tbuckley/cabot-search huggingface dataset:
Abstract 12258: Associations Between Serum Perfluoroalkyl Substances and Vascular Function
Authors: Sharine Wittkopp, Fen Wu, Joseph Windheim, Morgan Robinson, Kurunthachalam Kannan, Stuart D Katz, Yu Chen, Jonathan D Newman
Journal: Circulation (2021)

Introduction: Perfluoroalkyl substances (PFA)s are ubiquitous synthetic organic compounds used in packaging, flame retardants and stain resistant fabric. The use of older, long-chain, persistent PFAs in the U.S. has been phased out due to cardiometabolic health effects and replaced with short-chain, less persistent, alternative PFAs for which little data on cardiotoxicity exists. We evaluated the relationships between serum PFAs and noninvasive measures of vascular function by carotid-femoral pulse wave velocity (PWV) and brachial artery reactivity testing (BART). Methods: We measured 14 serum PFAs using hybrid solid-phase extraction and ultrahigh-performance liquid chromatography-tandem mass spectrometry in 94 adult outpatients without CVD from an urban medical center. Using medical records and questionnaires, we collected demographic and clinical data; and measured PWV and BART using standard protocols. We assessed associations of individual PFAs with log-transformed BART and PWV using linear regression. We used weighted quantile sum regression to assess effects of correlated PFA mixtures on BART and PWV. Results: Of the 14 measured PFAs, 10 were detectable in &gt;50% of samples, and were included for analysis. Each standard deviation increase in perfluroheptanoic acid (PFHpA) was associated with -0.17 (-0.34, -0.002) decrease in log BART. The weighted index of PFAs in mixture 1 (Table) was significantly and inversely associated with log BART; each tertile increase in the weighted index of mixture 1 was associated with a -0.29 (-0.52, -0.06) decrease in log BART, with PFHpA having the greatest weight (0.73) in the mixture. In contrast, neither individual PFAs nor PFA mixtures were associated with PWV. Conclusions: Increasing concentrations of a new, short-chain PFA, PFHpA, are associated with impaired vascular function among outpatients without CVD. Our findings contribute evidence of potential adverse cardiovascular effects of currently used PFAs.
PATH-26. EVALUATING THE DISTRIBUTION AND PROGNOSIS OF IMMUNE CELL SIGNATURES OF THE TUMOR MICRO-ENVIRONMENT IN DIFFUSE GLIOMAS
Authors: Bharati Mehani, Saleembhasha Asanigari, Hye-Jung Chung, Kenneth Aldape
Journal: Neuro-Oncology (2021)

Abstract The tumor micro-environment (TME) plays an important role in the biology of cancer, including gliomas. Single cell studies have highlighted the role of specific TME components in gliomas, and the methods to deconvolve bulk profiling data may serve to complement these studies on clinically annotated tumors. In this study, we estimated cell type proportions in 3 large glioma datasets (TCGA, CGGA-325, CGGA-693) using CIBERSORTx. Using a signature matrix comprising 22 immune cell types, we identified IDH mutation status-specific immune cell distributions and found that the proportions of 10 cell types were significantly different between IDHmut and IDHwt tumors across the 3 datasets. Looking further within IDHmut tumors, we found that monocytes were enriched in 1p/19q non-co-deleted tumors across the 3 glioma datasets, consistent with prior single cell studies. We then examined estimated gene expression among immune cell types relative to IDH mutation status and found clear separation of gene expression in 15 of 22 cell types in all 3 datasets. When we applied these 22 gene expression signatures in each tumor sample onto cluster-of-cluster analyses to identify tumor groups with distinct immune signature patterns, we found that samples were distributed largely according to the IDH status in all 3 datasets, confirming that immune cell expression is distinct based on IDH status. Among IDH-specific groups, cluster-of-cluster analyses showed that immune cell-based cluster groups had distinct survival outcomes, and that IDHwt samples were distributed significantly based on tumor grades as well as based on EGFR overexpression. Among IDHmut tumors, the distributions of tumor grade and 1p/19q co-deletion status were significantly different in the immune-based clusters in 2 of the 3 datasets examined. Overall, these results highlight the biological and clinical significance of the immune cell environment in gliomas, including distinctions based on IDH mutation status as well as prognosis within IDH-specific groups.
