bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANGI-11. MOLECULAR MECHANISM OF TARGETING EPITHELIAL MEMBRANE PROTEIN-2 IN MALIGNANT MENINGIOMAS
Authors: Yang Isaac , Mekonnen Mahlet , Chandla Anubhav , Aguirre Brian , Wadehra Madhuri 
Published: November 2023

Abstract

BACKGROUND
Meningiomas comprise approximately one-third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%. Targeting the tetraspan protein epithelial membrane protein-2 (EMP2)-HIF1α pathway through EMP2 knockdown may inhibit tumor growth, invasion, and neoangiogenesis in malignant meningioma.

METHODS
In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay.

RESULTS
Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p&lt; 0.001). Moreover, cellular migration and invasion regulated by EMP2 were tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti-EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2-mediated signal transduction (p = 0.0031).

CONCLUSIONS
Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefits for malignant meningioma.
BIOM-02. CSF LIQUID-BASED DIAGNOSIS OF LEPTOMENINGEAL DISEASE (LMD) FROM NON-SMALL CELL LUNG CANCER (NSCLC) USING DDPCR AGAINST EGFR MUTATIONS
Authors: Li Kay Ka-Wai , Fung Jackie Mei-Wah , Woo Peter Yat-Ming , Liu Anthony Pak-Yin , Chow Chit , Ng Ho-Keung 
Published: November 2023

Abstract
Leptomeningeal disease (LMD) due to spreading of solid cancers to the leptomeninges has a very poor prognosis and is poorly diagnosed. MR imaging may be negative and CSF cytology, the gold standard, is not sensitive enough, due to small number of cells inherent in CSF, small volume and inter-observer variability in microscopy. We tested the hypothesis that cfDNA from CSF could be a unique source of DNA from LMD which can be used for diagnosis as well as research. We collected 39 CSF samples from patients suspected of LMD from NSCLCs. CfDNA was extracted by cobas® cfDNA Sample Preparation Kit. Hotspot EGFR mutations (G719X, S768I, T790M, C797S, L858R, L861Q, and 19 del) were tested by multiplexed droplet-digital PCR (ddPCR). EGFR mutation status of the original primary NSCLCs were previously tested for by real-time PCR using formalin-fixed paraffin-embedded tissues. Six samples did not yield sufficient DNA. For the remaining 33 cases, EGFR mutations were detected in 16 samples. For fifteen of these positive cases, identical mutations were found in the matched tissue samples. EGFR status of one primary tumor was unknown. Cytology was negative in 10 cases, atypical in five and only positive in one case. For the 17 negative samples, in 11 cases, the corresponding tumor tissues lacked EGFR mutations. Five patients from the negative group were eventually found not to have LMD. Only in one case was the lung tissue found to have EGFR mutation but mutation was not found in CSF cfDNA. In a few selected cases, we studied the genomics of the cfDNA together with the primary tumor tissues with low-pass WGS and similar CNVs were found in both. CSF cfDNA is a unique source of DNA from LMD and can be used as a useful tool in clinical diagnosis and research.
BIOM-04. IMPROVEMENT OF LEPTOMENINGEAL DISEASE (LMD) WITH MEK AND BRAF INHIBITORS, CRANIOSPINAL IRRADIATION (CSI), AND INTRATHECAL (IT) CHEMOTHERAPY IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)
Authors: Nahm Joshua , Vu Mia , Schumann Eva Highberg , Bhattacharjee Meenakshi , Blanco Angel , Tandon Nitin , Zhu Jay-Jiguang 
Published: November 2023

