tbuckley/cabot-search huggingface dataset:
Abstract 12799: Changes in Plasma Hemopexin Are Inversely Associated With Myocardial Strain in Breast Cancer Patients Treated With Anthracyclines
Authors: Aarti Asnani, Debby Ngo, Qiong Yang, Mark Benson, Sumita Sinha, Dongxiao Shen, Igal Sebag, Juan C Plana, Marielle Scherrer-Crosbie, Robert E Gerszten
Journal: Circulation (2019)

Introduction: Anthracyclines are commonly used for the treatment of breast cancer, but they cause cardiotoxicity in 10% of all patients. We hypothesized that changes in circulating plasma proteins ...
SURG-02. INITIAL MANAGEMENT OF HYDROCEPHALUS IN THE PEDIATRIC AND YOUNG-ADULT PATIENTS WITH BRAIN TUMORS; THE EFFICACY OF LONG-TERM INDWELLING EXTERNAL VENTRICULAR DRAINAGE
Authors: Shigeru Yamaguchi, Hiroaki Motegi, Yukitomo Ishi, Michinari Okamoto, Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Atushi Manabe, Kiyohiro Houkin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric and Young-Adult (AYA) brain tumors often present with hydrocephalus. As temporary cerebrospinal fluid (CSF) diversion procedure, we perform long-term indwelling external ventricular drainage (EVD) in the case of the management of CSF diversion more than two weeks presumably. The aim of this study is to investigate the initial management for hydrocephalus in pediatric /AYA patients with brain tumor, especially about long-term EVD. MATERIALS AND METHODS The patients less than 30 years of age diagnosed with brain tumor between 2005 and 2019 were retrospectively analyzed. Procedures of long-term EVD were similar to that of ventriculoperitoneal shunt (VPS) operation. Using flow-control VPS system, peritoneal catheter passed out of the body at the anterior chest, and distal end of the catheter was connected to standard EVD system. RESULTS In total of 345 patients with brain tumor, 109 had hydrocephalus at presentation. Among them, 25 patients (23%) underwent long-term EVD. The main reasons for selecting long-term EVD were to avoid intraperitoneal dissemination (n=13), and to maintain longer period of CSF diversion for the treatment of tumor (n=12). The median of long-term EVD was 38 days (range: 12 – 222 days). Although one case suffered from drainage tube occlusion at 59 days, there were no other complications such as infection or accidental evulsion. Eventually, 3 cases required permanent VPS for persistent hydrocephalus. CONCLUSION Long-term EVD is safe and effective option for CSF diversion. This procedure should be taken into consideration if patients have a risk of dissemination and may elude permanent VPS.
ATRT-25. INTEGRATED QUANTITATIVE SWATH-MS PROTEOMICS ANALYSIS OF ATRTs UNCOVERS NEW THERAPEUTIC OPPORTUNITIES
Authors: Martina Anna Finetti, James Hacking, Emma Lishman-Walker, Silvia A Synowsky, Stephen Crosier, Emmma Martin, Jess Burns, Sally L Shirran, Simon Bailey, Steven C Clifford, Paul Huang, Daniel Williamson
Journal: Neuro-Oncology (2020)

Abstract The consequences of SMARCB1 loss in Atypical Teratoid Rhabdoid Tumors (ATRTs) have been extensively characterized at the epigenetic/transcriptomic level. In this study we detail the functional effect of SMARCB1 mutation on the MRT proteome, its relationship with RNA deregulation or lack thereof. We performed unlabeled discovery proteomics using MS-SWATH on MRT cells in which SMARCB1 was forcibly re-expressed (5 cell lines, +/-SMARCB1); analyzing changes in protein abundance within 3 fractions (total, membrane, nuclear). We generated a custom spectral library, covering &amp;gt;8,000 proteins, for analysis of the ATRT proteome using a pH fractionated pool of each cellular subfraction. This SMARCB1-dependent ATRT spectral library constitutes a powerful tool for profiling proteins of potentially therapeutic relevance in both model systems and primary ATRT samples. We show that whilst gene expression and protein abundance are significantly related there are many instances whereby expression changes do not reliably predict protein abundances. Several hundred proteins show significantly increased abundance (p&amp;lt;0.01) with no concomitant change by RNA-seq. SMARCB1 mutation is able to invoke critical changes in post-transcriptional/translational regulation as well as sub-cellular localization. By integration with whole-genome CRISPR/cas9 screening we describe functionally essential SMARCB1 dependent pathway/membrane biomarkers, evident at the protein but not the RNA level. We describe several which are druggable and suggest certain therapeutic modalities e.g. specific combinations of RTKs, RNA-binding proteins/splicing factors (SpliceosomeA, U4:U5:U6 tri-snRNP complexes). Our analysis links, for the first time in ATRT, genome-wide transcriptomic and proteome aberrations and reveals broad mechanisms underlying the effect of SMARCB1 mutation.
Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus
Authors: Shushu Song, Yinghong Shi, Weicheng Wu, Hao Wu, Lei Chang, Peike Peng, Lei Zhang, Jia Fan, Jianxin Gu, Yuanyuan Ruan
Journal: Gut (2020)

Objective Dysfunction of endoplasmic reticulum (ER) proteins is closely related to homeostasis disturbance and malignant transformation of hepatocellular carcinoma (HCC). Reticulons (RTN) are a family of ER-resident proteins critical for maintaining ER function. Nevertheless, the precise roles of RTN in HCC remain largely unclear. The aim of the study is to examine the effect of reticulon family member RTN3 on HCC development and explore the underlying mechanisms. Design Clinical HCC samples were collected to assess the relationship between RTN3 expression and patients’ outcome. HCC cell lines were employed to examine the effects of RTN3 on cellular proliferation, apoptosis and signal transduction in vitro. Nude mice model was used to detect the role of RTN3 in modulating tumour growth in vivo. Results We found that RTN3 was highly expressed in normal hepatocytes but frequently downregulated in HCC. Low RTN3 expression predicted poor outcome in patients with HCC in TP53 gene mutation and HBV infection status-dependent manner. RTN3 restrained HCC growth and induced apoptosis by activating p53. Mechanism studies indicated that RTN3 facilitated p53 Ser392 phosphorylation via Chk2 and enhanced subsequent p53 nuclear localisation. RTN3 interacted with Chk2, recruited it to ER and promoted its activation in an ER calcium-dependent manner. Nevertheless, the tumour suppressive effects of RTN3 were abrogated in HBV-positive cells. HBV surface antigen competed with Chk2 for RTN3 binding and blocked RTN3-mediated Chk2/p53 activation. Conclusion The findings suggest that RTN3 functions as a novel suppressor of HCC by activating Chk2/p53 pathway and provide more clues to better understand the oncogenic effects of HBV.
DDRE-31. EVALUATION OF HIGHLY POTENT AND SELECTIVE SINGLE-MOLECULE DUAL EGFR/PI3K INHIBITORS IN ADULT AND PEDIATRIC HIGH-GRADE GLIOMA
Authors: Achintyan Gangadharan, Yusha Sun, Cavan Bailey, Trever Carter, Alexsandra Espejo, Christopher Whitehead, Judith Leopold, Joya Chandra
Journal: Neuro-Oncology (2020)

Abstract High grade gliomas (HGG) carry poor prognosis with median survival rates under 15 months post diagnosis. Due to dysregulation of kinase signaling pathways within these tumors, targeted kinase inhibition has been considered as a promising clinical strategy. However in HGG, many single-agent inhibitors of EGFR or PI3K have shown limited response due to activation of compensatory signaling. Single-molecule multikinase inhibitors may decrease resistance, present a single pharmacokinetic dosage profile, and reduce risks of multi-agent toxicities, supporting this strategy over dual drug combination approaches. To test this concept, a panel of inhibitors exploiting known binding modes of structurally-related ATP binding site inhibitors of EGFR/PI3K were synthesized and characterized. Of these, MTX-241 was least likely to act as a substrate for drug efflux proteins such as P-glycoprotein. Treatment of MTX-241 in a panel of eight human adult and pediatric HGG lines showed strong cytotoxic potency measured by growth inhibitory activity, with IC50s in the &amp;lt; 10 µM range. Tumor selectivity of MTX-241 was observed, with normal human astrocytes (NHA) nearly insensitive to MTX-241 even at &amp;gt;100 µM. MTX-241 was significantly more potent than clinically relevant inhibitors targeting EGFR/RTKs (gefitinib, lapatinib, dasatinib, imatinib) or PI3K (alpelisib, idelalisib). Synthesis and evaluation of a new series of compounds based on MTX-241 structure, but optimized for improved stability is ongoing. Our data suggests that a dual inhibitor of EGFR and PI3K, represents a viable therapeutic strategy in adult and pediatric HGG. Future studies will focus on evaluation of in vivo efficacy in tumor bearing mouse models.
