tbuckley/cabot-search huggingface dataset:
IMMU-28. DECONVOLUTION OF SPATIALLY RESOLVED T CELL RECEPTOR PROFILING (SPTCR-seq) UNCOVERED REGIONAL ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA
Authors: Jasim Kada Benotmane, Jan Kückelhaus, Kevin Joseph, Jürgen Beck, Oliver Schnell, Vidyha Ravi, Dieter Henrik Heiland
Journal: Neuro-Oncology (2021)

Abstract The diversity to T cell responses and clonality in spatially heterogeneous glioblastoma is of paramount importance to explore underlying mechanisms of anti-tumor immunity. Spatial transcriptomics, a novel technology to map the transcriptional architecture, is technically limited to discover T cell receptor (TCR) sequences as the 3' approach lacks sufficient coverage. Here, we established SPTCR-seq, a method to capture TCR sequences followed by long-read sequencing to enable full-length TCR reconstruction. We performed 10X Visium spatial transcriptomics on 9 primary and recurrent glioblastoma with both 3’-sequencing and SPTCR-seq. For SPTCR-seq, we target enriched T cell receptor sequences by capturing by hybridization followed by Oxford-Nanopore long-read sequencing. The on-target rate was above 80% for captured TCR genes and spatial barcode was successfully aligned in more than 60%. IgBlast and MixCR were used to reconstruct the TCR and map T cell clonality. Within our recent developed spatial transcriptomic analysis framework (SPATA2), we build a novel toolbox, SPATA-Immunology, which enables integration of stRNA-sequencing data and spatially resolved TCR sequencing. Our data showed that clonal evolution of T cells is limited to regional areas underpinned by significant spatial autocorrelation coefficient (0.6-0.95, padj&amp;lt; 0.001). In the surrounding tumor cell spots, the recently described transcriptional program “reactive immune” (RI), was significantly enriched. Using spotlight, a computational approach to project scRNA-sequencing into the spatial space, we found a local enrichment of CD163 positive macrophages exclusively in areas of large T cell clonality. Imaging mass cytometry of a consecutive section confirmed the spatial confluence of T-cell infiltration and CD163-positive macrophages. Through DeepTCR we uncovered potential epitopes which correlate with T cell clonality and might help to discover novel targets for CART therapy. Spatial profiling of TCR sequences through SPTCR-seq is a powerful tool to investigate anti-tumor immunity in glioblastoma and allows to discover general and personalized targets for immunotherapy.
Abstract 9854: Somatic Mutations in Single Human Cardiomyocytes Reveal Rapid Age-Related DNA Damage and Cardiomyocyte Fusion
Authors: Sangita Choudhury, August Yue Huang, Junho Kim, Katherine Morillo, Eduardo Maury, Zinan Zhou, Sarah Araten, Eunjung Alice Lee, Christopher A Walsh, Ming H Chen
Journal: Circulation (2021)

Introduction: Advanced age is the most important risk factor for heart disease, yet we have an incomplete understanding of how aging promotes heart disease. Accumulation of somatic DNA mutations has been demonstrated to be a hallmark of aging in many human cell types. The underlying cause of these many aging phenotypes is likely molecular in nature, but its mechanism is not well understood. Methods: To define the effect of aging on cardiomyocytes we performed single-cell whole-genome or panel sequencing from ~1000 single cardiomyocytes from 10 individuals aged 0.4 ~ 82 yrs. Mutational signatures of aging cardiomyocytes were analyzed by non-negative matrix factorization and a cell lineage tree was constructed. Results and Conclusions: Tetraploid cardiomyocytes showed a significant increase of (somatic single nucleotide variants (sSNV) density with age ( p = 0.0027), and this age-dependent increase remained significant even after adjusting for differences in the evenness of amplification. The sSNVs were distributed broadly across the genome. We further confirmed the age-dependent trend in diploid cardiomyocytes. A consistent increase of somatic mutation burden in human heart muscle cells with age, regardless of cardiomyocyte nuclear ploidy was observed. Cardiomyocytes accumulate age-related SNVs at rates higher than those previously described in other noncycling cells like neurons. Signature analysis reveals that cardiomyocyte SNVs display distinctive signatures of mutagenic processes, including increased oxidative stress, defective mismatch repair. A cell lineage tree, constructed from shared somatic single nucleotide variants, revealed that many polyploid cardiomyocytes derive from multiple clonal origins, implicating cell fusion as a major mechanism contributing to polyploidization. Since age-accumulated sSNVs create many damaging mutations, the fusion of clonally distinct cells to form multiploid cardiomyocytes provides a mechanism of genetic compensation that may minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.
