tbuckley/cabot-search huggingface dataset:
IMMU-33. NEOANTIGEN-SPECIFIC T CELLS CAN INFILTRATE IDH-MUTANT LOWER GRADE GLIOMAS AND PERSIST IN THE PERIPHERAL BLOOD
Authors: Michael Zhang, Cliff Wang, Zheng Pan, Benjamin Yuen, Songming Peng, Darwin Kwok, Takahide Nejo, Michael Martin, Chibo Hong, Stephanie Hilz, Joanna Phillips, Anny Shai, Nancy Ann Oberheim-Bush, Shawn Hervey-Jumper, Michael McDermott, Stefanie Mandl, Hideho Okada, Joseph Costello
Journal: Neuro-Oncology (2021)

Abstract The prospect of using immunotherapy for IDH-mutant LGGs has been daunting given the immune-poor microenvironment and low mutational burden. We hypothesized that LGG-targeting T cells might still be present at low frequency and with limited regional infiltration into the tumor. To improve sensitivity, we combined high-density multi-region tumor sampling with high-throughput neoantigen-T cell screening for a patient with WHO Grade II diffuse astrocytoma who eventually progressed, at second recurrence, to anaplastic astrocytoma. We performed maximal-anatomic sampling from 10 distinct regions of the tumor at the initial resection, as well as single sampling at first recurrence, for exome-based prediction of clonal and subclonal expressed neoantigens, RNAseq-based estimation of regional immune cell composition, and T cell receptor (TCR) beta deep sequencing. Based on our predictions, we then generated a barcoded library of patient-specific peptide-HLA multimers loaded with predicted neopeptides. Using this library, neoantigen-specific CD8 T cells were captured and isolated from patient peripheral blood and subjected to single cell TCR sequencing. We screened patient-derived peripheral blood drawn two years after initial resection and identified five T cell clones recognizing three LGG neoepitopes. Two neoepitopes were derived from truncal, tumor-wide mutations, including a truncating splice-site mutation in TP53 and a missense mutation in MRPL46. Each of these neoepitopes were recognized by two distinct TCRs, consistent with TCR convergence. A third neoepitope was derived from a subclonal MRPL46 mutation. Using the TCR beta sequence as a molecular barcode, TCRs specific to the 2 clonal neoepitopes, but not the subclonal neoepitope, were detectable in the glioma and blood at initial resection, as well as in the recurrent glioma. In summary, we demonstrate the existence and persistence of neoantigen-targeting T cells within the blood and tumor of an IDH-mutant LGG patient. These findings suggest a feasible methodology to develop personalized T cell-based immunotherapies for IDH-mutant LGGs.
Abstract P384: Distinct Roles Of Cellular And Extracellular TRNA-derived Small RNAs In Myocardial Fibrosis
Authors: Guoping Li, Manning Aidan, Alex Bagi, Priyanka Gokulnath, Michail Spanos, Haobo Li, Jochen D Muehlschlegel, Robert Kitchen, Todd Lowe, Saumya Das
Journal: Circulation Research (2021)

Heart failure (HF) remains the leading cause of morbidity and mortality in the US, affecting approximately 6.2 million Americans with an anticipated 46% increase in overall prevalence by 2030. Myocardial fibrosis, defined as increased cardiac fibroblast (CF) activation and excessive extracellular matrix (ECM) deposition, is a leading contributor to the progression of adverse heart remodeling that leads to HF. Despite this clinical importance, no FDA-approved antifibrotic drug is available to prevent the development of HF. There is therefore an urgent need to understand pathways important in myocardial fibrosis that can be targeted with novel therapies. Non-coding RNAs, particularly miRNAs and lincRNAs, have emerged as promising novel biomarkers or therapeutic targets for myocardial fibrosis. As an emerging category of small regulatory non-coding RNAs that was discovered only a decade ago, tRNA-derived small RNAs (tDRs), have been shown to play important