rajat M Gupta
Journal: Circulation (2021)

Introduction: Multiple lines of evidence support the causal role of serum lipoprotein (a) [Lp(a)] in the pathogenesis of cardiovascular disease, including CAD/MI and ischemic stroke. Mendelian randomization studies demonstrate that genetic variation is the principal determinant of serum Lp(a) level, and that variants associated with higher Lp(a) are associated with higher vascular disease risk. Though 80-90% of variation in serum Lp(a) levels is genetically-determined, single nucleotide polymorphisms (SNPs) contribute a small fraction of this risk. SNPs, however, may be used to identify LPA alleles based on a reference panel. These LPA alleles are the primary genetic determinants of serum Lp(a). New methods that identify these alleles using extended SNP haplotypes may improve serum Lp(a) prediction and identify at-risk patients. Hypothesis: The use of reference panels of extended LPA haplotypes can identify patients with elevated Lp(a) in a genotyped, hospital-based cohort. Methods &amp; Results: We identified all genotyped subjects in the Massachusetts General Brigham Biobank with a history of CAD or ischemic stroke for genetic prediction of serum Lp(a) (n = 3202). The majority of these patients (n = 2578, 80.5%) did not have a prior Lp(a) measurement as part of clinical care. We computed genetic predictions of Lp(a) in all patients by matching their SNP haplotypes to a reference panel of ~50,000 UK Biobank participants (and ~440,000 haplotypes) for whom LPA alleles had been matched to Lp(a) levels. The 90th percentile, 258 patients, had predicted Lp(a) of &gt;75mg/dl (~159nM), equal to the 90th percentile of the general population. We observed strong correlation between predicted and clinically-measured Lp(a) (R2 = 0.75-0.92 across four clinical assays; p&lt;0.0001 for all; n = 372). Conclusions: We demonstrate the validity of a serum Lp(a) genetic prediction with very high fidelity in a disease cohort using a new method of imputed SNP haplotypes. Using LPA alleles, as determined by SNPs, we identified patients who are likely to have elevated serum Lp(a) without a prior measurement. This method may be applied to biobank populations to identify patients at risk for cardiovascular disease mediated by elevated serum Lp(a).
IMMU-30. IDENTIFICATION OF COORDINATELY REGULATED IMMUNO-MODULATORY GENES USING SINGLE-CELL RNA SEQUENCING OF DECITABINE TREATED GLIOMA CELLS
Authors: Thomas Lai, Janet Treger, Jingyou Rao, Robert Prins, Richard Everson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Our previous data has shown that the hypomethylating agent decitabine (DAC) is a strong sensitizer of GBM to NY-ESO-1 specific adoptive T-cell induced cytotoxicity. However, we hypothesized that DAC alters expression of other immuno-modulatory genes in addition to NY-ESO-1 that may also increase T-cell mediated killing in GBM. The extent of regulation of other immuno-modulatory genes to DAC demethylation has not yet been thoroughly investigated. METHODS We performed single-cell RNA sequencing on DAC and non-DAC treated glioma cells. We confirmed DAC treatment induced NY-ESO-1 expression with quantitative real-time PCR and demethylation using bisulfite sequencing. We analyzed our single-cell RNA sequencing data with Seurat and our customized R-based pipelines to identify coordinate differential expression of immuno-modulatory genes and their tumor subpopulations. RESULTS Using our single-cell data, we identified tumor subpopulations with coordinate differentially expressed immuno-modulatory genes including cancer testes antigens, antigen presentation proteins, and apoptosis regulators. Amongst these candidate genes, we validated their expression with qPCR and promoter demethylation with bisulfite sequencing and TA bisulfite cloning. CONCLUSION Exposure of glioma cells to DAC results in promoter demethylation of NY-ESO-1, with increased expression of CTA and other immunomodulatory genes. DAC treatment may therefore sensitize GBM to the immunotherapeutic targeting of these antigens and reveals a feasible strategy for clinical translation.
Abstract P487: Impact Of Oxidative Dna Damage On Heart Health
Authors: Kaitlin Lowran, Colin Wu, Ingrid Petersen
Journal: Circulation Research (2021)