FDA Regulation of Medical Devices—Moving Beyond the Horse and Buggy
Authors: Jessica Holtzman, Christina Lalani, Rita F. Redberg
Journal: JAMA Internal Medicine (2021)

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Abstract P373: The Occurrence Of Neurovascular And Adipose Neuropathy In The Genetically Diverse Het3 Mouse With Aging
Authors: Jake Willows, Morganne Robinson, Harrison Cyr, Gargi Mishra, Peter Reifsnyder, David E Harrison, Kristy Townsend
Journal: Circulation Research (2021)

Energy homeostasis and adipose tissue metabolism are regulated in large part through peripheral sympathetic nerve innervation of metabolically important tissues and organs. This neural communication from the brain to adipose tissues results in release of the neurotransmitter norepinephrine that regulates energy expenditure through modulation of lipolysis, adipogenesis, ‘browning’ (development of brown adipocytes in white adipose depots), and non-shivering thermogenesis. Subcutaneous white adipose tissue (scWAT) is an energy storing tissue that is highly plastic, responding to metabolic need by changing mass and cellularity, as well as responding to challenges (including cold temperature, exercise, fasting) by modifying neural activity and metabolism. Within scWAT lies a dense bed of nerves and blood vessels that are integrated closely, and in large part, rely on one another to function properly. Even if not directly innervating the blood vessels themselves (as is the case with capillaries), neurites that appear to innervate single adipocytes use these blood vessels as scaffolding to traverse the tissue. We have recently demonstrated that under pathological conditions (obesity and aging), scWAT innervation decreases through a process termed ‘adipose neuropathy’. With advanced age the small fiber peripheral nerve endings in adipose die back, including reducing contact with adipose-resident blood vessels (as observed previously in the C57BL6/J mouse). This likely poses a physiological challenge for metabolism and for vascular or adipose tissue health and function. For this work, we compared C57BL6/J mice with the more genetically diverse HET3 mouse model, established for the NIA’s Intervention Testing Program to more accurately represent the variability of age-related mortality/morbidity. We investigated incidence of peripheral neuropathy with aging (skin, scWAT muscle) as well as changes to the neurovascular supply of scWAT across several ages in both males and females. We also investigated the anti-aging drug Rapamycin as a potential means to prevent or reduce adipose neuropathy. We found that HET3 mice display a reduced neuropathy phenotype compared to inbred C56BL6/J mice. Importantly, the nerve die-back around blood vessels was not observed in the HET3 model. However, male HET3 mice did reveal neuropathic phenotypes by 62wks of age, characterized by decreased mechanoreception in hind paw skin, reduced NMJ occupation, and decreased expression of the Schwann cell marker Sox10 in scWAT. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126wks) when they began to show stronger phenotypes than males (excluding Sox10 analysis.) Despite its success as a longevity treatment in mice, rapamycin had little to no effect on reducing or preventing the onset of adipose neuropathy.
INNV-06. BRAF AND MEK DUAL INHIBITORS THERAPY IN RECURRENT OR ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)
Authors: Karolina Kata, Juan Carlos Rodriguez Quintero, Octavio Arevalo-Espejo, Meenakshi Bidwai Bhattacharjee, Cornelius Ware, Antonio Dono, Roy Riascos-Castaneda, Nitin Tandon, Angel Blanco, Yoshua Esquenazi, Leomar Y Ballester, Mark Amsbaugh, Arthur L Day, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND AND OBJECTIVE Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity. METHODS Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0. RESULTS Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected. CONCLUSION BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.
