bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-18. PEPTIDE NANO-STRUCTURES ENHANCE PEDIATRIC BRAIN TUMOR CHEMOTHERAPEUTIC EFFICACY
Authors: XI Guifa , Mahenthiran Ashorne , Best Benjamin , Nayak Sonali , Smith Cara , McClendon Mark , Mania-Farnell Barbara , Kessler John , James Charles , Stupp Samuel , Tomita Tadanori 
Published: November 2019

Abstract
Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.
EXTH-21. DIFFERENTIAL PROTEIN EXPRESSION LEVELS OF ABC AND SOLUTE CARRIER TRANSPORTERS AT THE BLOOD-BRAIN BARRIER OF HUMAN BRAIN AND GLIOBLASTOMA
Authors: Bao Xun , Wu Jianmei , Xie Youming , Kim Seongho , Michelhaugh Sharon , Jiang Jun , Mittal Sandeep , Sanai Nader , Li Jing 
Published: November 2019

Abstract

BACKGROUND
Mechanistic understanding and quantitative prediction of drug penetration across the human blood-brain barrier (BBB) is critical to rational drug development and treatment for brain cancer especially glioblastoma. However, prediction of drug brain/tumor penetration has been significantly hindered mainly due to the lack of quantitation data on transporter protein expression levels at the human BBB. This study was to determine protein expression levels of major transporters and markers at the BBB of human brain and glioblastoma.

METHOD
The absolute protein expression levels of major transporters and markers were determined in isolated microvessels of human brain (N=30), glioblastoma (N=47), rat (N=10) and mouse brain (N=10), using liquid chromatography with tandem mass spectrometry (LC-MS/MS) based targeted proteomics.

RESULTS
In isolated microvessels of 30 human brain specimens, the median protein abundances for ABCB1, ABCG2, GLUT1, GLUT3, LAT1, MCT1, Na/K ATPase, and Claudin-5 were 3.38, 6.21, 54.51, 7.17, 3.42, 5.71, 32.14, and 1.15 fmol/µg protein, respectively. In glioblastoma microvessels, ABCB1, ABCG2, MCT1, GLUT1, Na/K ATPase, and Claudin-5 protein levels were significantly reduced, while LAT1 was increased and GLU1 remained the same. ABCC4, OATP1A2, OATP2B1, and OAT3 were undetectable in isolated microvessels of both human brain and glioblastoma. There was species difference in transporter protein expression levels in isolated microvessels of human, rat and mouse brain. Specifically, rodent BBB expressed significantly higher ABCB1 but similar ABCG2, as compared to human BBB.

CONCLUSION
The physical and biochemical barriers of the BBB in glioblastomas are largely disrupted, as indicated by the loss or significant reduction in protein expression of the tight junction marker (claudin-5), brain endothelial cell marker (GLUT1), and major efflux transporters (ABCB1 and ABCG2) as compared to normal human BBB. Differential BBB transporter protein expression levels provides mechanistic and quantitative basis for the prediction of heterogeneous drug penetration into human normal brain and glioblastoma.
EXTH-23. COMBINED EFFECTS OF NICLOSAMIDE AND TEMOZOLOMIDE AGAINST HUMAN GLIOBLASTOMA TUMORSPHERES
Authors: Cheol Oh Hyeong , Yoo Jihwan , Shim Jin-Kyoung , Park Junseong , Lee Ji-hyun , Joo Choi Ran , sil Kim Hyun , hee Kim Nam , Hyung Moon Ju , Hyun Kim Eui , Hee Chang Jong , Kang Seok-Gu , In Yook Jong 
Published: November 2019

Abstract

PURPOSE
Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs.

METHODS
Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model.

RESULTS
The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models.