EXTH-04. INTRATHECAL (IT) DELIVERY OF TYPE I POLARIZED DENDRITIC CELL VACCINE (DC1) ERADICATES TUMOR GROWTH IN BREAST CANCER (BC) XENOGRAFT MODEL WITH BRAIN METASTASES (BM) AND LEPTOMENINGEAL DISEASE (LMD)
Authors: Vincent Law, Krithika Kodumudi, Colin Snyder, Brian Czerniecki, Peter Forsyth
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Approx. 5% of BM will also develop LMD. Currently there is no effective treatment for BC-associated BM/LMD. As systemic therapies do not prevent the disease recurrence and eventual death, the better option would be direct-targeted approach. We have shown that there is a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune response in BC patients (pts). In a clinical setting, administration of class II HER2 peptide-pulsed Type I polarized dendritic cell vaccine (HER2-DC1) partially restored anti-HER2 Th1 immune responses with pathologic complete response in HER2+ BC patients. In this study, we examined the IT delivery of HER2/HER3- DC1 in BC-LMD model. METHODS Luciferase-labeled HER2+ TUBO BC cell line was injected into the cisterna magna of BALB/c mice to develop BM/LMD. We developed a technique, coined the “Top Hat” (TH) for mouse model that mimics the Ommaya reservoir in BC-pts. The TH essentially allows us to administer IT treatment directly into CSF. BC-BM/LMD bearing mice were given HER2- and Her3 peptide-pulsed Type I polarized DC1 through the TH. RESULTS AND DISCUSSION BM/LMD mice were randomized into following groups: 1) systemic Her2-DC1 2) IT Her2-DC1 3) IT Her2-/Her3-DC1. The median survival (MS) of control mice was 10 days and systemically treated mice was 19 days. IT Her2-DC1 animals did significantly better than both control and systemic treated groups (MS: 63 days; p&amp;lt; 0.0001) and overall survival (OS): 44%. Interestingly, mice given IT Her2-/Her3-DC1 had the best OS (78%). Surviving animals were eventually disease free. Mice that had complete tumor regression were immune to subsequent rechallenge with TUBO cells. Immune cell infiltration in the of CSF, spinal cord and tissues of experimental mice are currently ongoing. CONCLUSIONS Our preclinical data supports the clinical relevance of using intrathecal delivery of DC1 vaccine as a potential treatment for BM and LMD of BC-pts.
The regulatory factors and pathological roles of autophagy‐related protein 4 in diverse diseases: Recent research advances
Authors: Fan Xia, Peiqing Liu, Min Li
Journal: Medicinal Research Reviews (2020)

Abstract Macroautophagy (autophagy) is an evolutionarily conserved and dynamic degradation/recycling pathway in which portions of the cytoplasm, such as dysfunctional proteins and surplus organelles, are engulfed by double‐membrane bound vesicles through a lysosome‐dependent process. As the only proteolytic enzyme of the core mammalian autophagy proteins, autophagy‐related protein 4 (ATG4) primes newly synthesized pro‐light chain 3 (LC3) to form LC3‐I that attaches to phosphatidylethanolamine and delipidates LC3‐PE to LC3‐I for recycling. Besides autophagy, ATG4 has been shown to be involved in regulating various biological and pathological processes. The roles of ATG4 in cancer therapy, a methodology for ATG4 activity detection, and the discovery of chemical modulators have been well‐reviewed. However, a comprehensive summary on how ATG4 is regulated by multiple factors and, thereby, how ATG4 influences autophagy or other pathways remains lacking. In this paper, we summarize multiple processes and molecules that regulate the activity of ATG4, such as micro‐RNAs, posttranslational modifications, and small molecules. Additionally, we focus on the relationship between ATG4 and diverse diseases, including cancer, neurodegeneration, microbial infection, and other diseases. It provides insight regarding potential ATG4‐targeted therapeutic opportunities, which could be beneficial for future studies and human health.
GCT-10. CAN HIGH LEVEL SERUM hCG-β BE CONSIDERED EQUIVALENT TO A DIAGNOSIS OF CHORIOCARCINOMA IN PRIMARY CENTRAL NERVOUS SYSTEM GERM-CELL TUMOR?
