tbuckley/cabot-search huggingface dataset:
Significant down-regulation of growth hormone receptor expression revealed as a new unfavorable prognos- tic factor in hepatitis C virus-related hepatocellular carcinoma
Authors: Ching-Chih Lin, Ta-Wei Liu, Ming-Lun Yeh, Yi-Shan Tsai, Pei-Chien Tsai, Chung-Feng Huang, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai, Ming-Lung Yu
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC.Methods: The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed.Results: GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of &gt;60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein &gt;100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C.Conclusions: Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.
Intraplaque Hemorrhage as a Stimulator of Episodic Growth of Advanced, But Nonsymptomatic Atherosclerotic Lesions: Bridging the Gap⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Mat J. Daemen, Marianne Eline Kooi
Journal: JACC. Cardiovascular imaging (2009)
EPCO-20. RELATING GLIOBLASTOMA HETEROGENEITY TO HUMAN FETAL GLIAL DEVELOPMENT THROUGH HIGH RESOLUTION SINGLE NUCLEI TRANSCRIPTOMICS
Authors: Zarmeen Mussa, Susana Ramos, Elisa Nabel, Kimaada Allette, Ammar Hamid, Maggie Cai, Will Zhao, Ying-chih Wang, Kristin Beaumont, Robert Sebra, Alexander Tsankov, Nadejda Tsankova
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is thought to be driven by a therapy-resistant cancer stem cell population that recapitulates developmental phenotypes. Direct comparisons of GBM to glial states during human fetal development are limited due to paucity of data from late prenatal gestation, when gliogenesis is thought to occur. Here, we generated a comprehensive single nuclei RNA sequencing (snRNAseq) dataset of approximately 200,000 nuclei taken from the germinal matrix and the cortical plate of 16 fetal postmortem samples, ranging from 17 to 41 gestational weeks, enabling high spatiotemporal resolution of late neurogenesis and early-to-peak gliogenesis. We performed unbiased clustering to identify broad cell types within each sample and integrated all fetal samples to analyze evolving glial states and relationships across two regions and four developmental stages. Subclustering analysis of developing glia from the germinal matrix and cortical plate resolved developmental cell type signatures that are absent in the adult brain. Trajectory inference and pseudo-time analyses reconstructed relationships within these glial lineages and states, identifying a robust common glial progenitor population (GPC) with distinct signature, preceding both oligodendrocyte progenitor cell (OPC) and astrocyte lineage commitment during late prenatal development. We then performed snRNAseq on approximately 30,000 nuclei taken from the core and infiltrating edge of two surgically resected GBM samples with IDH-mutant and IDH-wildtype status and EGFR amplification. Uniform manifold approximation and projection (UMAP) dimensionality reduction revealed distinct neoplastic and non-neoplastic population clusters within each GBM sample. Projecting our previously defined neural stem cell / progenitor signatures onto each GBM UMAP identified notable predominance of the GPC-like developmental signature throughout both GBM tumors with focal minor contributions from the OPC-, transit amplifying-, and astrocyte-like signatures. The high spatial and temporal resolution of the generated roadmap dissolves GBM intratumoral heterogeneity into distinct developmental molecular states driven by potentially targetable regulatory networks.
IMG-21. PROSPECTIVE PREOPERATIVE DETERMINATION OF ISOCITRATE DEHYDROGENASE MUTATION IN GLIOMAS USING SPECTRAL EDITING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Thanh Nguyen, Gerd Melkus, Michael Taccone, Diana Ghinda, Carlos Torres, Nader Zakhari, John Woulfe, Gerrard Jansen, Ian Cameron, Ioana Moldovan, Fahad Alkherayf
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Gliomas are the most common malignant brain tumors in children and adults. A subset of these tumors harbour mutations in the enzyme isocitrate dehydrogenase (IDH) which produces the novel oncometabolite 2-hydroxyglutarate (2HG). In general, patients with an IDH mutant glioma have a longer survival—often necessitating more re-treatment sessions over the span of a patient’s life and surveillance monitoring for tumor recurrence. The need to non-invasively detect early evidence of tumor recurrence is therefore heightened in this unique subset of patients with extended survival. As magnetic resonance spectroscopy (MRS) has been demonstrated to measure biochemical components of intracranial tumors using MRI, we conducted a study in 58 pre-operative adult patients to determine if a diagnosis of IDH mutant glioma could be made confidently using imaging data. METHODS Patients underwent neuroimaging for diagnosis or preoperative planning on a 3 tesla MR scanner. A MEGA-PRESS spectral editing technique was employed. Imaging findings were directly compared to post-operative histopathologic diagnosis. RESUTLS: For all patients with gliomas from grade II to IV, detection of 2-HG with MEGA-PRESS sequence had a sensitivity between 48% and 81%, specificity between 60% and 100%, PPV between 53% and 100% and NPV between 77% and 85% depending on the CRLB threshold. Among the different metabolite ratios, a 2-HG/NAA ratio &amp;gt;0.034 had the highest sensitivity and specificity, 86% and 73% respectively. DISCUSSION Magnetic resonance spectroscopy (MRS) is an underused advanced MR technique that deserves consideration in pediatric neuro-oncology given its utility in non-invasively detecting malignant gliomas.