The transcription factor Egr1 binds to the promoters of numerous EGF Receptor target genes and regulates their coordinate expression
Authors: Shilpi Arora, Zhenyu Jia, Yipeng Wang, Saynur Vardar-Sengul, Ayla Munawar, Michael McClelland, Eileen Adamson, Dan Mercola
Journal: Cancer Research (2008)

5279  Egr1 is an immediate early transcription factor that is over-expressed in prostate cancer and has been shown to mediate tumor growth. It is minimally detected in resting prostate cancer cells whereas irradiation of living cells with UV-C leads to its increased expression. We used Chip-on-chip to identify the genes that are bound and regulated by Egr1 in a prostate cancer cell line (M12) upon UV irradiation.  We utilized in-house promoter arrays that contain ~13,000 promoter sequences amplified from the region between 1000 bp upstream and 500 bp downstream of the putative or known transcription start site. This region contains most of the Egr1 consensus sites of the human genome. ChIP on chip analysis of UV treated M12 cells using Egr1 antibody led to the identification of 288 significantly differentially bound gene promoters (based on p  1.4). Of the 288 gene promoters, 40% have perfect Egr1 consensus sites while another 18% have a probable Egr1 binding site (58.3% in total) which is significant (p
Abstract 14357: Increased Left Atrial Volume Index is Associated With Syncope in Hypertrophic Cardiomyopathy Patients
Authors: Armando R Martinez, Jorge Silva Enciso
Journal: Circulation (2021)

Introduction: Syncope in hypertrophic cardiomyopathy patients (HCM) is associated with high risk for sudden death, presence of fibrosis and LV structural changes. However, it is unclear if left atrial structural changes associate with syncope. Our aim is to evaluate changes in left atrial volume index (LAVI) and occurrence of syncope in HCM patients. Methods: Retrospective study of 123 HCM patients identified at our institution from 2016-2019. Syncope was identified by chart review of ICD codes, past medical history, and keyword search. Left atrial volume index was determined by tracing the LA endocardial border from standard views in two-dimensional echocardiography. HCM subtypes were classified as obstructive (oHCM) and non-obstructive (noHCM). Results: A total of 123 patients, 29 (23.6%) had syncope. No difference in age, gender, or BMI was found between those with syncope and without syncope. More ventricular arrhythmic events and stroke events occurred in those with syncope vs. without syncope. LAVI showed a correlation with syncope in HCM patients (p&lt;0.05). Mean LAVI was larger in those with syncope compared to those without syncope (43.8±12.6 mL/m2 vs. 37.7±14.3 mL/m2). Each 1 mL/m2 increase in LAVI corresponded to a 1.03 OR risk for syncope. ROC analysis showed a LAVI threshold of 31.8mL/m2 for predicting syncope in all HCM (sensitivity 89.7%, specificity 40.4%) Conclusions: Syncope showed a strong correlation in those with larger LAVI with incremental risk of syncope for each 1 mL/m2 added to LAVI size. Additionally HCM patients with syncope had worse outcomes. Our findings suggest LAVI may have utility as a marker to stratify HCM patients at risk for syncope. Further studies in HCM patients are needed to assess the impact of changes in LAVI size over time on cardiovascular outcomes.