The accumulation of DNA damage in human cardiomyocytes causes apoptosis which can lead to heart failure or other cardiovascular diseases. Although the effects of oxidative stress on heart health and on the DNA Damage Response network are well-known, the two fields have evolved as separate areas of research. The precise impact of oxidative DNA damage on cardiomyocyte contractile function still remains poorly understood. The human FANCJ helicase participates in multiple DNA repair pathways, including interstrand crosslink repair and double-stranded break repair. We have shown previously that FANCJ targets and unfolds 8-oxoguanine modified DNA secondary structures that arise from oxidative damage. We predict that human cardiomyocytes expressing mutations of FANCJ would be more susceptible to oxidative DNA damage and will negatively influence their contractile motion. To test this, hiPSC-CMs were treated with hydrogen peroxide, camptothecin, or bleomycin to induce different forms of DNA damage. The relative abundance of single-stranded DNA breaks and double-stranded DNA breaks were determined by modified comet assays, while contractile function was monitored using video-based detection methods. Cells that overexpress FANCJ protein were able to overcome the chemical stress from hydrogen peroxide. On the contrary, cells that produce a FANCJ K141/K142AA variant, which was previously characterized in the lab, resulted in a hypersensitivity to double-stranded DNA breaks. Based on this evidence, FANCJ plays a vital role in alleviating the effects of oxidative stress. Our long-term goal is to use the established methods to develop functional assays that characterize the cardiovascular risks of other FANCJ variants. These assays can be used to develop screening methods to identify patients who may be predisposed to FANCJ-associated cardiovascular diseases.
The Longitudinal Dynamics and Natural History of Clonal Hematopoiesis
Authors: Margarete A Fabre, Jose Guillherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orru, Michele Marongiu, MS Vijayabaskar, Joanna E Baxter, Claire Hardy, Federico Abascal, Michael Spencer Chapman, Nicholas Williams, Jyoti Nangalia, Inigo Martincorena, Peter J Campbell, Eoin F Mckinney, Francesco Cucca, Moritz Gerstung, George S Vassiliou
Journal: Blood (2021)
Abstract 10584: Transitioning a Pediatric Cardiac Intensive Care Unit Rounding Checklist from Paper to the Electronic Health Record to Improve Utilization - A Quality Improvement Project
Authors: Michael C Mowrer, Prashanth Shanmugham, Joscyln Patrick, Rong Huang, Joshua S Wolovits, Olivia L Hoffman
Journal: Circulation (2021)

Background: Delivering excellent clinical care in a pediatric cardiac intensive care unit (PCICU) involves coordination of a multidisciplinary team and consistent implementation of best practices. A rounding checklist (RC) may mitigate failures in communication and reduce practice variability. Multiple barriers to successful RC utilization remain, including poor provider compliance. Aim: The primary aim of this quality improvement (QI) project is to implement and evaluate the utilization and effectiveness of an electronic health record (EHR)-based RC in the PCICU. Methods: In collaboration with key stakeholders, we used Plan-Do-Study-Act (PDSA) QI methodology to adapt our existing paper-based RC into an EHR-embedded tool (Fig 1). We conducted educational sessions prior to implementation of the RC to review its potential benefits. We evaluated project impact through pre- and post-implementation surveys of PCICU attendings, fellows and advanced practice providers. Our primary outcome metric was RC utilization. Results: Most pre-implementation survey respondents (n=33), agreed or strongly agreed that they would be interested in using a RC (78%), and it would be helpful (87%). During the first PDSA cycle, of 65 eligible patients, 74% (n=48) had the checklist completed at least once during their CVICU admission. Of 28 eligible providers during the same PDSA, 71% (n=20) completed a RC in the EHR at least once. Most survey respondents (n=25) after the first PDSA agreed or strongly agreed that using the RC is helpful (64%), easy (60%) and can be improved (60%). We continue to modify evaluate the RC and its utilization in subsequent PDSA cycles. Conclusion: Transitioning a RC from paper to the EHR is feasible and improves tracking of utilization. Engaging providers for feedback and making real-time modifications may improve future RC compliance. Continued data collection will improve our understanding of the RC’s impact on health care delivery and patient safety.
Timing of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study
Authors: Edouard L Fu, Marie Evans, Juan-Jesus Carrero, Hein Putter, Catherine M Clase, Fergus J Caskey, Maciej Szymczak, Claudia Torino, Nicholas C Chesnaye, Kitty J Jager, Christoph Wanner, Friedo W Dekker, Merel van Diepen
Journal: BMJ (2021)