RARE-53. PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION (PPTID) AND DICER1 SYNDROME: A CASE REPORT
Authors: Stephanie Toll, Avanti Gupte, Sandeep Sood, William Kupsky, Deniz Altinok, Steven Miller, Kanta Bhambhani
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND DICER1 syndrome is a rare inherited tumor predisposition syndrome linked to an increased risk of several malignancies. Affected individuals most commonly develop pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors. Brain tumors in these patients are rare, however; the increased frequency of pineoblastoma in this population has been established. Traditionally, pineal parenchymal tumors of intermediate differentiation (PPTIDs) have not been associated with DICER1 syndrome, with research suggesting alternative mutations driving tumorigenesis. These tumors are pathologically and clinically diverse, with long-term surveillance based on therapeutic interventions. Here we describe a case of a germline DICER1 mutation in a patient with a PPTID, suggesting that this mutation is not limited to pineoblastoma as previously reported. CASE: We describe a 19 year-old female with a WHO grade III PPTID treated with multimodal therapy including surgery, craniospinal irradiation (CSI) and chemotherapy. She was noted to have a thyroid mass at diagnosis and was subsequently diagnosed with a benign thyroid nodule, followed most recently by a cataract with pathology concerning for medulloepithelioma of the ciliary body. Due to the known association between medulloepithelioma and DICER1 syndrome, targeted germline sequencing was obtained and confirmed a pathogenic heterozygous mutation. CONCLUSION To our knowledge this is the first report of a PPTID in a patient with DICER1 syndrome. This association highlights the clinical implications of molecular evaluation in pediatric brain tumors, for both immediate therapeutic decisions and long-term surveillance.
CBIO-06. MKlp2 INHIBITION AS A NOVEL ANTIMITOTIC FOR GLIOBLASTOMA
Authors: Morgan Schrock, Luke Scarberry, Benjamin Stromberg, Adrian Torres, Arnab Chakravarti, Monica Venere, Matthew Summers
Journal: Neuro-Oncology (2020)

Abstract Despite innovations in therapy and surgery, glioblastoma remains one of the deadliest tumor types with a 5-year survival rate of approximately 5%. There is a desperate need for new therapeutic strategies to block the growth and survival of glioblastoma. To circumvent toxicities associated with traditional antimitotics, there has been a growing interest in developing therapies that impede mitosis-specific microtubule functions, such as the inhibition of kinesins, mitotic motor proteins that travel along microtubules. Our work with motor kinesin-like protein 2 (MKlp2), in combination with reports from published literature, suggest a previously undescribed role for MKlp2 in early mitosis that would make its inhibition effective at impeding glioblastoma cell growth without neurologic side effects. The objective of this study was to further define this novel function of MKlp2 and to determine the efficacy of MKlp2 inhibition in glioblastoma. Our data indicate that MKlp2 inhibition induced a spindle assembly checkpoint-mediated arrest, suggesting that function of MKlp2 is important for recovery progression to anaphase in addition to its well-known function in late mitosis. In addition, MKlp2 inhibition with a small molecule MKlp2 inhibitor significantly decreased short-term and long-term survival of human glioblastoma patient-derived lines. Furthermore, our data indicate that it is loss of this early mitotic function that is responsible for the anti-proliferative effects caused by MKlp2 inhibition. Ongoing work will continue to delineate the mechanism of MKlp2 in early mitosis and determine the effect of small molecule MKlp2 inhibition in vivo, all the while exploring a new therapeutic strategy for glioblastoma
NCOG-76. BASELINE COGNITIVE ASSESSMENT IN GLIOMA PATIENTS WITH MGMT PROMOTOR METHYLATION AND/OR 1p19q CODELETION
Authors: Sydney Park, Abigail Giles, Grace Liberatore, Katherine Morgan, Cynthia DeBruhl, Fang-Chi Hsu, Christina Cramer, Roy Strowd, Michael Chan, Glenn Lesser, Adrian Laxton, Stephen Tatter, Tiffany Cummings