Abstract
Anaplastic pleomorphic xanthoastrocytomas (aPXA) are rare gliomas with a five-year survival of 57%. Standard treatment involves maximal safe resection followed by radiotherapy. BRAF mutation is frequently seen in these patients and is a promising target with concurrent BRAF and MEK inhibitors. However, there is no standard treatment for patients with aPXA and leptomeningeal disease (LMD). Literature review identified four cases with overall survivals (OS) of 3, 4, 18, and 66 months, respectively. We report a 23-year-old female who presented with headache, nausea, vomiting, and aphasia with MRI evidence of a left temporal lobe enhancing mass. Her tumor was initially diagnosed as epithelioid glioblastoma, WHO grade IV after craniotomy. She received concurrent radiation and temozolomide with subsequent 12 cycles of TMZ. After identification of BRAF V600E mutation by next generation sequencing, we revisited her diagnosis, and it was changed to aPXA. Three years later, she presented to the ER with aphasia, headache, weakness, nausea, and vomiting with MRI evidence of hydrocephalus and LMD by brain and spine MRI as well as cerebrospinal fluid analysis. Her treatment regimen consisted of the MEK inhibitor cobimetinib, the BRAF inhibitor vemurafenib, partial craniospinal irradiation (CSI), and intrathecal (IT) chemotherapy with methotrexate, topotecan, cytarabine, and thiotepa sequentially. She is currently doing well with mild bilateral leg weakness. She continues on therapy with BRAF and MEK inhibitors. Her OS is 56 months. Adverse events (AE) were tabulated according to the Common Terminology Criteria for Adverse Events Version 5.0 and included grade IV neutropenia, grade III anemia, grade II rash acneiform, and grade II nausea/vomiting. All AEs were manageable and reversible. Despite the limitations of a case report and retrospective review, our findings suggest that MEK and BRAF inhibitors, CSI, and IT chemotherapy may be effective treatment options for patients with aPXA and LMD.
BIOM-11. THE ROLE OF INSULIN-LIKE GROWTH FACTOR 2 BINDING PROTEIN 3 (IGF2BP3) AS A DRIVER OF TUMORIGENESIS IN GLIOBLASTOMA
Authors: Chow Jocelyn , Chen Alexander , Oh Se-yeong , Young Elizabeth , Boyd Nathaniel , Read Renee 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor with a poor median survival of fifteen months after diagnosis. GBM accounts for half of malignant and fifteen percent of all primary brain tumors diagnosed in adults. To promote targeted therapy, there are ongoing efforts to understand GBM at a molecular level. This involves characterization of these tumors via their transcriptional and mutational profile. Recent studies indicate aberrations in receptor tyrosine kinase (RTKs), including EGFR and PDGFRA, and the Pi-3 kinase (PI3K) signaling pathways are major drivers of tumorigenesis in GBM. Using a proteomics approach to locate downstream targets of these pathways, we identified IGF2 Binding Protein 3 (IGF2BP3), which is an RNA binding protein, as a downstream effector of aberrant RTK-PI3K signaling in gliomagenesis. Our subsequent follow-up studies indicate that IGF2BP3, which is overexpressed in RTK mutant human GBMs, drives survival and proliferation of RTK-PI3K-dependent human GBM cells. To understand how IGF2BP3 functions to promote RTK-PI3K driven tumorigenesis, we used cultured human GBM cells and in GBM xenograft models to test the effects of loss of IGF2BP3 function in tumorous glia as well as normal glia. Our results indicate that IGF2BP3 activity is essential for self-renewal and maintenance of neural stem-cell like features of GBM tumor cells, but dispensable for the growth of normal glia. Currently, we are using genetic approaches to identify and validate RNA targets of IGF2BP3 function in tumor cells and to understand how these targets are specifically regulated by RTK-PI3K-dependent signaling in glioma. Overall, our data suggests that IGF2BP3 may play a role in promoting GBM tumorigenesis and our future directions aim to reveal an important tumor-specific RNA target signaling pathway for consideration in potential therapeutics.
BIOM-15. CIRCULATING EXOSOMES CORRELATE WITH RADIOGRAPHIC PROGRESSION IN GLIOBLASTOMA PATIENTS AFTER ULTRASOUND-BASED OPENING OF THE BLOOD-BRAIN BARRIER
Authors: Youngblood Mark W , Kumari Abha , Gould Andrew , Kang Yoon-Tae , Chen Li , Habashy Karl , Amidei Christina , Ward Rachel , Gomez Cristal , Bouchoux Guillaume , Canney Michael , Stupp Roger , Nagrath Sunitha , Sonabend Adam 
Published: November 2023

