bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-26. INVESTIGATING THE ROLE OF QUAKING IN REGULATING MHC II ANTIGEN PRESENTATION IN TUMOR-ASSOCIATED MACROPHAGES OF GBM
Authors: Hwang Spring , Zeng Ailiang 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor with a median survival rate of 14 months. Despite the success of immunotherapy in treating various cancer types, its efficacy remains poor in GBM. Such limitation can be attributed to the profound immunosuppressive tumor microenvironment of GBM enriched with the tumor-associated macrophages (TAMs). Quaking (Qki) is an RNA-binding protein that is mutated or deleted in more than 35% of GBM patients. Decreased levels of Qki in TAMs associates with worsened survival rates and responsiveness to immunotherapy in GBM mouse and patients. Moreover, Qki is a tumor suppressor gene in GBM and a major regulator in phagocytosis, a fundamental biological process in delivering antigens to major histocompatibility complex class II (MHC II). MHC II-restricted antigen presentation in macrophages of GBM is important in maintaining the fitness of cytotoxic and helper T cells required in anti-tumor response. However, the mechanism through which Qki regulates MHCII expression and presentation has yet to be elucidated. I hypothesize that Qki promotes MHC II expression in TAMs, thereby constraining the development and progression of GBM. In vitro assays like immunofluorescent staining, qRT-PCR, cell co-culture system, and flow cytometry will be performed involving QPP (Qk-/-Trp53-/-; Pten-/-) mouse brains, QPP cells, and mouse macrophage cell lines. A positive correlation between transcriptomic and protein expression levels of Qki, MHC II, and CIITA (a master regulator of MHC II) was confirmed in both mouse QPP and human GBM samples. Moreover, bone-marrow-derived macrophages activated by QPP cell supernatant shows upregulated levels of Qki and thus MHC II genes. A preliminary conclusion is that Qki plays a permissive role in MHCII expression in TAMs of GBM. Further downstream impact of Qki in TAMs will be evaluated in T cell activity and in transcription of MHC II in TAMs.
CNSC-37. ROLE OF PGE2-REGULATED NEUROINFLAMMATION IN CONSTRUCTING NEURON-NK-GLIOMA CIRCUIT FOR GLIOBLASTOMA
Authors: Chen Hsien-Chung , Chang Wen-Chang , Hsu Tsung-Yi 
Published: November 2024

Abstract
Glioblastoma (GBM), known for its aggressive nature and poor prognosis, frequently recurs and resists standard treatments such as temozolomide (TMZ). This resistance is partly due to complex interactions within the tumor microenvironment, particularly involving neuronal excitation. Recent insights suggest that neuronal activity, through mechanisms like neurogliomal synapses, not only promotes glioma cell proliferation but also contributes to the chemoresistance observed in recurrent tumors. Our focus is on Prostaglandin E2 (PGE2), a mediator that regulates neuronal excitation, and its role in the recurrence and resistance of GBM. We discovered that PGE2 upregulates synaptic proteins and alters neurotransmitter profiles, enhancing tumor cell survival and resistance to TMZ. Specifically, increased levels of neurotransmitters such as glutamine and asparagine were observed in PGE2-rich environments, correlating with heightened chemoresistance and tumor recurrence. Co-culture experiments further demonstrated that PGE2-treated neuronal cells could induce resistance in adjacent GBM cells. These findings highlight the potential of targeting PGE2 pathways as a therapeutic strategy. A significant advancement in our study was the development and application of compound #038, a novel celecoxib derivative designed to cross the blood-brain barrier (BBB). This compound demonstrated enhanced efficacy in inhibiting GBM growth and improving survival rates in mouse models, indicating its potential as an effective therapeutic agent against GBM.
CNSC-39. INTEGRATED CLINICAL GENETIC ANALYSIS REVEALS NEUROTRANSMITTER RECEPTOR DYSREGULATION IN MENINGIOMAS CAUSING SEIZURE
Authors: Basit Khan A , McDonald Malcolm , Harmanci Akdes , English Collin , Harmanci Arif , Klisch Tiemo , Patel Akash 
Published: November 2024