CONCLUSIONS
The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM. KEYWORDS: Glioblastoma; Invasion; Niclosamide; Temozolomide; Tumorsphere
EXTH-38. ENGINEERED EXOSOMES FOR THERAPEUTIC GENE DELIVERY IN BRAIN TUMORS
Authors: McDonald Malcolm , Hasan Irtiza , Adachi Satoshi , Gumin Joy , Ledbetter Daniel , Daou Marc , Gopakumar Sricharan , Momin Eric , Long Lihong , Phillips Lynette , Parker-Kerrigan Brittany , Hossain Anwar , Lang Frederick 
Published: November 2019

Abstract
The poor outcome of patients with glioblastoma (GBM) is at least partly due to the inability to deliver therapeutic agents to the tumor. We have shown that exosomes, naturally occurring nano-size extracellular vesicles, are capable of delivering antiglioma microRNAs (MiRs) to brain tumors (Lang, FM et al. Neuro Oncol, 2018;20(3):380–390). However, our studies suggested that there is significant opportunity to increase packaging efficiency and delivery specificity of exosomes. To this end, we engineered exosomes to express specific viral proteins (called eExos) in order to enhance packaging and delivery capabilities of antiglioma genes. These eExos are created by transfecting HEK 293 cells with plasmids containing viral proteins and a plasmid of the therapeutic gene. After 72 hrs, differential ultracentrifugation was used to isolate the exosomes. To test the efficacy of these novel eExos, we transfected them with a plasmid containing Cre recombinase (as the therapeutic gene), and treated U87 cells harboring a dsRed/eGFP Cre recombinase/LoxP site (U87dsR/GFP). In in vitro studies, treatment of U87dsR/GFP with a single dose of eExos resulted in 82% conversion rate of cells from red to green, compared to control exosomes (< 18% green cells). In in vivo studies, a single intratumoral injection of eExos into mice harboring 7-day old intracranial U87dsR/GFP gliomas, resulted in significant increases in green cells compared to control exosomes when tumors were harvested at day 10. Mechanistic studies employing florescent microscopy demonstrate that in contrast to natural exosomes, eExos deliver their cargo to the nucleus rather than to lysosomes, avoiding degradation of the delivered agent and facilitating expression of the plasmid. We conclude that eExos, engineered to contain specific viral proteins, are capable of packaging and delivering antiglioma genes more effectively than natural exosomes and may overcome the current inability to deliver biological therapeutic agents to brain tumors.
EXTH-45. THERAPEUTIC EFFICACY OF MUTANT ISOCITRATE DEHYDROGENASE 1 (IDH1) INHIBITOR SYC-435 WITH STANDARD THERAPY IN PATIENT-DERIVED IDH1 MUTANT GLIOMA XENOGRAFT MOUSE MODELS
Authors: Kogiso Mari , Qi Lin , Zhang Huiyuan , Braun Frank , Du Yuchen , Huang Lei , Guo Lei , Huang Yulun , Lindsay Holly B , Zhao Sibo , Injac Sarah , Baxter Patricia , Su Jack , Perlaky Laszlo , Parsons Williams , Chintagumpala Murali , Adekunle Adesina , Wang Jialiang , Song Yongcheng , Li Xiao-Nan 
Published: November 2019