Abstract 13987: Efficacy and Safety of Surgical Repair of Atrial Septal Defect in Asymptomatic Children Less Than 3 Years of Age
Authors: Erica Del Grippo, Gunjan Banga, Majeed Bhat, Christian Pizarro, Takeshi Tsuda
Journal: Circulation (2021)

Background: Elective surgical closure of atrial septal defect (ASD) in asymptomatic children is commonly performed at 3 to 6 years of age when catheter-guided closure is not feasible. However, a recommended timing of surgical closure is not based on recent evidence. Hypothesis: Surgical ASD closure can be done safely in any age group. Methods: Asymptomatic patients with surgically closed isolated ASDs who were not indicated for catheter-guided closure in our cardiac center from 2002 to 2019 were studied. The patients were divided into 4 groups based on the age at surgery (&lt;3 years, ≥3 to &lt;6 years, ≥ 6 to &gt;10 years, and ≥ 10 years). Demographic data, type of ASD, cardiopulmonary bypass time (CPBT), intensive care unit (ICU) stay, total hospitalization days, post-operative adverse events, and readmission rate were studied. Effects of creation of pericardial window (PW) was also examined. Data are shown as mean ± standard deviation. Results: Total 163 patients were studied (Table). There was no statistically significant difference in CPBT, ICU stay, or total hospitalization days among the 4 groups. There were no mortalities. Incidence of adverse events during hospitalization was low in &lt; 6 years (1.9 to 4.2%) but higher in older ages (10.8 to 13.5%). Readmission rate was higher in younger groups: 18.6% in &lt; 3 years old, 13.2% in ≥ 3 and &lt; 6 years old, 8.0% in ≥ 6 and &lt; 10 years, and 10.8% in ≥ 10 years, which was mainly due to pericardial effusion (PE). Total 18 patients developed PE postoperatively, 14 of whom were readmitted for treatment. With the creation of PW at the time of initial surgery, the incidence of PE and readmission rate were significantly reduced compared with without PW, especially in younger children. There was no complication due to PW. Conclusion: Surgical ASD closure can be performed safely even in younger children with ages &lt;3 years, especially with creation of PW. Routine application of PW markedly reduced postoperative adverse events in surgical ASD closure.
Flares of mixed cryoglobulinaemia vasculitis after vaccination against SARS-CoV-2
Authors: Marcella Visentini, Laura Gragnani, Stefano Angelo Santini, Teresa Urraro, Annalisa Villa, Monica Monti, Andrea Palladino, Luisa Petraccia, Francesca La Gualana, Serena Lorini, Silvia Marri, Francesco Madia, Lucia Stefanini, Stefania Basili, Massimo Fiorilli, Clodoveo Ferri, Anna Linda Zignego, Milvia Casato
Journal: Annals of the Rheumatic Diseases (2021)

LettersHLA-B27 status was obtained in only 21 (31.8%)patients, of which one in the polyarthritis subgroup tested positive.Most patients were treated with glucocorticoids (50%-78%), non-steroidal anti-inflammatory drugs (33%-52%) or analgesics (14%-28%), while disease-modifying antirheumatic drugs were used in five (28%) patients with polyarthritis, five (24%) patients with oligoarthritis and only three (11%) patients with PMR-like presentation.Despite the limitation of a very short follow-up, the clinical course seemed excellent in patients with PMR-like onset with 74% achieving full remission of symptoms after 2 weeks; on the other hand, 67% of patients with polyarthritis had active disease after an average follow-up of 6 weeks.In conclusion, despite the fact that a clear cause-effect relationship is far to be ascertained, our data suggest that inflammatory musculoskeletal symptoms may occasionally develop in close temporal association with COVID-19 vaccine administration.However, even assuming a direct causal relationship, we feel that the overall safety of COVID-19 vaccines remains unaffected, and the benefits of vaccination largely outweigh the minimal risks associated with such uncommon inflammatory complications, probably reflecting a transient reactogenic response to the vaccine rather than a structured, chronic inflammatory joint disease.