roles in cancer and neurological disorders. However, the knowledge of tDRs in myocardial remodeling remains scarce. Here, by using a recently developed tDR sequencing technique, called ARM-seq, we have discovered the unique extracellular tDR fragmentation profile and created an atlas of stress-specific cellular and extracellular tDR signatures in both CFs and cardiomyocytes (CMs). Notably, we identified a nutritional deprivation-induced cellular tRNA-Asp-GTC-3’tDR (cl-tRNA-Asp-GTC-3’tDR) that demonstrates potent antifibrotic effects. In vitro mechanistic studies and transcriptome analysis suggest that the lysosome-localized cl-tRNA-Asp-GTC-3’tDR inhibits CF activation through targeting ECM deposition program and cellular response to TGFβ stimulus and the G-quadruplex motifs are required for its functionality. Meanwhile, a related extracellular tDR derived from the same canonical tRNA, ex-tRNA-Asp-GTC-3’tDR, which has two additional nucleotides at both 5’ and 3’ end of cl-tRNA-Asp-GTC-3’tDR, is specifically enriched in the extracellular vesicles derived from CFs and CMs. Our pilot data suggest that the secretion of ex-tRNA-Asp-GTC-3’tDR may be required for maintaining the homeostasis of CFs and CMs. Importantly, we found that cardiac ischemia significantly decreases the circulating ex-tRNA-Asp-GTC-3’tDR level in both cell culture models and human patients during cardiopulmonary bypass surgery or following acute coronary syndrome. Together, our findings identify a cellular tDR that represents an attractive therapeutic target against myocardial fibrosis and an extracellular tDR with the same origin that has a distinct function and may be translated into novel biomarkers for cardiac ischemia.
STEM-16. TRYPTOPHANYL tRNA SYNTHETASE (trpRS) FUNCTIONS AS A PRO-STEMNESS CYTOKINE DURING CHEMOTHERAPY IN GLIOBLASTOMA
Authors: Khizar Nandoliya, Shreya Budhiraja, Jack Shireman, Andrew Zolp, Peiyu Lin, Ella Perrault, Cheol Park, Shivani Baisiwala, Sebastian Pott, Anindita Basu, Atique Ahmed
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common adult malignant brain tumor. Despite an aggressive standard of care involving surgical resection, radiation therapy, and temozolomide (TMZ)-based chemotherapy, GBM remains a fatal disease due to a 100% recurrence rate. Tumor heterogeneity and cell plasticity are the main contributors to GBM recurrence after treatment, and thus it is essential to study the mechanisms of therapy-induced cellular plasticity. To identify these mechanisms, we performed in vivo single-cell analysis of primary (no therapy), during therapy, and post-therapy recurrent model patient-derived xenograft model of GBM. The analysis revealed a higher transcription of tryptophanyl-tRNA synthetase (trpRS) during TMZ therapy (p &amp;lt; 0.0001). Across multiple datasets, elevated trpRS was shown to correlate significantly with shorter GBM patient survival times (p = 0.0069). TrpRS has been noted to have non-canonical functions, including the ability to be secreted and act as a cytokine in response to injury, often to upregulate stemness pathways to promote healing and regeneration. Based on this observation, we hypothesized that during TMZ treatment, trpRS secretion promotes stemness in neighboring GBM cells via activation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway. This study shows that in response to TMZ treatment, secreted trpRS levels are significantly elevated compared to control in multiple GBM cell lines as analyzed by western blotting. Additionally, expression of trpRS is elevated in TMZ-resistant GBM6R cells compared to TMZ-sensitive GBM6. Furthermore, phosphorylated Akt levels, indicative of the activation of the pro-stemness PI3K/Akt pathway, correlate positively with trpRS. This study, one of the few to examine genetic changes during therapy, sheds light on a novel therapeutic target for GBM.