Abstract
Mutation in isocitrate dehydrogenase 1 (IDH1) occurs in >70% of WHO grade II/III astrocytomas, oligodendrogliomas and secondary glioblastoma. The mutant enzyme catalyzes the reduction of α-ketoglutaric acid to D-2-hydroxyglutaric acid, leading to cancer initiation. In this study, we examined therapeutic efficacy of SYC-435 (1-hydroxypyridin-2-one), a newly developed mutant IDH1inhibitor, in IDH1 mutant gliomas. IDH1 R132H mutation (homozygous) was detected in BT142 anaplastic oligoastrocytoma (AOA) and R132C mutation (mutant allele frequency 39–50%) in V0914AOA by pyrosequencing. Suppression of cell growth by SYC-435 was observed with more sensitive of mutant over wild-type IDH1. Patient-derived orthotopic xenograft mouse models of BT142AOA and V0914AOA were treated with vehicle, SYC-435 (15 mg/kg/day x 28 days), temozolomide (50 mg/kg/day x 5 days)/fractionated radiation (2 Gy/day x 5 days) (standard therapy), and SYC-435/standard therapy starting 2 weeks after intracranial tumor implantation. Log rank analysis showed SYC-435 alone did not alter survival times. Although standard therapy significantly prolonged survival times in both models (P< 0.0005), SYC-435/standard therapy further extended survival times (P< 0.05) in V0914AOA and exhibited similar trend in BT142AOA. Elevation of 2-HG/α-KG ratio and methylation of H3K4/H3K9 in V0914AOA tumor compared to wild-type model was detected at the end of treatments. SYC-435 with/without standard therapy tended to reduce 2-HG/α-KG ratio and dramatically reduced methylation of H3K4/H3K9. RNA-seq analysis showed sirtuin signaling pathway, mitochondrial dysfunction and oxidative phosphorylation pathways with mitochondrial DNA (mtDNA) encoded molecules were highly affected by all treatments. However, mtDNA regulation did not correlate to survival benefits. In conclusion, SYC-435 possesses anti-tumor effects that are more sensitive in IDH1 mutant gliomas and generated strong synergistic activities with standard therapies for survival benefits with reduced methylation of H3K4/H3K9. Treatments significantly affected mtDNA but significance to survival benefits remains to be elucidated. Our data support the clinical testing of SYC-435 in patients with IDH1 mutant glioma.
EXTH-68. INTRANASAL DELIVERY OF DRUG-LOADED LIPOSOMES SENSITIZES TUMORS TO IRRADIATION IN SYNGENEIC MODEL OF GLIOMA.
Authors: Zhang Peng , Zannikou Markella , Lesniak Maciej S , Balyasnikova Irina 
Published: November 2019

Abstract
Tumor-associated myeloid cells (TAMCs) are appealing therapeutic target in glioblastoma (GBM) due to their immunosuppressive function and robust presence in the tumor tissue. We designed a lipid nanoparticle (LNP) modified with anti-PD-L1 antibody (αPD-L1) for targeted delivery to PD-L1 expressing cells within the tumor. We demonstrate that αPD-L1-LNP are effectively and specifically taken up by TAMCs. The encapsulation of dinaciclib, an inhibitor of a cyclin-dependent kinase, into αPD-L1-LNP, leads to a robust depletion of TAMCs upon local delivery. We next investigated the therapeutic relevance of non-invasive intranasal delivery of αPD-L1-LNP drug nano formulation in a GL261 syngeneic model of glioma. We show that intranasal administration of αPD-L1-LNP/dinaciclib alone did not significantly affect the survival of tumor-bearing mice, whereas a regimen combing with fractionated irradiation led to a significantly improved animal survival of mice bearing GL261 glioma over monotherapies. Histological analysis of tissue demonstrated about a four-fold increase in the uptake of nanoparticles within the tumor bed but not in the normal brain in mice treated with fractionated irradiation over the control mice. These results warrant further development and validation of intranasal delivery of therapeutic nanoformulations targeting TAMCs in preclinical animal models to improve the outcome in GBM patients.
EXTH-72. MANZAMINE A-DERIVED COMPOUNDS AS POTENTIAL ANTI-BRAIN TUMOR AGENTS AND IT MECHANISM STUDY
Authors: Huang Chiung-Yin , Chen Pin-Yuan , Wei Kuo-Chen , Hwang Tsong-Long 
Published: November 2019

Abstract
Glioma is a severe disease with poor prognosis. Chemotherapy plays an important role but very few drugs are effective. There are two major issues: (1) the specialized blood-brain barrier blocks most large molecules from penetrating into target area; (2) tumor cells frequently develop drug resistant. Therefore, developing new chemotherapeutic agents for malignant brain tumor treatment may significantly improve the current difficulties. Compounds derived from nature products have been considered as potential sources for new discovery of anti-cancer drug. Manzamine A-derived compounds, showed significant anticancer activities against colon adenocarcinoma DLD cells, lung large cell carcinoma NCI-H661 cells, and hepatoma HepG2/A2 cells. In this study, we used in vitro model for screening these compounds and discovered both cytotoxic and anti-proliferative effects against brain tumor cells, such as A172, U87MG, and GL261 cell lines. We then used animal models to test the toxicities and treatment effect of compound A3 in vivo, and delivered the agent by convection-enhanced delivery to improve drug concentration in brain. Survival benefit for brain tumor-bearing animal was found for optimal dosage of compound A3. Details of anti-tumor mechanism need further evaluation.
GENE-04. THE ONCOGENIC FUNCTIONS OF YAP1-GENE FUSIONS CAN BE INHIBITED BY DISRUPTION OF YAP1-TEAD INTERACTION
Authors: Szulzewsky Frank , Hoellerbauer Pia , Wu Hua-Jun , Cimino P J , Michor Franziska , Paddison Patrick , Vasioukhin Valeri , Holland Eric 
Published: November 2019