TAMI-63. INHIBITION OF LINEAGE STATES WITHIN GBM OVERCOMES CHEMO-RESISTANCE
Authors: Kevin Joseph, Julian Maier, Vidyha Ravi, Jürgen Beck, Ulrich Hofmann, Dieter Henrik Heiland, Oliver Schnell
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Novel insights into the developmental trajectory exhibited by glioblastoma (GBM) have shown that it has the capability to respond to its microenvironment by clonal selection of specific transcriptional phenotypes. Using the same mechanisms, malignant GBM develop intrinsic mechanisms to resist chemotherapeutic treatments. In this study, we determine the role of the metabotropic glutamate receptor 3 (mGluR3) in chemoresistance and show that inhibition of mGluR3 leads to significant loss of tumor growth volume when concomitantly treated with Temozolomide. METHODS Transcriptomic analysis was carried out post mGlur3 receptor inhibition using LY341495 (100nM), to study loss of transcriptional programs. Morphological and cellular kinetic analysis was carried out post inhibition, to determine apoptosis/necrosis rate, when combined with Temozolomide. The efficacy of the treatment within a human like environment was assessed using our novel human cortical GBM model. RESULTS We present transcriptional and morphological evidence that mGluR3 inhibition using LY341495 leads to loss of both lineage (FDR&amp;lt; 0.01) and reactive (FDR&amp;lt; 0.01) transcription programs. This leads to a loss of ability to evade cytotoxicity when combined with Temozolomide treatment, validated using kinetic apoptosis (p&amp;lt; 0.01). When our cortical GBM model was used to study the effect of treatment within the appropriate microenvironment, we see that the combination therapy leads to a significant reduction in tumor growth (p&amp;lt; 0.01) over the course of 10 days. CONCLUSION Through the integration of diversified molecular-biological analyses, we illustrate a new picture of how glutamate signaling via mGluR3 interacts with phenotypical GBM transcriptional programs to evade effective therapy, the inhibition of which leads to loss of chemo-resistance.
NIMG-09. DETECTION OF ASYMPTOMATIC MALIGNANT LESIONS BY [18F]FDG PET/MRI IN CHILDREN AND ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Alicia-Christina Baumgartner, Hannes Platzgummer, Oskar Aszmann, Gabriele Amann, Anna Berghoff, Gregor Kasprian, Tatjana Traub-Weidinger, Amedeo A Azizi
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Plexiform neurofibromas (PN) are a hallmark feature of Neurofibromatosis type 1 (NF1). 10% of PN undergo malignant transformation. As malignant peripheral nerve sheath tumors are a leading cause of death in NF1-patients, early detection of malignancy is essential. 2-deoxy-2-[ 18F]fluoro-D-glucose [18F]FDG PET/CT imaging is used in patients with NF1 to judge malignant transformation. AIMS: The present study evaluated [18F]FDG PET/MRI in pediatric NF1 patients at high risk for MPNST and its utility as a possible screening tool for malignant transformation of yet asymptomatic lesions. METHODS Patients aged 0-25 with symptomatic and asymptomatic neurofibromas who underwent PET/MRI from 2014 to 2021 were included. Chart review of imaging data, clinical and histological findings was performed retrospectively. RESULTS 41 patients (18 female) with a median age at first PET/MRI of 16.87 years (6.21-24.41) were included. 40 lesions were operated as indicated by clinical (e.g. pain, rapid growth) or imaging findings. Based on histopathological analysis 7 lesions in 4 patients were categorized as malignant, 3 as atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP). 4/7 malignant and 2/3 ANNUBP lesions were asymptomatic (i.e. without rapid growth, pain, neurologic dysfunction). 5/7 symptomatic tumors were without significant FDG-PET and proven benign by histology. 18 lesions (2 symptomatic) in 9 patients that showed an increased uptake suspect of malignant transformation were histologically classified as benign. None of the patients died during follow-up, 1 symptomatic MPNST patient received postsurgical radio- and chemotherapy. CONCLUSION Our data indicate that malignant transformation of PN also occurs in asymptomatic patients. [18F]FDG PET/MRI is feasible in pediatric and adolescent patients with the tumor predisposition syndrome NF1 and is an alternative to PET/CT when assessing for malignancy thereby drastically reducing radiation exposure. Early detection through screening of high-risk NF1 patients with [18F]FDG PET/MRI could potentially increase overall survival by facilitating early curative resection.