Abstract 11365: Electronic Cigarette Vaping with or Without Heating Induces Differential Pathological Remodeling in the Lungs and Right Heart
Authors: Yohannes Estifanos, Matthew R Peterson, Tatiana Rice, Guanglong He
Journal: Circulation (2021)

Introduction: One of the obstacles in dissecting the specific underlying mechanisms of electronic cigarette (EC) “vaping”-related health effects is the complexity in the chemical composition of EC aerosols. As various chemicals are generated through the heating coil in addition to the intact components presented in the aerosol, we hypothesize that the heating-associated by-products and the intact components would have differential pathological impact to the remodeling of right ventricular (RV) and pulmonary system. Methods: Using a prototype exposure system, C57BL/6 mice were exposed to room air or EC vapor with and without heating the EC liquid (ECL) for 3 hours per day, 5 days per week for 6 months. Echocardiography with color Doppler was used to evaluate cardiac structure and function. To assess inflammatory and fibrotic signaling, Western-blotting was performed. Results: Comparable plasma cotinine levels were found between heating and non-heating exposure, respectively (59.34±8.57ng/mL vs 59.02± 4.83ng/mL; n=5-7). Without heating exposure caused thinning of RV free wall (0.57±0.028 mm control vs 0.43±0.03 mm exposed; p&lt;0.05), whereas with heating, an increase in the RV wall thickness (0.79±0.06 mm exposed, p&lt;0.01) and a reduction in RV chamber size at diastole (1.57±0.04mm control vs 1.34±0.03mm exposed, p&lt;0.01) were observed. While exposure without heating elevates peak pulmonary artery (PA) pressure (2.46±0.31 mmHg control vs 3.34±0.13 mmHg exposed; p&lt;0.05), a lower peak (1.36± 0.12 mmHg exposed; p&lt;0.05) and mean pressure gradient (0.75±0.08 mmHg control vs 0.51± 0.05 mmHg exposed; p&lt;0.05) were recorded with heating exposure. As for pulmonary response, exposure without heating did not affect NF-κB p-p65 level, but reduced p65 expression to 37% of controls (±6%, n=5, p&lt;0.0001) and increased TGF-β1 by 67% (±11%, n=5, p&lt;0.05). In contrast, exposure with heated ECL did not affect p65 and TGF-β1 but increased p-p65/p65 by 39.4% (±5%, n = 5, p &lt; 0.05), indicating activation of NF-κB inflammatory signaling. Conclusions: EC exposure without heating the ECL resulted in fibrotic lung, higher peak PA pressure and RV dystrophy without obvious pulmonary inflammation. Heating the ECL, however, contribute to RV hypertrophy and pulmonary inflammation.
Liver transplant with controlled donors after circulatory death with normothermic regional perfusion and brain dead donors: A multicenter cohort study of transfusion, one-year graft survival and mortality
Authors: Laura Viguera, Annabel Blasi, Enric Reverter, Begoña Arjona, Marta Caballero, Ivette Chocron, José Antonio García-López, Rosa Gutierrez, Maria Jesús Martin, Jose Pérez-Peña, Javier Pitera, Iratxe Zarragoikoetxea, Antoni Sabaté, C. Belmonte, J. Bustamante, J. Beltran, J. Colmenero, M. Costa, C. Fondevila, P. Galan, C. García-Palenciano, J. L. Garrido, J. Gomez-Serrano, S. Gonzalez, Jimenez C. de la Fuente, C. Jimeno, A. Leon, P. Lopez-Toribio, A. Marín, A. del Mazo, M. de Nadal, G. Ojinaga, J. Padilla, J. Tevar, M. Torres, M. Zaballos
Journal: International Journal of Surgery (2021)
TAMI-65. FASN-MEDIATED LIPID SYNTHESIS HAMPERS ANTI-CANCER IMMUNITY OF GLIOBLASTOMA
Authors: Mara De Martino, Camille Daviaud, Claire Vanpouille-Box
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most aggressive type of primary brain tumor in adults. Radiation therapy (RT) is an essential modality for GBM treatment and is recognized to stimulate anti-cancer immunity by at least generating type I interferon (IFN-I) responses. However, RT also exacerbates potent immune inhibitory mechanisms that facilitate immune evasion. Notably, increased lipid synthesis by the fatty acid synthase (FASN) is an emerging mechanism that can account for the deceiving treatment efficacy and immune escape of GBM. Therefore, we hypothesize that FASN-mediated lipid synthesis represents an innate immune evasion mechanism of irradiated GBM. Supporting this hypothesis, we observed that 10 gray (Gy) irradiation of murine GBM cell lines, GL261 and CT2A, upregulates FASN protein expression and increase cellular lipid content determined by BODIPY staining and electronic microscopy. Interestingly, this effect was abrogated when GBM cells were incubated with an inhibitor of FASN. Next, to ask whether FASN was impairing RT-induced IFN-I, GL261 and CT2A cells were engineered to express an inducible shRNA silencing FASN (GBMshFASN) or its non-silencing control (GBMshNS). Irradiation of GBMshNS cells enhanced the secretion of IFN-beta and CXCL10, but this effect was more pronounced when FASN was blocked. Finally, GBMshNS and GBMshFASN cells were orthotopically implanted in mice on day 0. On day 10, selective irradiation (10Gy) was performed to the tumor. Tumor growth and immune contexture were evaluated on day 17. Magnetic resonance imaging revealed that FASN knockdown reduces tumor growth independently from RT. However, in situ immunofluorescence of GBMshFASN tumors showed increased infiltration of CD8+ T cells and CD11c+ cells only in irradiated mice bearing GBMshFASN tumors. Altogether, our data suggest that RT rewires the energy supply of GBM by promoting FASN-mediated lipid synthesis to foster immune evasion. Targeting FASN is a promising strategy to promote anti-cancer immunity and sensitize irradiated GBM to immunotherapies.