Abstract
Molecular correlates of seizures in meningioma remain unexplored. Previously, we identified MenG molecular grouping, wherein MenG C meningiomas recur more than MenG A or B. We therefore sought to identify molecular and clinical drivers of seizures in meningioma. We identified 144 primary supratentorial meningiomas, excluding those with pre-existing epilepsy. Whole exome sequencing assessed somatic mutation burden. Bulk RNA-sequencing identified differentially expressed genes and gene ontologies (GO). Immunohistochemistry confirmed protein levels. No differences in canonical gene mutation burden (NF2, TRAF7, AKT1, KLF4, SMO, SMARC) was found between seizure and non-seizure groups. MenG C tumors had higher seizure incidence compared to MenG A or B (p=0.03). Seizure causing meningiomas, though extra-axial, exhibited dysregulated neuronal signaling genes. GABAA receptor subunit genes GABRA3 and GABRG1 were downregulated in tumors causing seizure (Log2FC=-1.67, padj=0.014; Log2FC=-2.24, padj=0.009). Immunohistochemistry confirmed expression of GABRB2 subunit, the first documentation of GABA receptor expression in meningiomas. Neuropeptide Y Receptor Y1 (NPY1R) is downregulated in seizure causing meningiomas (Log2FC=-1.64, padj=0.002). NPY1R loss correlates is observed in mesial temporal lobe epilepsy and post-electroconvulsive shock mouse brains. In GO analysis, the terms “GABA signaling pathway,” “neuropeptide signaling,” “excitatory postsynaptic membrane potential,” and “ionotropic glutamate pathway,” were downregulated in meningiomas with seizure (padj&lt;0.05). We assessed which alterations within MenG C tumors caused seizures by identifying genes associated with both seizure presentation and MenG C classification. Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) is downregulated in MenG C tumors (Log2FC=-2.29, padj=6.02E-07) and seizure causing tumors (Log2FC=-1.75, padj=0.03). Clinically, patients experiencing pre-operative seizures more frequently had cerebral edema, non-homogenous enhancement, intratumoral calcification, higher MIB-1, atypical grade 1, reduced GCS, and ER presentation; they were less likely to have incidental or headache presentation (p&lt;0.05 for all). MenG classification predicts seizure presentation whereas somatic mutation status does not. Meningiomas causing seizures show pathologic neurotransmitter receptor dysregulation.
CNSC-42. PROGNOSTIC VALUE OF INTERLEUKIN-6 IN PATIENTS WITH GLIOBLASTOMA
Authors: Kim Kyung Hwan 
Published: November 2024

Abstract
Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been implicated in the invasiveness and progression of glioma. However, the association between serum IL-6 levels at specific time points during treatment and patient prognosis remains unclear. This study was aimed to investigate the prognostic value of IL-6 measured at milestones in the treatment of patients with glioblastoma. Between January 2021 and December 2022, consecutive patients with newly diagnosed glioblastoma were enrolled. Serum IL-6 concentrations were measured at different time points, including preoperative, pre- and post-radiation period, and two-month intervals thereafter. Patients with incomplete data were excluded, and increase of IL-6 values due to the overlapping with systemic infection were also excluded from the analysis. During the study period, 26 patients and 270 IL-6 levels at different time points were evaluated. The median follow-up time was 11 months. Tumor progression was evident in 19 patients (73.1%) and 13 patients (50%) were expired. Preoperative and pre-radiation IL-6 values were available in 20 and 23 patients with the median 5.25 and 4.5 pg/mL, respectively. With the cut-off value of pre-radiation IL-6 at 4.5 pg/mL, high IL-6 group showed significantly worse progression-free survival and overall survival than low IL-6 group (p = 0.027 and 0.008, respectively). However, IL-6 levels at other milestone were not related to the patient prognosis. Serum IL-6 elevation in pre-radiation period is an unfavorable prognostic factor in tumor progression and patient survival. Further research is necessary to validate the prognostic role of IL-6 and explore the underlying mechanisms.
CNSC-45. EXTRINSIC ELECTRICAL MODULATION IMPACTS GLIOBLASTOMA TUMOR GROWTH BY DISRUPTING ITS INTERCELLULAR COMMUNICATION
Authors: Aliana Irina Palacin , Eshac Yasmina , Perez Alicia Casanova , Cerda Elian Saiz , Tripathi Shashwat , Najem Hinda , Heimberger Amy , Lesniak Maciej , Sita Timothy 
Published: November 2024