Abstract 9866: Novel Oral Anticoagulants versus Vitamin K Antagonists in Patients with Atrial Fibrillation and Concomitant Valvular Heart Disease: A Systematic Review and Meta-Analysis
Authors: Muhammad Memon, Asad Ali Siddiqui, Khadijah Ahmad Tarique, Emaan Amin, Mohammad Khan, Rami Doukky, Richard Krasuski
Journal: Circulation (2021)

Background: Currently, vitamin-K antagonists (VKAs) are the anticoagulant of choice for treating atrial fibrillation (AF) patients with valvular heart disease (VHD). Novel oral anticoagulants (NOACs) suggest better outcomes and could be a potential replacement for some patients. We aimed to conduct an updated systematic review and meta-analysis to resolve this matter. Methods: We queried MEDLINE, Embase and Cochrane central up until May 29, 2021 for studies comparing NOACs to VKAs in AF patients with VHD. Results from studies were presented as risk ratios (RR) with 95% confidence intervals (CI) and pooled using a random-effects model. Subgroup analysis by study design was performed to explore heterogeneity. Results: A total of 10 studies (4 RCTs and 6 retrospective observational) containing 196,124 patients (mean age 75.3 years; 54.0% men) were identified and included in the analysis. All 10 studies excluded patients with artificial valves while all 4 RCTS excluded moderate-to-severe mitral stenosis. Pooled analysis revealed significant risk reduction by NOACS of stroke or systemic embolism (RR 0.58 [95% CI 0.46, 0.74]; p&lt;0.001, I 2 =91%), major bleeding (RR 0.60 [95% CI 0.43, 0.83]; p=0.002, I 2 =97%), intracranial hemorrhage (RR 0.40 [95% CI 0.28, 0.57]; p&lt;0.001, I 2 =78%), all-cause mortality (RR 0.67 [95% CI 0.47, 0.96]; p=0.03, I 2 =97%) , myocardial infarction (RR 0.65 [95% CI 0.51, 0.84]; p=0.001, I 2 =0%), and major adverse cardiovascular events (RR 0.89 [95% CI 0.80, 0.99]; p=0.03, I 2 =0%). A significant difference was found upon subgroup analysis between RCTs and observational studies for all-cause mortality (p-value for interaction=0.005) Conclusions: NOACs were found to significantly reduce risk of all studied outcomes in patients with AF and VHD. Future RCTs are required to further validate these results.
Abstract 10660: Genome-Wide Scan Identifies Variants Increasing Triglycerides Only Among Diabetics
Authors: Margaret Selvaraj, Kaavya Paruchuri, Sara Haidermota, Rachel Bernardo, Gina M Peloso, Pradeep Natarajan
Journal: Circulation (2021)

Introduction: Increased triglycerides (TG) frequently accompanies type 2 diabetes (T2D) mellitus and poor glycemic control. The extent to which genetics influences triglycerides differently in individuals with T2D is not well understood. Methods: We conducted a genome-wide association study (GWAS) of log(TG) stratified by T2D using imputed UKB genotypes with minor allele count&gt;20. We used linear regression model with a leave-one-out cross-validation using REGENIE adjusted for PC1-10, age, age 2 , gender, array-type, and race. We assessed the heterogeneity (I 2 ) between the effects of TG in T2D and non-T2D individuals. We sought replication in the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 17 and 45 loci significantly associated with TG levels, respectively. Only one loci exhibited significant genome-wide heterogeneity (I 2 =98.4%; p heterogeneity =2x10 -15 ). The most significantly heterogenous variant was an intronic variant of the HLA-DQB1 gene, where the major allele (frequency 91.3%) was associated with increased TGs among those with T2D but not non-T2D (T2D group: beta=0.066, p-value=3.9x10 -15 ; non-T2D group: beta=-0.002, p-value=0.21). Among 25,136 participants (6,951 T2D cases) of MGBB, we replicated this finding (p heterogeneity =0.01). Conclusions: An intronic variant at HLA-DQB1 significantly associates with increased TGs only in those with T2D.