Authors: Hiroaki Motegi, Shigeru Yamaguchi, Yukitomo Ishi, Michinari Okamoto, Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Atsushi Manabe, Kiyohiro Houkin
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Primary central nervous system(CNS) choriocarcinoma(CC) is very rare and has the poorest prognosis among germ cell tumor (GCT). CC usually has extremely high level (HL) of serum beta-human chorionic gonadotropin (bhCG) over than 1,000 mIU/ml. Some studies assign HL bhCG cases to poor prognosis group even without biopsy. The purpose of this study was to find out if there was a good prognosis subset in the HL bh group. MATERIALS AND METHODS We analyzed 103 cases diagnosed with GCT from 1998 to 2019 in Hokkaido University Hospital and reviewed the literature of CNS CC and bhCG. Survival was assessed using Kaplan-Meier method and log-rank statistics between the group with CC component and that with no CC component but HL bhCG. RESULTS One out of 103 our cases was diagnosed as a mixed GCT with CC component and did not respond to treatment and died 9 months later. Two cases were treated as CC because of HL bhCG (1,226 and 2,739 mIU/ml) despite that the biopsy showed only germinomas and survived(105 and 37 months), that is, no CC component. Combining our cases with 69 cases in the literature, all 7 cases with no CC component but HL bhCG survived but the median survival of the other 65 cases with CC component was 38.2 months (P=0.02). CONCLUSION This study has a limitation of selection bias, however, it suggests that patients with no CC component but HL bhCG may have a better prognosis.
DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Robyn Borsuk, Lanlan Zhou, Yiqun Zhang, Varun Prabhua, Joshua Allen, Wolfgang Oster, Nikos Tapinos, Rishi R Lulla, Wafik El-Deiry
Journal: Neuro-Oncology (2020)

Abstract Imipridones induce apoptosis in cancer via p53 independent upregulation of TNF-related apoptosis inducing ligand (TRAIL) pathway and its proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being evaluated alone and with radiotherapy for children with H3K27M mutant diffuse glioma. We sought to determine if ONC201 and its imipridone analogs (ONC206, ONC212) are synergistic with other chemotherapy agents. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SF8628) and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to ONC201, ONC206, and ONC212 alone and in combination with histone de-acetylase inhibitors (HDACi) or etoposide. A dose-dependent response to ONC201, ONC206, and ONC212 was demonstrated in all cell lines, with mean IC50 values of 1.46 µM, 0.11 µM, and 0.03 µM respectively. ONC206 and ONC212 induced apoptosis measured by increased expression of cleaved PARP and ISR by increased expression ATF4. In two cell lines, synergy studies revealed combination indices (CI) &amp;lt; 1 for ONC206 and etoposide, with a best CI of 0.62 in SU-DIPG-IV and 0.46 in SU-DIPG-25. Synergy was also observed between ONC201 and etoposide (CI 0.46) and ONC201 and panobinostat (CI 0.01). Imipridones and analogs were superior to panobinostat and etoposide in triggering apoptosis as measured by sub-G1 phase content. Additional synergy and mechanistic analyses are ongoing and will be reported. Our results suggest that H3K27M mutant DIPG cells demonstrate increased sensitivity to imipridone analogs (ONC206 and ONC212) when compared to ONC201. Combinational strategies with etoposide or HDACi should be considered for clinical translation.
PATH-09. SJMB12 CLINICAL TRIAL: DISCREPANCY BETWEEN LOCAL AND CENTRAL PATHOLOGY IN ASSESSING ANAPLASTIC MEDULLOBLASTOMA – REPORT FROM A SINGLE SITE EXPERIENCE
Authors: Dong-Anh Khuong-Quang, Karli Williamson, Duncan MacGregor, Brent A Orr, Amar Gajjar, Giles W Robinson, Michael J Sullivan, Jordan R Hansford
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION SJMB12 is a phase 2 clinical trial led by the St. Jude Children’s Research Hospital (St. Jude) that enrolls patients with medulloblastoma based on their biological subgroup. The large cell/anaplastic (LCA) histologic variant has been identified as an important independent risk factor associated with poor outcome. However, the histologic criteria for LCA is subjective, making the distinction between anaplastic and non-anaplastic medulloblastoma difficult in some cases. METHODS Pathological central review was performed at St. Jude. For all patients enrolled in the study to date, concordance was assessed between the initial and central review diagnosis and histologic variant calls made at the Royal Children’s Hospital Melbourne (RCH) and at St. Jude, respectively. RESULTS Since the SJMB12 clinical trial opened locally in 2014, 34 patients were enrolled, and 31 were eligible for this retrospective study. A total of 12 (39%) cases with discordance were identified. The most frequent disagreement was between the designation of LCA (10 cases, 32%). In five cases the tumour was not designated as LCA variant locally. In five cases the initial designation of LCA was refuted centrally. Overall, this led to a change of treatment stratum for four patients (13%). CONCLUSION A high discordance rate exists between neuropathologists in the designation of LCA variant. Differences in interpretation of the subjective histologic criteria and inconsistencies in the material submitted for central review contributed to the discordance. Incorporation of more objective histologic criteria and implementation of unbiased diagnostic tools may improve the generalisability of future risk stratification.