Abstract
Non-invasive methods to detect progression of glioblastoma (GBM) are needed to optimize patient management. Circulating blood-based biomarkers for GBM progression are limited by the blood-brain barrier, which restricts leakage of tumor-related elements into circulation. To address this, we investigated circulating GBM-associated exosomes using samples obtained as part of a clinical trial where the blood-brain barrier was temporarily opened with a skull-implantable ultrasound system (NCT04528680). Samples were collected after an intra-operative sonication procedure at multiple time points, as well as longitudinally before and after subsequent outpatient sonication cycles. Plasma exosomes were isolated using a newExoChip microfluidic device, and enrichment of tumor-derived exosomes was based on expression of Phosphatidylserine (which binds to Annexin V on the device). Tumoral origin of the exosomes was validated with GBM cell lines as positive controls, using Western blots and variant-specific ddPCR to confirm tumor contents. We observed a 2.1-fold increase in exosome concentration in plasma samples obtained intraoperatively between 2 and 45 minutes after sonication, relative to pre-operative baseline (n = 4 patients; 19 plasma samples; one-tailed t-test p = 0.02). In a longitudinal analysis of eight patients, volumetric MRI analysis of enhancement was compared with changes in exosome concentration after sonication. Among patients with short progression-free survival (PFS) (n = 4; PFS &lt; 90 days), multi-subject analysis yielded a repeated-measures correlation of -0.59 (p = 0.06), compared to 0.01 among long PFS patients (p = 0.96). In both cohorts, use of raw pre-sonication exosome concentrations had less association with MRI enhancement (p = 0.67 and 0.98 respectively). Considering each sample independently, we found the average Pearson correlation among short PFS patients was 0.73 (avg. p = 0.39), while no correlation was seen among long PFS patients (avg. r value = 0.10; avg. p-value = 0.54). Circulating exosomes hold promise as a non-invasive method to track GBM progression upon opening of the blood-brain barrier. Further refinement and validation in larger cohorts is warranted.
BIOM-18. MOLECULAR FEATURES RELATED TO LONG-TERM SURVIVAL IN GLIOBLASTOMA
Authors: Nisnboym Michal , Raphael Itay , Drappatz Jan 
Published: November 2023

Abstract
Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2years of survival despite multimodal treatment. Strikingly, small fractions of GBM patients seem to display extended survival. However, the underlying mechanisms for this peculiarity remain largely unknown. Long-term survival (LTS) is often defined as a survival time of more than 3-5years from diagnosis. Several clinical variables have been associated with patients' survival, with age, Karnofsky performance score (KPS), and extent of resection being the most consistent. With advances in multi-omics technologies and their integration with disease diagnostics, numerous prognostic molecular markers have been proposed. So far, only O6-methylguanine-DNA-methyltransferase (MGMT) gene promotor hypermethylation is a well-established biomarker that is linked to outcome and therapy response. The objective of this study is to revisit patients diagnosed with GBM according to the 2021 WHO classification and investigate molecular characteristics associated with LTS. We analyzed records of IDH-wildtype GBM patients, &gt; 18 years old, operated and treated at our institution between 2013 and 2020. From a patient perspective, we defined long-term survivorship as patients surviving more than 5 years. We compared LTSs to an equal number of matched controls (by clinical features and MGMT status) with STS, surviving less than 18 months. The analysis of their molecular features was performed by using the well-established and commonly used next-generation sequencing (NGS) assay, Glioseq. RESULTS: will be presented. With this retrospective work, we hope to shed a broader light on the still unknown molecular features as possible mechanisms behind the LTS of GBM patients. This is to pave the way for a consolidated conclusion on this important topic.
BIOM-19. PLASMA EXTRACELLULAR VESICLE SAMPLING FROM HIGH GRADE GLIOMA PATIENTS DEMONSTRATES A SMALL RNA SIGNATURE INDICATIVE OF DISEASE AND IDENTIFIES LNCRNA RPPH1 AS A HIGH GRADE GLIOMA BIOMARKER
Authors: Han Jae Ho , Wajnberg Gabriel , Attwood Kathleen , Hannay Brandon , Cormier Robert , Chacko Simi , Croul Syndey , Wilms Maya , Schmidt Matthias , Hebb Andrea , MacNeil Mary , Roy Jeremy , Weeks Adrienne 
Published: November 2023