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Methylguanine methyltransferase (MGMT) methylation status is associated with better overall survival while 1p19q co-deletion is associated with long-term survival. Cognitive dysfunction is a common complication of brain tumors and treatment; however, information regarding the relationship between MGMT status, 1p19q codeletion, and cognition is limited. METHOD Baseline neuropsychological testing was performed in patients with malignant glioma prior to radiation and/or chemotherapy administration. A retrospective data analysis was conducted. We calculated composite and subdomain scores for attention/executive functioning, memory, and language in patients with or without MGMT promotor methylation and/or 1p19q codeletion. RESULTS Thirty-eight patients (Age M = 48.73 ± 14.98; 50% female) diagnosed with glioma (29% grade II, 16% grade III, 21% grade IV; Karnofsky Performance Status score (KPS) M = 88.75 ± 14.24) were selected from a retrospective. Memory was marginally significant, such that methylated participants performed better on memory tasks than the unmethylated group (p = .053). Independent samples t-test revealed no significant differences between either marker across the overall cognitive composite (methylated M = 41.35; unmethylated: M = 39.91; p = .955; 1p19q co-deleted: M = 50.94; 1p19q intact: M = 43.66; p = .158) and subdomains attention/executive functioning (p = .585; p = .157) and language (p = .581; p = .765). Logistic regression showed MGMT does not predict cognitive status (p =.052) and there were not enough cases to complete the model with 1p19q. CONCLUSION MGMT status may be correlated with baseline cognitive status as MGMT methylated patients had better memory scores than their unmethylated counterparts. We did not find any significant association between the remaining cognitive domains and MGMT or 1p19q although sample size is a significant limitation. These results suggest further assessment of changes in cognition during treatment through serial neuropsychological testing of glioma populations with defined marker status is warranted.
Abstract 14657: Circulating Mitochondrial DNA Released by Ischemic Myocaridium Exacerbate Reperfusion Injury by Activating Inflammatory Response via HMGB1-RAGE Pathway
Authors: Mingbiao Li, Shihi Chang, Degang Liang, Zequang Yang, Yikui Tian
Journal: Circulation (2019)

Introduction: Our previous researches demonstrated that the released circulating cell free DNA exacerbates myocardial reperfusion injury. However, the precise mechanism underlying this phenomenon i...
DDRE-13. DECONVOLUTING MECHANISMS OF RESISTANCE TO BRAF INHIBITORS IN BRAF V600E HUMAN GLIOMA
Authors: Karisa Schreck, Andrew Morin, Guisheng Zhao, Bridget Sanford, Adam Green, Kenneth Jones, Anurhada Banerjee, Kellie Nazemi, David Samuel, Lindsay Kilburn, David Solomon, Christine Pratilas, Theodore Nicolaides, Jean Mulcahy Levy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND While BRAF-targeted therapy can be effective in a subset of patients with glioma, resistance to treatment can emerge over time. The description and validation of mechanisms of resistance in BRAF-mutant glioma are not previously described. METHODS Pre- and post- BRAF inhibitor (BRAFi) or BRAFi/MEK inhibitor (MEKi) treated patient samples were obtained under IRB-approved protocols at University of Colorado Denver, UCSF, and Johns Hopkins. Targeted DNA sequencing or whole exome sequencing (WES), and RNA-seq were conducted on paired samples. Functional validation of putative resistance mechanisms was performed using established glioma cell lines with BRAF V600E mutation (DBTRG-5MG, AM38, B76). RESULTS Analysis of 15 tissue sample pairs identified point mutations in 15 genes (including CBL, NF1, PTEN, and MAP2K1) and expression changes in RAF1 leading to putative mechanisms of resistance. We performed functional validation of loss of NF1 and CBL as resistance mechanisms and demonstrated growth inhibition and cell death in response to BRAFi with siRNA/sgRNA-mediated knockdown of each gene. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. Ingenuity pathway analysis suggested that a switch from BRAF to CRAF dependence mediated resistance in some tumors. Indeed, inhibition of CRAF expression using siRNA in a patient-derived glioma cell line re-sensitized cells to BRAFi. CONCLUSIONS Analysis of pre-/post-treatment BRAF mutant glioma sample pairs, primarily from pediatric patients, identified a variety of putative resistance mechanisms, some of which have been validated in vitro. Resistance mechanisms to BRAFi in glioma are varied and may be susceptible to different combinations of targeted therapy, highlighting the importance of a personalized approach.