Abstract
Glioblastoma (GBM) is an incurable primary malignant neoplasm of the central nervous system. GBM as an electrically active neoplasm diffusely colonizes healthy brain tissues, disrupting the neurotransmission balance and causing glioma-related epilepsy (GRE) in up to 50% of patients. Interestingly, GRE is an independent favorable prognostic factor for survival in GBM. The therapeutic induction of seizure may have a previously unexplored oncologic value in GBM. We have previously reported in CT-2A-bearing mice subjected to daily extrinsic electrical modulation (EEM) diminished tumor progression and increased overall survival relative to sham-treated mice, but the mechanism by which EEM produces its anti-tumor effect remains uncertain. Therefore, GBM-bearing mice (CT-2A cells xenografted into 5-7 weeks old C57BL/6 female mice, n=5/group) received either a single EEM of 2.0 millicoulombs (mC) or sham treatment. The mice were terminated at 3 hours, 24 hours, 4, 7, and 10 days post-EEM, and tumors and contralateral brain cortex were analyzed using bulk RNA-sequencing and Sequential immunofluorescence (SeqIFTM). SeqIFTM revealed how EEM activates neuronal activity via cFOS expression and induces tumor-specific cell damage through cleaved caspase-3 expression, without affecting healthy brain tissue. Furthermore, RNA-seq performed post-EEM revealed gene expression changes of not only synapse organization markers but also of several tumor-tumor and tumor-neuron connectivity key markers, such as growth-associated protein 43 (GAP43), neuroligin-3 (NLGN3), and glutamate receptors such as GRIA4 and GRIN1 between others. However, the expression of these markers diminished significantly 96h after-EEM, indicating a reduction in intercellular electrical communication by the inhibition of the neoplasm cells electrical integration with neuronal circuits by downregulating glutamatergic receptor expression, blocking the synapse-forming protein NLGN3, and the network-connecting protein GAP43. Taken together, our findings reveal how by the disruption of these critical interactions within the tumor microenvironment though EEM impacts on GBM growth making it more susceptible to therapeutic interventions.
CNSC-48. DIFFERENTIAL GENE EXPRESSION UNDERLYING EPILEPTOGENICITY IN PATIENTS WITH GLIOMAS
Authors: Mortazavi Armin , Khan Anas , Nieblas-Bedolla Edwin , Boddeti Ujwal , Bachani Muzna , Ksendzovsky Alexander , Johnson Kory , Zaghloul Kareem 
Published: November 2024

Abstract

BACKGROUND
Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression associated with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences.

METHODS
Total RNA sequencing was obtained from The Cancer Genome Atlas - Lower Grade Glioma project, comprised of 2021 WHO classification low grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to further characterize differential expression.

RESULTS
Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and Semaphorin Neuronal Repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis.

CONCLUSIONS
In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.
CNSC-50. PRIMARY INTRACRANIAL CONGENITAL GLIOBLASTOMA (PICG): A SYSTEMATIC REVIEW OF CASE REPORTS FROM 2000 TO 2023
Authors: Qadri Haseeb Mehmood , Bashir Asif 
Published: November 2024

Abstract

BACKGROUND AND OBJECTIVE
The most commonly reported congenital intracranial space occupying lesions are teratoma, glioma and neuroblastoma. Primary intracranial congenital glioblastoma (PICG) is one of the most lethal and extremely rare neoplasms. Most pediatricians and gynecologists are unable to detect it congenitally, posing an ominous risk of spread and disease severity. We aim to determine the clinical manifestations, number of reported cases, radiological findings and neuro-oncological management of PICG.

MATERIALS AND METHODS
A comprehensive literature search using PubMed Central and Google Scholar was done, retrieving 17 case reports and five case series of 31 patients with PICG and included using the Preferred Reporting items for Systematic Reviews and Meta-Analyses guidelines, published between 2000 and 2023.

RESULTS
The mean age at presentation was 86.00 ± 88.36 days, with both genders affected equally, i.e. 45.16%. The most common symptoms and signs at presentation were seizures (38.70%) and hydrocephalus (51.61%), respectively. Left hemispheric (48.38%), with frontoparietal involvement (16.12%) was the frequently affected site. MRI findings were suggestive of low intensity signal significant of hemorrhage or calcification and a heterogenous mass in 35.58% and 32.25% cases, respectively. Gross total resection (GTR) was achievable in 48.38% patients. Glial fibrillary acid protein and vimentin were positive in 45.16% and 29.03% cases, respectively. Intraoperative mortality and recurrence were noted in 25.80% and 9.68% of patients, respectively. The average follow up duration was 20.57 months.