Clinical, Cytogenetic, and Molecular Characteristics Analysis in Myelodysplastic Syndromes with Elevated Ferritin Levels
Authors: Atsushi Wada, Naoki Shingai, Daichi Sadato, Chizuko Hirama, Satoshi Sakai, Chika Kato, Yasuhiro Kanbara, Shiori Nakashima, Yuya Atsuta, Ryosuke Konuma, Yuya Kishida, Yusuke Uchibori, Daishi Onai, Akihiko Nishijima, Junichi Mukae, Takashi Toya, Hiroaki Shimizu, Yuho Najima, Takeshi Kobayashi, Keisuke Oboki, Hironori Harada, Kazuteru Ohashi, Yuka Harada, Noriko Doki
Journal: Blood (2021)
NCOG-44. FEASIBILITY AND UTILITY OF THE MONTREAL COGNITIVE ASSESSMENT IN ROUTINE CLINICAL EXAMS AND TELEHEALTH VISITS IN NEURO-ONCOLOGY
Authors: Varna Jammula, Elizabeth Vera, James Rogers, Alexa Christ, Heather Leeper, Alvina Acquaye, Nicole Briceno, Anna Choi, Ewa Grajkowska, Jason Levine, Matthew Lindsley, Jennifer Reyes, Kayla Roche, Michael Timmer, Lisa Boris, Eric Burton, Nicole Lollo, Marissa Panzer, Matthew Smith-Cohn, Marta Penas-Prado, Valentina Pillai, Brett Theeler, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2021)

Abstract Cognitive dysfunction (CD) is common among primary brain tumor (PBT) patients and adds to the overall symptom burden. Standardized assessments able to be incorporated into routine clinical in-person and telehealth care are needed. Here, we report the feasibility, utility, and satisfaction with use of the Montreal Cognitive Assessment (MoCA) in telehealth and clinical settings by trained clinical providers. Feasibility and provider satisfaction were assessed through survey responses, and patient performance on the MoCA, after a reliability check, was reported through descriptive statistics. Seventy-nine MoCAs on 71 patients were completed in clinic (n=55) or telehealth (n=24). Majority of patients were white (83%) males (54%) with high grade PBTs (66%), and half of patients had completed at least a college education. In clinic, providers (n=9) reported the MoCA took 5-20 minutes to complete, was easy to incorporate into routine practice (78%), believed it was accurate in assessing cognition (67%), and was useful in determining treatment (88%). The average in-person MoCA score was 25 (range: 6 to 30), with 31% of scores classified as abnormal (≤26). In telehealth, providers (n=11) found the administration of the MoCA prior to attending participation in the telehealth visit helpful (75%), discussed the results with their clinical team (75%) and patient (63%), and believed the MoCA was accurate in assessing cognition remotely (63%). On average, patients took 13 minutes (9-22) to complete testing, with three tests discordant on reliability scoring and one patient unable to complete testing. The average telehealth MoCA score was 26 (12-30), with 29% of scores classified as abnormal. Overall, testing was feasible in both clinical and telehealth settings, and providers reported satisfaction with its use. Future studies should evaluate validity in a larger sample and include analysis of relevant cut-off scores, impact of disease, tumor treatment, and genomic predispositions.
Abstract 11149: Psychological Functioning and Parameters of Physiological Status in Youth with Fontan Circulation
Authors: Nicholas P Seivert, Christine Park, Jack Rychik, David J Goldberg, Abigail Demianczyk, Katie Dodds
Journal: Circulation (2021)

Individuals with Fontan circulation (FC) are at high risk for physical and psychological problems. Many have poor growth, low weight gain, and low oxygen saturation (O2 sat). They also often have learning problems, inattention, and mood/anxiety disorders. Research on associations between these physical and mental challenges is limited. This study explores potential relations among these variables in a cohort with FC. We hypothesize that poorer growth, weight, and O2 sat are associated with greater problems with school, mood/anxiety, and inattention. A team, including pediatric cardiologist, psychologist, and other medical specialties, evaluated participants in our FORWARD program, a dedicated multidisciplinary clinic for patients with FC. Data were extracted from medical records. Height, weight, and resting O2 sat were measured at the clinic visit. Patients completed a psychological screening questionnaire (BASC-3); scales selected for analyses were based on commonly recognized problems in FC: school (academic difficulties, negative school attitude), internalizing (mood/anxiety), and attention problems. Sample consisted of 45 subjects; 53% male, 84% White, 81% had private health insurance. Plurality had hypoplastic left heart syndrome (47%). Mean age was 12.7 + 2.7 years, O2 sat 93.9 + 2.7 %, height z-score -0.58 + 1.42, and weight z-score -0.23 + 1.43. Mean values on all psychological measures were not indicative of problems. Height and weight were not related to psychological measures. O2 sat was inversely correlated with school problems (r= -.350, p= .018). Internalizing (r= .503, p&lt; .001 ) and attention (r= .427, p= .002) problems were correlated with school problems. O2 sat, internalizing and attention problems were entered into a regression predicting school problems; the model explained 35.4% of the variance (p&lt; .001). School problems of individuals with FC are likely determined by both physical and psychological factors. In our relatively small and young cohort of patients, lower O2 sat may reflect relative overall FC unwellness, and is associated with greater psychological health challenges. Exploration of potential mechanisms underlying relations between physical and psychological health in those with FC is warranted.