TAMI-12. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA
Authors: Daniel Silver, Gustavo Roversi, Nazmin Bithi, Chase K Neumann, Katie Troike, Grace Ahuja, Ofer Reizes, J Mark Brown, Christopher Hine, Justin Lathia
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
4P IgM-rheumatoid factor as a novel biomarker for a reduced survival in anti-PD-1 treated NSCLC patients through the decrease of CD137+ T-cells
Authors: A. Ugolini, I.G. Zizzari, F. Ceccarelli, A. Botticelli, T. Colasanti, L. Strigari, A. Rughetti, H. Rahimi, F. Conti, G. Valesini, P. Marchetti, M. Nuti
Journal: Annals of Oncology (2020)
Interpretable Machine Learning Framework Reveals Robust Gut Microbiome Features Associated With Type 2 Diabetes
Authors: Wanglong Gou, Chu-wen Ling, Yan He, Zengliang Jiang, Yuanqing Fu, Fengzhe Xu, Zelei Miao, Ting-yu Sun, Jie-sheng Lin, Hui-lian Zhu, Hongwei Zhou, Yu-ming Chen, Ju-Sheng Zheng
Journal: Diabetes Care (2020)

To identify the core gut microbial features associated with type 2 diabetes risk and potential demographic, adiposity, and dietary factors associated with these features.We used an interpretable machine learning framework to identify the type 2 diabetes-related gut microbiome features in the cross-sectional analyses of three Chinese cohorts: one discovery cohort (n = 1,832, 270 cases of type 2 diabetes) and two validation cohorts (cohort 1: n = 203, 48 cases; cohort 2: n = 7,009, 608 cases). We constructed a microbiome risk score (MRS) with the identified features. We examined the prospective association of the MRS with glucose increment in 249 participants without type 2 diabetes and assessed the correlation between the MRS and host blood metabolites (n = 1,016). We transferred human fecal samples with different MRS levels to germ-free mice to confirm the MRS-type 2 diabetes relationship. We then examined the prospective association of demographic, adiposity, and dietary factors with the MRS (n = 1,832).The MRS (including 14 microbial features) consistently associated with type 2 diabetes, with risk ratio for per 1-unit change in MRS 1.28 (95% CI 1.23-1.33), 1.23 (1.13-1.34), and 1.12 (1.06-1.18) across three cohorts. The MRS was positively associated with future glucose increment (P < 0.05) and was correlated with a variety of gut microbiota-derived blood metabolites. Animal study further confirmed the MRS-type 2 diabetes relationship. Body fat distribution was found to be a key factor modulating the gut microbiome-type 2 diabetes relationship.Our results reveal a core set of gut microbiome features associated with type 2 diabetes risk and future glucose increment.
COVD-04. CHARACTERISTICS OF SARS-COV-2 IN 64 CHILDREN WITH CNS TUMORS: A REPORT FROM THE SIOP/ST. JUDE CHILDREN’S RESEARCH HOSPITAL (SJCRH) GLOBAL COVID-19 CHILDHOOD CANCER REGISTRY
Authors: Daniel Moreira, Eric Bouffet, Nickhill Bhakta, Guillermo Chantada, Yichen Chen, Lane Faughnan, Yuvanesh Vedaraju, Maghana Avula, Maysam Homsi, Paula Naidu, Andrew Pappas, Radhikesh Ranadive, Victor Santana, Michael Sullivan, Lorena Baroni, Miguela Caniza, Meenakshi Devidas, Kathy Pritchard-Jones, Carlos Rodriguez-Galindo, Sheena Mukkada
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The GCCCR is a collaboration between SIOP and SJCRH to describe the natural history of SARS-CoV-2 in children with cancer across the world. METHODS The GCCCR is a deidentified registry of patients &amp;lt;19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30-days and 60-days post infection. RESULTS As of August 10th 2020, the GCCCR included 730 cases from 35 countries, including 64 children with CNS tumors (8.8%) from 17 countries. The most frequent diagnoses were embryonal tumors (31.2%) and low-grade glioma (17.2%). Thirty-nine (60.9%) children were asymptomatic from infection, while 19 (29.7%) patients required hospital admission and 2 (6.3%) transferred to the intensive care unit. There was a significant association between infection severity and ANC &amp;lt;500 (p=0.04). At the time of infection, 44 (68.8%) patients were undergoing cancer-directed therapy. Thirty-two cases have follow-up data. No modification in cancer-directed therapy occurred in 11 (34.4%) patients, while chemotherapy was modified in 6 (18.8%), radiotherapy delayed in 2 (6.3%), and surgery postponed in 1 (3.1%). No patients died from SARS-CoV-2 infection, although 2 died from non-COVID-19 related causes. CONCLUSION The frequency and severity of COVID infection among children with CNS tumors appears to be proportionally lower compared to other children with cancer. Although this is the largest cohort of patients reported to date, additional insight is needed, including the effects of treatment modifications on outcomes.