Abstract 10596: Telephone-Based Stress Management in Women with Myocardial Infarction: Findings from the Go Red for Women Strategically Focused Research Network
Authors: Tanya M Spruill, Chorong Park, Jolaade Kalinowski, Amanda J Shallcross, Pallavi Visvanathan, Milla E Arabadjian, Olivia O'Hare, Nathaniel R Smilowitz, Anais Hausvater, Sripal Bangalore, Yuhe Xia, Hua Zhong, Ellen Hada, Ki Park, Catalin Toma, Puja K Mehta, Laxmi S Mehta, Janet Wei, Dwithiya Thomas, Bina Ahmed, Kevin Marzo, Jeffrey Trost, Kevin R Bainey, Bryan Har, Victoria V Dickson, Gbenga Ogedegbe, Jeffrey S Berger, Judith S Hochman, Harmony R Reynolds
Journal: Circulation (2021)

Introduction: Elevated perceived stress is associated with adverse outcomes following myocardial infarction (MI) and accounts in part for poorer recovery in women compared with men. The goal of this multicenter randomized controlled trial was to assess efficacy of a telephone-based stress management program on perceived stress, depressive symptoms, anxiety and quality of life (QOL) among women with MI. Methods: Women with elevated stress levels (Perceived Stress Scale [PSS-4]≥6) at least 2 months after MI were enrolled from 12 hospitals in the U.S. and Canada participating in the NYU Women’s Heart Attack Research Program (HARP). Participants were randomized in 12 cohorts to stress management (mindfulness-based cognitive therapy adapted for telephone; MBCT-T) or enhanced usual care (EUC; heart disease education) and followed for 6 months. Both programs were delivered by phone in 8 weekly sessions (group and individual, respectively). Linear mixed effects models were used to test between-group differences in PSS-10 scores (primary outcome), depressive symptoms (PHQ-9), anxiety (Hospital Anxiety and Depression Scale) and QOL (Seattle Angina Questionnaire, PROMIS-Global) at 6 months. Results: The sample included 130 women with elevated stress at ≥2 months from MI (age 59.8±12.8 years, 33.8% racial/ethnic minorities, 26.2% with MI with non-obstructive coronary arteries [MINOCA]). Mean baseline PSS-10 scores were similar (18.2±5.2 MBCT-T vs. 18.3±5.6 EUC). The median number of sessions completed was 7 (IQR 3,8) for MBCT-T and 8 (IQR 6,8) for EUC. The 6-month retention rates were 82.1% (MBCT-T) and 82.5% (EUC). Perceived stress and anxiety declined in the EUC arm (p&lt;.05) and anxiety and depressive symptoms declined in the MBCT-T arm (p&lt;.01) but there were no significant group by time interactions. We will report results of sensitivity analyses that explore predictors of treatment response (e.g., age, race/ethnicity, clinical history, baseline psychosocial factors, intervention adherence, satisfaction). Conclusions: Stress management did not improve perceived stress or secondary outcomes more than enhanced usual care. Identifying predictors of treatment response will inform future studies of psychosocial interventions for women with MI.
Functional Genomic and Immune Response Characterization of PTEN Loss: Therapeutic Implications for Myeloma
Authors: Olga Dashevsky, Ricardo De Matos Simoes, Benjamin G Barwick, Sara Gandolfi, Ryosuke Shirasaki, Michal Sheffer, Aedin Culhane, Richard WJ Groen, Aviad Tsherniak, Francisca Vazquez, Jonathan D. Licht, Lawrence H. Boise, Constantine S. Mitsiades
Journal: Blood (2021)