TAMI-10. CIRCULATING ANGIOGENIC CELLS (CACS) IN GLIOBLASTOMA: TOWARDS DEFINING CRUCIAL FUNCTIONAL DIFFERENCES IN CAC-INDUCED NEOPLASTIC VERSUS REACTIVE NEOVASCULARIZATION
Authors: Karin Huizer, Andrea Sacchetti, Sigrid Swagemakers, Peter van der Spek, Dana Mustafa, Johan M Kros
Journal: Neuro-Oncology (2020)

Abstract In order to identify suitable therapeutic targets for glioma anti-angiogenic therapy, the process of neovascularization mediated by circulating angiogenic cells (CACs) needs to be scrutinized. In the present study we compared the expression of neovascularization-related genes by three circulating CAC subsets (HPCs, CD34+ and KDR+ cells; internal controls: PBMCs and circulating endothelial cells) of treatment-naïve patients with glioblastoma (GBM) to those of patients undergoing reactive neovascularization (myocardial infarction (MI). CACs from umbilical cord (representing developmental neovascularization) and healthy subjects served as controls. Fluorescent activated cell sorting was used to isolate CACs, RT-PCR to determine the expression levels of a panel of 48 neovascularization-related genes, Luminex assays to measure plasma levels of 21 CAC-related circulating molecules. We found essential differences in gene expression between GBM and MI CACs. GBM CACs had a higher expression of pro-angiogenic factors (esp. KITL, CXCL12 and JAG1); growth factor and chemotactic receptors (IGF1R, TGFbR2, CXCR4 and CCR2); adhesion receptor monomers (ITGA5 and ITGA6) and matricellular factor POSTN. In addition, we found major differences in the levels of neovascularization-related plasma factors. A strong positive correlation between plasma MMP9 levels and expression of CXCR4 in the CAC subset of hematopoietic progenitor cells (HPCs) was found in GBM patients. Our findings indicate that CAC-mediated neovascularization in GBM is characterized by more efficient CAC homing to target tissue and a more potent pro-angiogenic response than in physiologic tissue repair in MI. Our findings can aid in selecting targets for therapeutic strategies acting against GBM-specific CACs.
The Interventional Cardiologist and Structural Heart Disease: The Need for a Team Approach⁎⁎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: Anthony A. Hilliard, Rick A. Nishimura
Journal: JACC. Cardiovascular imaging (2009)
Impact of Temporal Changes in Left Ventricular Systolic Function on Outcomes in Takotsubo Cardiomyopathy
Authors: Nicolas Isaza, Alaa Alashi, Jackson Faulx, Zoran B. Popovic, Venu Menon, Stephen G. Ellis, Michael Faulx, Samir R. Kapadia, Brian P. Griffin, Milind Y. Desai
Journal: JACC. Cardiovascular imaging (2020)
TAMI-38. CYSTEINE-PROMOTING COMPOUNDS INDUCE MITOCHONDRIAL TOXICITY IN GLIOBLASTOMA THROUGH ALTERED PYRUVATE AND SERINE METABOLISM
Authors: Evan Noch, Laura Palma, Isaiah Yim, Bhavneet Binder, Elisa Benedetti, Jan Krumsiek, Olivier Elemento, Lewis Cantley
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the metabolic alterations that are specific to GBM and that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through System Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Metabolic tracing experiments with 13C6-glucose demonstrate that L-serine is rapidly depleted in GBM cells upon treatment with NAC and CTX, and exogenous serine rescues NAC- and CTX-mediated cell growth inhibition. In addition, these compounds reduce GBM mitochondrial pyruvate transport. We show that cysteine-promoting compounds reduce cell growth and induce mitochondrial toxicity in GBM, which may be due to rapid serine depletion and reduced mitochondrial pyruvate transport. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.
76P Highly potent fully human anti-VISTA antibodies efficiently abrogate the interaction of this new target checkpoint inhibitor to its different putative receptors at different pH
Authors: S. Iadonato, E. Tarcha, R. Bader, B. Dutzar, N. Eyde, E. Frazier, D. Jurchen, R. Lance, C. Loomis, K. Lustig, Y. Ovechkina, D. Peckham, J. Posakony, S. Sridhar, M. Xu, T. Guillaudeux
Journal: Annals of Oncology (2020)