DDRE-21. LOMUSTINE AND TARGETED-CYTOKINE THERAPY: A BENEFICIAL LIAISON FOR RECURRENT GLIOBLASTOMA
Authors: Tobias Weiss, Thomas Look, Emanuele Puca, Roberto De Luca, Teresa Hemmerle, Patrick Roth, Dario Neri, Michael Weller
Journal: Neuro-Oncology (2021)

Abstract Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).
Abstract 10495: Mechanism of Cardiac Repair in Rat Myocardial Infarction Model Treated with Extracellular Vesicles from Differentiating Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Yuji Tominaga, Shigeru Miyagawa, Takuji Kawamura, Emiko Ito, Maki Takeda, Masaro Nakae, Akima Harada, Yoshiki Sawa
Journal: Circulation (2021)

Introduction: A few reports showed the therapeutic effects of extracellular vesicles (EVs) secreted from induced pluripotent stem cell-derived cardiomyocytes (iPSCM) on animal ischemic cardiomyopathy models. However, the mechanism of the cardiac function restoration after EVs administration remained unclear. Then, this study aimed to identify the mechanism for the restoration of cardiac function after iPSCM-EVs treatment. Methods: We collected EVs from differentiating iPSCM (TnT positive &amp;gt; 80%) culture medium. Comprehensive miRNA-seq and proteome analysis in the EVs were performed. In vitro myocardial contraction assay and wound healing assay, and ex vivo aortic ring assay were performed. In vivo , we designed a rat model of myocardial infarction by left anterior descending artery (LAD) ligation and divided rats into two groups. Two weeks after LAD ligation, iPSCM-EVs (Group EV) or PBS (Group Ctl) were injected peri-infarct zone. We analyzed the sequential cardiac function, histological analysis, and comprehensive RNA sequence analysis of the border zone before the treatment and 3, 7, 14, and 28 days after the treatment (n=5 at each time point in each group). Results: EVs showed the potential of increased myocyte contraction velocity (11±0.7 vs 6.6±0.6 μm/s, mean±SD, p &amp;lt; 0.01) and enhanced endothelial migration in vitro and facilitated angiogenesis (46±6 vs 13±5 sprouting count, p=0.02) ex vivo . In vivo , Group EVs showed higher LVEF (57±5 vs 38±4 % at day28, p &amp;lt; 0.01) and smaller LVDd (6.8±0.3 vs 8.5±0.8 mm at day28, p &amp;lt; 0.01). Histological analysis showed a lower % fibrosis area in Group EV (22±6 vs 12±5 % at day28, p &amp;lt; 0.01) and significantly higher microvascular (vWF positive: 1.7 at day14 and 2.1 times higher at day28) and arterial (vWF and αSMA positive: 4.3 at day14 and 6.2 times higher at day28) density. RNA expression analysis showed the expression of HGF, SDF-1, and IGF-1 increased in Group EVs on day3 and 7. CTGF and collagen 1 increased in Group Ctl on day14 and 28. Conclusions: Intracardiac injection of iPSCM-EVs improved cardiac function in rat MI model via angiogenesis, increased myocyte contraction, and reduced fibrosis. Comprehensive expression analysis suggested the mechanism of action of EVs in cardiac repair.