Abstract
Supratentorial ependymoma can be sub-stratified into clinically relevant subtypes characterized by distinct molecular features. The subtype defined by high YAP1 activity harbored two distinct YAP1 gene fusions, YAP1-MAMLD1 and YAP1-FAM118B. In addition, YAP1 gene fusions have been detected in several other cancer types, including Epithelioid Hemangioendothelioma and Endocervical Adenocarcinoma. YAP1 is a key transcriptional co-activator and proto-oncogene that is negatively regulated by the Hippo pathway. Here, we show that both YAP1-MAMLD1 and YAP1-FAM118B, as well as additional YAP1 fusion genes found in other cancer types, are potent oncogenic drivers that cause tumor formation in the brain and the hindlimb in mice upon overexpression by somatic cell gene transfer. Using different in vitro assays, including Luciferase, RNA-, and ChIP Seq, we show that both the N-terminal YAP1 part and the C-terminal fusion partners exert activity. We can show that the YAP1 activity still relies on the binding to TEAD transcription factors, whereas the C terminal activity does not. Furthermore, the different fusion proteins have become independent from negative Hippo pathway signaling by constitutive nuclear localization and protection from degradation. In addition, by introducing point mutations and truncations to block the YAP1 and the MAMLD1 function we can show that the activity of both halves contributes to the oncogenic function of YAP1-MAMLD1. Using in vitro and in vivo assays we can show that pharmacological and genetic ablation of YAP-TEAD interaction diminishes the oncogenic potential of the fusions, indicating that this might be a potential therapeutic approach for these tumors in the future.
GENE-05. THE LOSS OF SUCCINATE DEHYDROGENASE B EXPRESSION IS FREQUENTLY IDENTIFIED IN HEMANGIOBLASTOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Kim Se-Hyuk , Hoon Roh Tae , Yim Hyunee , Roh Jin , Beom Lee Kyi , Jeong Seon-Yong , Kim Jang-Hee , Hyun Park So 
Published: November 2019

Abstract
Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.
GENE-08. SECONDARY GLIOBLASTOMA, IDH-WILDTYPE ARISING IN DIFFUSE ASTROCYTOMA, IDH-MUTANT: A CASE REPORT
Authors: Sang Lee Kyu , Choe Gheeyoung 
Published: November 2019