Abstract
High grade gliomas (HGGs) and cells of the tumour microenvironment (TME) secrete extracellular vesicles (EVs) into the plasma that contain genetic and protein cargo which function in paracrine signaling. Isolation of these EVs and their cargo from plasma could lead to a simplistic tool that can inform on diagnosis and disease course of HGG. In the present study, plasma extracellular vesicles (EVs) were captured utilizing a peptide affinity method (Vn96 peptide) from high grade glioma (HGG) patients and normal controls followed by next generation sequencing (NovaSeq6000) to define a small RNA (sRNA) signature unique to HGG. Over 750 differentially expressed sRNA (miRNA, snoRNA, lncRNA, tRNA, mRNA fragments and non-annotated regions) were identified between HGG and controls. MiEAA 2.0 pathway analysis of the miRNA in the sRNA signature revealed miRNA highly enriched in both EV and HGG pathways demonstrating the validity of results in capturing a signal from the TME. Also revealed were several novel HGG plasma EV sRNA biomarkers including lncRNA RPPH1 (Ribonuclease P Component H1), RNY4 (Ro60-Associated Y4) and RNY5 (Ro60-Associated Y5). Furthermore, in paired longitudinal patient plasma sampling, RPPH1 informed on surgical resection (decreased on resection) and importantly RPPH1 increased again on clinically defined progression. The present study supports the role of plasma EV sRNA sampling (and particularly RPPH1) as part of a multi-pronged approach to HGG disease course surveillance.
BIOM-21. LIQUID BIOPSY IN SERA OF HIGH-GRADE GLIOMA PATIENTS: PROTOPORPHYRIN IX AS A BIOMARKER
Authors: Walke Anna , Krone Christopher , Stummer Walter , König Simone , Molina Eric Suero 
Published: November 2023

Abstract
High-grade gliomas (HGG) carry a dismal prognosis. Diagnosis comprises magnetic resonance imaging (MRI) followed by histopathological evaluation of tumor tissue after biopsy collection; no blood biomarker is currently available. Patients are subjected to repeated surgery and MRI for relapse monitoring. Protoporphyrin IX (PpIX) is already in routine use for selectively visualizing HGG tissue during fluorescence-guided resection (FGR). We investigated if it can also serve as serum HGG marker. Patients (HGG: n = 23 primary, pHGG; n = 5 recurrent, rHGG) undergoing FGR received 5-aminolevulinic acid (5-ALA) following standard clinical procedure. The control group of eight healthy volunteers (HCTR) also received 5-ALA. Serum was collected before and repeatedly up to 72 h after drug administration. PpIX was analyzed following liquid-liquid and solid-phase extraction using liquid chromatography coupled to ion trap mass spectrometry. The serum PpIX level before 5-ALA administration was similar in patient and control groups. Significant PpIX accumulation in HGG was observed after 5-ALA administration (ANOVA: p = 0.005, post-hoc: HCTR vs. pHGG p = 0.029, HCTR vs. rHGG p = 0.006). Separation of HCTR from pHGG was possible within CI95% of tMax (AUC: 0.943, CI95% 0.884 - 1.000, p &lt; 0.001); the optimal cut-off for diagnosis was 1275 pmol PpIX/ml serum, reaching 87.0 % accuracy, 90.5 % positive predictive value and 84.0 % negative predictive value. Distinguishing pHGG patients from healthy controls based on serum PpIX is possible. The prodrug 5-ALA is required for PpIX induction, which is safe for the standard clinical dosage. Thus, PpIX is a new target for liquid biopsy in glioma, but larger clinical studies are required to characterize its full potential.
BIOM-23. IDENTIFICATION OF NOVEL BIOMARKERS FOR BRAIN TUMOR USING PRECISION MEDICINE APPROACHES: ORC6 PLAYS A CRITICAL ROLE IN GLIOBLASTOMA THERAPEUTICS
Authors: Chang Pei-Chi , Huang Jin-Hong , Li Yao-Feng 
Published: November 2023

Abstract

INTRODUCTION
Brain tumors remain challenging to treat despite diagnostic advancements. Current approaches involving surgery, radiotherapy, and chemotherapy tend to fail due to drug resistance. Our team identified potential biomarkers associated with aggressive brain tumors, including ORC6 and GPC4. ORC6, implicated in DNA replication and overexpressed in many cancers, presents a promising therapeutic target. In this study, we leverage advanced bioinformatics and experimental validation to further elucidate ORC6's potential for cancer treatment. Material and methods: This study uses R programming and packages to identify biomarkers from genomic databases like TCGA, CGGA, and GLASS. Protein expression is also assessed via tissue microarray and immunohistochemistry. Changes in the ORC6 gene are studied using GO, KEGG, and gene set enrichment analysis techniques. The tumor microenvironment is predicted using CIBERSORT.

RESULTS
are presented with 3D CLARITY images, and a deep learning algorithm is introduced for potential clinical application optimization.