To identify the optimal estimated glomerular filtration rate (eGFR) at which to initiate dialysis in people with advanced chronic kidney disease.
Abstract 12247: Mitochondrial Metabolic Transcriptome Profiles During Cardiomyocyte Differentiation From Mouse and Human Pluripotent Stem Cells
Authors: Sung Woo Cho, Hyoung Kyu Kim, Ji-Hee Sung, Jin Han
Journal: Circulation (2021)

Introduction: Simultaneous increase of myofibrils and mitochondria is a key process of cardiomyocyte differentiation from pluripotent stem cells (PSCs). Specifically, development of mitochondrial oxidative energy metabolism in cardiomyocytes is essential to providing the beating function. Although previous studies reported that mitochondrial oxidative metabolism have some correlation with the differentiation of cardiomyocytes, the mechanism by which mitochondrial oxidative metabolism is regulated and the link between cardiomyogenesis and mitochondrial function are still poorly understood. Methods: We performed transcriptome analysis on cells at specific stages of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs). We selected highly upregulated mitochondrial metabolic genes at cardiac lineage commitment and time-dependent manner during cardiomyocyte differentiation and identified the protein-protein interaction network connecting between mitochondrial metabolic and cardiac developmental genes. Results: We found several mitochondrial metabolic regulatory genes at cardiac lineage commitment (Cck, Bdnf, Fabp4, Cebpa, Cdkn2a in mESC-derived cells and CCK, NOS3 in hiPSC-derived cells) and time-dependent manner during cardiomyocyte differentiation (Eno3, Pgam2, Cox6a2, Fabp3 in mESC-derived cells and PGAM2, SLC25A4 in hiPSC-derived cells). Notably, mitochondrial metabolic proteins are highly interacted with cardiac developmental proteins time-dependent manner during cardiomyocyte differentiation rather than cardiac lineage commitment. Furthermore, mitochondrial metabolic proteins are mainly interacted with cardiac muscle contractile proteins rather than cardiac transcription factors in cardiomyocyte. Conclusions: Mitochondrial metabolism is critical at cardiac maturation rather than cardiac lineage commitment.
Abstract 11370: Track and Trigger System Based on Patient Analytics for Cardiac Arrest Risk Identification
Authors: Hayden Zaccagni, Ahmed Asfari, Kristal M Hock, Jordan Huskey, Adam Tomczak, Evan Butler, Santiago Borasino
Journal: Circulation (2021)

Introduction: Cardiac Arrest (CA) is a serious, yet not infrequent complication in the cardiacvascular intensive care unit (CVICU). A recent quality improvement project, Cardiac Arrest Prevention (CAP), showed a decrease in CA by applying a bundle to pre-identified patients at higher risk. Despite this success, CA still occurs among “low” risk patients. Automated risk analytics can offer patient-specific tools to identify risk periods in real time. Hypothesis: Methods: Time series data including vitals and laboratory values were collected (6/2019 - 8/2020). These data were fed into a risk analytics algorithm [Etiometry Inc., Boston, MA] which uses a model of patient physiology to compute risk indices for various physiologic variables. Risk indices examined in this study include IDO2 (likelihood of SvO2 &lt; 40%), HLA (likelihood of lactate &gt; 4 mmol/L), and IVCO2 (likelihood of PaCO2 &gt; 50 mmHg). Various criteria using these risk indices were retrospectively evaluated for categorizing risk status. Once criteria were met a 12-hour “watcher period” was established after a 1-hour assumed response period (figure 1A). CAP status was assigned on a daily basis. Results: 665 encounters for 484 patients were included. 128 (19.2%) neonatal (&lt;28days) encounters and 537 (80.8%) older patients, for a median age of 7.7 (IQR 2, 46) months. There were a total of 29 CA, of which 11 (38%) were captured by CAP. Figures 1B and 1C show two versions of Track and Trigger Systems (TTS) with their capture of CA events compared against CAP and when combined with CAP. TTSv1 and TTSv2 alone were able to capture 31% and 41% of the CA events. When combined with CAP these numbers increase to 55% and 62% respectively. Conclusions: A TTS based on risk indices could provide a patient/pathophysiologic status specific tool to increase our ability to identify patients at risk of CA when used in conjunction with CAP criteria. Further validation of these data in other cohorts and prospective application of the tool is warranted.