BIOM-04. SENSITIVE DETECTION OF LEPTOMENINGEAL DISEASE USING CELL-FREE DNA FROM CEREBROSPINAL FLUID
Authors: Michael White, Robert Klein, Brian Shaw, Albert Kim, Megha Subramanian, Joana Mora, Anita Giobbie-Hurder, Deepika Nagabhushan, Aarushi Jain, Mohini Singh, Benjamin Kuter, Naema Nayyar, Jackson Stocking, Samuel Markson, Matthew Lastrapes, Christopher Alvarez-Breckenridge, Daniel Cahill, Maura Mahar, Justin Rhoades, Denisse Rotam, Mia Bertalan, Greg Gydush, Viktor Adalsteinsson, Alexander Kaplan, Kevin Oh, Ryan Sullivan, Elizabeth Gerstner, Scott Carter, Priscilla Brastianos
Journal: Neuro-Oncology (2021)

Abstract Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.
Nuclear deformation guides chromatin reorganization in cardiac development and disease
Authors: Benjamin Seelbinder, Soham Ghosh, Stephanie E. Schneider, Adrienne K. Scott, Alycia G. Berman, Craig J. Goergen, Kenneth B. Margulies, Kenneth C. Bedi, Eduard Casas, Alison R. Swearingen, Justin Brumbaugh, Sarah Calve, Corey P. Neu
Journal: Nature Biomedical Engineering (2021)
Abstract 12495: Differentiating Slow- And Rapid-growing Abdominal Aortic Aneurysms Using Computational Modeling
Authors: Kevin Sunderland, Tonie Johnson, David Liedl, Jan J Hofer, Xiaoming Zhang, Robert D McBane, JingFeng Jiang
Journal: Circulation (2021)

Introduction: Abdominal aortic aneurysms (AAA) are common among individuals over age 65 with a prevalence of 9%. Most AAAs are small and require surveillance imaging to monitor size and growth rates. Tools capable of predicting growth rates would be clinically useful. Hypothesis: We investigated how computational hemodynamics derived from CT angiography (CTA) differentiated slow and rapid-growing AAAs. Methods: Using readily available computing power in the clinical workflow, 3D models were generated for 25 subjects with AAA from available 3D CTA data. AAA growth rates were categorized as slow ( less than 5 mm/year) or rapid (greater than 5 mm/year) based on serial imaging. A geometrical analysis was performed using 7 indices (Volume, Surface Area, Length, Max/Min radius, Expansion Ratio [Mean radius/vessel radius], Proximal vessel area, Voronoi diagram-based metrics) for each AAA. Computational hemodynamics were performed using commercial software (ANSYS-Fluent). Computational hemodynamics were completed for all cases (see Fig. 1). In-house software assessed wall shear stress-(WSS) and vortex-based hemodynamics. Support vector machine (SVM) was run with cross-validation (50 iterations) to assess predictive strength using these 16 parameters. Results: Among 25 AAAs studied, 7 were rapid and 18 were slow-growing. The combination of proximal vessel area, spatiotemporally averaged WSS, and spatially averaged OSI provided the best accuracy for growth differentiation. The area under receiving operating curve (AUROC) and total accuracy are 0.770 and 0.765, respectively, with 48% and 86% of rapid and slow-growing AAAs correctly identified, respectively. Conclusions: Computational hemodynamics appears feasible with reasonable growth rate prediction. With optimization, this tool may enable resource utilization refinement for imaging surveillance strategies by distinguishing rapid from slow-growing AAAs.