Abstract 13957: Predicting In-Hospital Mortality Among Patients Hospitalized With Heart Failure Using a Convolutional Neural Network and Transfer Learning on a Single Admission Chest X-Ray
Authors: David Hidalgo-Goto, Lovedeep Dhingra, Veer Sangha, Evangelos K Oikonomou, Rohan Khera
Journal: Circulation (2021)

Background: Early identification of mortality risk among patients hospitalized with heart failure (HF) is critical for therapeutic decisions. Early warning systems have relied on large datasets with frequent outcomes. We evaluate the use of transfer learning to use a single chest x-ray obtained at presentation in a small sample of HF hospitalizations to predict in-hospital mortality. Methods: In MIMIC-IV - a publicly available electronic health record dataset of consecutive hospitalizations from the ED or those requiring ≥1 day of ICU stay during 2008-2019 - we identified all hospitalizations with a primary diagnosis of HF. We combined this with chest x-rays (CXRs) drawn from the MIMIC-CXR dataset with available radiographic labels. We evaluated the risk of mortality based on CXR using a convolutional neural network (CNN) based on the Efficient Net B3 architecture. We compared 2 strategies - (1) training on primary HF hospitalizations directly for mortality risk (direct learning), or (2) pre-training the model on a non-mortality radiographic label, before training for mortality (transfer learning) (Fig A). Results: There were 3604 hospitalizations with a primary diagnosis of HF (mean age 70.8 years, 48% women) who had a corresponding CXR, of whom 87 (2.4%) died in the hospital. There were 102,551 hospitalizations without a diagnosis of HF with a CXR. The CNN model developed on HF data (60% training, 20% validation, 20% test) led to modest predictive performance (AUROC 0.67) for mortality (Fig B). In the second model that was pre-trained on identifying pleural effusion on CXRs in the absence of a HF diagnosis, and was tuned on the HF data for mortality, was associated with a large predictive gain (AUROC 0.80) (Fig B). Conclusion: A single CXR can accurately classify the mortality risk of patients with HF with high model discrimination. Transfer learning allows the use of unstructured data inputs in predictive models for small datasets and few inputs.
CBIO-18. TP53-MUTANT OLIGODENDROGLIOMA: A SINGLE INSTITUTION CASE SERIES
Authors: Mason Webb, Sani Kizilbash, Thomas Kollmeyer, Robert Jenkins, Sarah Sung, Aditya Raghunathan, Caterina Giannini, Kar-Ming Fung, John-Paul Bouffard, Cristiane Ida
Journal: Neuro-Oncology (2021)

Abstract TP53 mutations are frequent in IDH-mutant astrocytomas but unusual in oligodendroglioma and the clinical significance of TP53 mutations in oligodendroglioma are not well characterized. We reviewed genetically defined oligodendroglioma (i.e., IDH-mutant, whole-arm 1p/19q-codeleted diffuse glioma) cases that were molecularly profiled (2017-2020) at our institution and identified 7 cases with TP53 mutation (9%; n=76). Molecular testing was performed using targeted neuro-oncology NGS panel (50-gene mutation and/or 187-gene mutation/rearrangement) and OncoScan™ microarray. Four (of 7) patients were female. Median age at diagnosis was 43 years (range, 23-63). Most common presenting symptom was seizures (3 of 7). All tumors were supratentorial. Histologically, 3 tumors were WHO grade II and 4 were WHO grade III. Two (of 3) patients with a WHO grade II tumor underwent biopsy and radiotherapy at diagnosis followed by temozolomide at recurrence (progression at 67 and 157 months after diagnosis; overall survival of 124 and 201 months). Three (of 4) patients with a WHO grade III tumor were diagnosed within the last two years and are currently progression-free after standard therapy. Molecularly, in addition to TP53 mutation(s), all cases had an IDH1 and TERT promoter mutation as well as other gene mutation(s) including FUBP1 (n=5), SETD2 (n=4), PIK3R1 (n=4), PIK3CA (n=3), NF1 (n=3) and CIC (n=3). In 3 (of 7) cases, the mutational profile with high mutation count enriched for C &amp;gt;T/G &amp;gt;A transitions was highly suggestive of a hypermutation phenotype (2 cases were recurrent tumors treated with temozolomide; a recurrent and a treatment-naïve tumor had mismatch repair gene mutation). Five (of 7) cases, including the 3 hypermutant cases, lacked functional TP53 (1 case with 2 mutations, 2 cases with 1 mutation plus loss of other copy, 2 cases with 1 mutation plus copy neutral loss-of-heterozygosity). TP53 mutations are uncommon in oligodendroglioma and appear enriched in hypermutant tumors.