Abstract
Primary glioblastoma develops de novo without clinical or histological evidence of a low-grade precursor lesion, while secondary glioblastoma develops from a low-grade glioma. The same IDH mutation is observed in almost secondary glioblastomas that occurs in low-grade gliomas with IDH mutation. Present report is an extraordinary case of secondary glioblastoma, IDH-wildtype arising in diffuse astrocytoma, IDH-mutant. A 31-year-old female presented with seizure 3 months ago, who had a history of operation for diffuse astrocytoma, IDH-mutant on the left frontal lobe 6 years ago. Magnetic resonance imaging test revealed new infiltrative lesions (6.5cm) in left frontal lobe and corpus callosum, in addition to the non-enhancing mass (3.4cm). New infiltrative lesion suspected anaplastic change and the patient underwent tumorectomy. Microscopically, non-enhancing lesion showed high cellularity, moderate nuclear atypia and brisk mitosis. Microvascular proliferation and necrosis were absent that can be diagnosis as anaplastic astrocytoma. However, new infiltrative lesion showed microvascular proliferation and necrosis that acceptable for diagnosis as glioblastoma. IDH-1 immunohistochemistry (IHC) was positive in anaplastic astrocytoma but negative in glioblastoma. In addition, we assessed NGS based on the SNUBH Brain v1.0 (Macrogen, Seoul, South Korea) panel. Similar to IHC result, IDH-1 (p.Arg132His) mutation was found in anaplastic astrocytoma but not in glioblastoma. Interestingly, ATRX (p.Gln1670Ter) and TP53 (p.His193Arg) mutations were found in both lesions. Additionally, PTEN (p.His296Pro) mutation was identified in glioblastoma component only. Until now, it is well-known hypothesis that the IDH mutation initiated in glial progenitor cell and the other genetic mutations occur sequentially in pathogenesis of secondary glioblastoma. Notably, this is the first case report that other genetic alterations can be initiated before IDH mutation contrary to previous hypothesis. In our case, mutation of ATRX and TP53 might be initiated, and PTEN and IDH-1 mutations were sequentially occurred in glioblastoma and anaplastic astrocytoma, respectively.
GENE-09. LONG NONCODING RNA lncHLX2-7 A PUTATIVE MOLECULAR MARKER AND A THERAPEUTIC TARGET FOR GROUP III MEDULLOBLASTOMA
Authors: Katsushima Keisuke , Joshi Piyush , Lee Bongyong , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan 
Published: November 2019

Abstract
Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. It can recur as resistant disease and is recurrent medulloblastoma is frequently fatal. There are four groups of MBs (WNT, SHH, Group III, and Group Ⅳ) and they are characterized by specific mutations, copy number alterations, transcriptomic profiles, and clinical outcomes. Recent advances in noncoding RNA genome could contribute to sub-classification of medulloblastoma. The focus of this study is to identify novel long noncoding RNAs (lncRNAs) as molecular markers and potential therapeutic targets within each subgroup of MBs, in particular within the Group III. We analyzed publicly available 723 microarrays and 123 RNA-seq datasets using machine-learning statistical algorithms (random-forest and Lasso) to identify a group of putative lncRNA signatures that may be able to differentiate medulloblastoma subgroups accurately. Among those, lncHLX2-7 was highly upregulated in Group III MBs compared to other groups. RNA-FISH analysis revealed that lncHLX2-7 is highly expressed primarily in Group III MB as compared to other groups and normal brain (cerebellum). Furthermore, depletion of lncHLX2-7 significantly reduced 20- 30% of cell growth together with the induction of apoptosis in MED211 and D425-MED Group III MB cell lines (n=3, p< 0.01, t-test). We present here supporting evidence that lncHLX2-7 is a novel molecular marker and potential therapeutic target for Group III MBs in children.
GENE-13. GENOMIC AND RADIOMIC LANDSCAPE OF IDH WILDTYPE-TERT PROMOTER MUTATION IN LOWER-GRADE GLIOMAS
Authors: Liu Shuai , Zhang Chuanbao , Qiu Xiaoguang 
Published: November 2019

Abstract

BACKGROUND
Recently, a rare subset of lower grade glioma (LoG), characterized by wild-type isocitrate dehydrogenase (IDH) and mutated TERT promoter (IDHWT-TERTpMut), has been highlighted for its dismal clinical behavior and classified as world health organization (WHO) grade IV.

METHODS
We examined this distinct tumor subset through genome-wide analysis of 745 gliomas and radiomic analysis of 129 LoGs.

RESULTS
We found that the prognosis and genetic lineage of IDHWT-TERTpMut LoGs were similar to those of glioblastoma. Importantly, a signature of 7 radiomic features from magnetic resonance imaging data differentiated IDHWT-TERTpMut LoGs from other LoGs. In addition, we found the radiomic related genes involved in many tumorigenic processes.

CONCLUSIONS
Overall, our findings suggest that the biological characteristics of IDHWT-TERTpMut LoGs and the radiomic signature could help in the non-invasive diagnosis of this tumor subtype.