RESULTS
Utilizing bioinformatics analyses, we identified ORC6 and GPC4 as potential biomarkers impacting tumor growth. This study focuses on ORC6, which demonstrated significantly increased expression in IDH-wildtype astrocytoma versus normal brain tissue. This heightened ORC6 expression correlated with tumor grading, poor prognosis, and increased KI67 expression in all glioma subgroups. ATAC sequencing and gene set enrichment analysis revealed E2F factors as potential ORC6 regulators and showed that increased ORC6 expression affected cell proliferation signaling pathways. Single-cell sequencing data further indicated ORC6 expression correlation with tumor cells, proliferative stem cells, and M0, M1, and M2 macrophages. Additionally, high ORC6 expression was observed in several brain tumor cell lines (U87MG, U118MG, LN229, GBM8401) that could be down-regulated using siRNA, paving the way for more complex gene editing and functional modeling experiments.

CONCLUSION
This study employs sophisticated bioinformatics and experimental validation techniques to explore the potential of targeting ORC6 for cancer therapy. Keywords: ORC6, Glioblastoma, TCGA, CGGA, GLASS, biomarker
BIOM-26. RAPID IDENTIFICATION OF IDH1-R132 VARIANTS IN GLIOMA WITH LOCKED NUCLEIC ACID LOOP-MEDIATED ISOTHERMAL AMPLIFICATION (LNA-LAMP)
Authors: Choate Kristian , Raack Edward , Line Veronica , Jennings Matthew , Belton Robert , Winn Robert , Mann Paul 
Published: November 2023

Abstract
Point mutations that impact the catalytic site of isocitrate dehydrogenase 1 (IDH1) are associated with an extended overall survival of approximately 3.8 years for glioma patients compared to 1 year for those with wild-type IDH1. The difference in survival benefit is associated with the maximal surgical resection of IDH1 mutant tumors, making intraoperative knowledge of the mutational status valuable. Unfortunately, current methods used to determine IDH1-R132 mutational status are incompatible with obtaining real-time results. We have developed a panel of assays that use LNA-LAMP to identify commonly encountered IDH1-R132 variants (R132H, R132C, R132G, R132S, R132L) within 40 minutes. These assays require little preanalytical processing, no complex equipment, and yield results which are easily interpreted by the naked eye. Tumor samples are initially subjected to a 5-minute alkaline digest, then added directly to LNA-LAMP reactions containing primers unique to each IDH1-R132 variant. Discrimination between the wild-type and mutant allele is achieved with the integration of locked nucleic acids within primers. A reaction with an IDH1-R132R specific primer serves as the sample positive control, as all tumor lysates are expected to contain wild-type IDH1 DNA. Lysates are incubated for 35 minutes in a hot water bath, followed by visual interpretation using a pH-based colorimetric indicator, where samples positive for the mutation appear a vibrant yellow while those lacking the mutation remain pink. This method has been rigorously tested with patient-derived tumor lysates, yielding reproducible and accurate results, and has an analytical sensitivity of about 20% mutant DNA in a background of wild-type DNA. This sensitivity is comparable to that of Sanger Sequencing while simultaneously offering a more cost-effective and efficient workflow. LNA-LAMP is amenable for use in the intraoperative window to allow patients with an IDH1-R132 mutation the benefit of a maximal surgical resection.
BIOM-33. TRNA FRAGMENTS IN PLASMA EXTRACELLULAR VESICLES FROM HIGH GRADE GLIOMA PATIENTS, POTENTIAL BIOMARKERS?
Authors: Weeks Adrienne , Phinney Thomson , Alwadei Ali , Wajnberg Gabriel , Han Jae , Chacko Simi , Atwood Kathleen , Roy Jeremy 
Published: November 2023

Abstract
Transfer RNA (tRNA) are non-coding RNAs responsible for bringing the amino acids to the ribosome during translation. Recent studies in cancer have shown that fragments (tRFs) derived from tRNA cleavage serve regulatory roles in epigenetics, signalling and translation. tRFs are also released from cells bound to proteins and can be found in extracellular vesicles to perform some aspects of paracrine signalling. Utilizing high throughput small RNA sequencing we have identified over 750 uniquely or multi-mapped (6.9% of total sRNA mapped reads) tRNA and tRFs in extracellular vesicles of high-grade glioma patient plasma (IDH-WT). Consistent with novel literature in other cancers there was a general trend to decreased expression of tRNA and tRFs (n = 76 with FDR &lt; 0.05) in high grade glioma plasma EVs compared to controls. However, further analysis of tRFs reveals a much more complex story, as fragment distribution differs between cancer and controls. tRNAs and tRFs may serve as important biomarkers and regulators with therapeutic potential in the future.