CONCLUSION
PICG has an extremely aggressive course of natural progression. Congenital presentation and its lack of awareness among clinicians is itself a challenge for disease management. Adjuvant chemo-radiotherapy has proven fruitful along with GTR. Post-operative CSF diversion is warranted.
CNSC-53. SHH ACTIVATION IN DEDIFFERENTIATION DURING TUMOR PROGRESSION IN MPNST
Authors: Yakubov Rebeca , Bunda Severa , Zadeh Gelareh 
Published: November 2024

Abstract

BACKGROUND
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with little progress on outcomes and treatment strategies. Previously, unsupervised analyses of methylome and transcriptome profiles of 108 peripheral nerve sheath tumors uncovered two subgroups of MPNSTs that predict progression-free survival, MPNST-G1 (characterized by SHH-pathway activation) and MPNST-G2 (characterized by WNT/ß-catenin/CCND1-pathway activation). Further, single nuclear RNA sequencing revealed that MPNST-G1 and MPNST-G2 cells resemble neural crest-like and Schwann cell precursor-like cells, respectively.

PURPOSE & HYPOTHESIS
To examine whether the activation of the SHH pathway in MPNST-G1 cell lines induces overexpression of factors known to play canonical roles in early neural crest cell specification (TWIST1, SNAI2, PAX3, PAX6, SOX9, OTX2) and to investigate the role of Src activation on SHH pathway-induced dedifferentiation. We hypothesize that MPNST-G1 cells will exhibit SHH pathway activation, synergizing with Src to induce the overexpression of early neural crest cell (ENCC) transcription factors.

METHODS
SHH pathway activation, expression of ENCC transcription factors, and effects of inhibitors were analyzed in MPNST-G1 cells using RT-PCR, western blotting, Alamar Blue assay, Trypan Blue assay, and Soft Agar Transformation assay.

RESULTS
Compared to MPNST-G2 cells, MPNST-G1 cells displayed SHH-pathway activation, SMO-dependent activation of Src, and elevated expression of the ENCC transcription factors. Sonidegib (SMO inhibitor) and Dasatinib (Src inhibitor) were able to revert dedifferentiation.

CONCLUSIONS
The SHH-pathway cooperates with Src to promote expression of important transcription factors in dedifferentiation. This finding provides insights into the transformation process of MPNST and novel therapeutic options.
CNSC-54. CENTRAL AND BOUNDARY-DRIVEN GROWTH PATTERNS DOMINATE RESPECTIVELY IDH WILD-TYPE AND MUTANT GLIOMAS
Authors: Kyriakidou Maria , Urbaniak Konnie , Mbegbu Mimi , Rockne Russell , Wesseling Pieter , Eijgelaar Roelant , Anderson Kevin J , Verhaak Roel , de Witt-Hamer Phillip , Verburg Niels , Branciamore Sergio , Barthel Floris P 
Published: November 2024

Abstract
Diffuse gliomas are the most prevalent primary malignant brain tumors in adults and are characterized by invasive growth and poor prognosis. Tumor cells infiltrate the brain parenchyma and spread to distant sites. The aim of this study is to characterize the spatial heterogeneity, mode, and direction of tumor development to identify key areas for localized treatment. Neuronavigation was employed to collect n=134 image-guided samples from n=16 adult patients with diffuse gliomas, including n=7 IDH wild-type (IDHwt) and n=9 IDH mutant (IDHmut) tumors from regions with and without MRI abnormalities. Collected samples were subjected to targeted and shallow whole-genome sequencing. Somatic variants were used to determine the evolutionary processes governing heterogeneity. Examination of the dN/dS ratio, Tajima’s D score, and MOBSTER model suggested that all tumors are consistent with neutral evolution, as previously reported. Considering that genetic heterogeneity was a result of stochastic mutations, we used phylogeographic relationships between samples to dissect the spatiotemporal development of these tumors. Evolutionary (patristic) and cartesian (Euclidean) distances between sample pairs from the same patient were correlated in n=2/9 IDHmut and n=2/7 IDHwt patients, suggesting that migratory or punctuated evolutionary processes play a major role in tumor diffusion. An examination of spatial diffusion revealed that the latest descendant appeared peripherally in n=5/9 IDHmut patients, suggesting boundary-driven growth. In the remaining cases, three patients exhibited centrally-driven growth, whereas a fourth patient displayed a mixed pattern. In contrast, in n=4/7 IDHwt patients, descendants appeared closer to the tumor center, suggesting centrally-driven growth. In the remaining three IDHwt patients, one patient showed a diffusion that was consistent with boundary-driven growth, while the other two patients showed a mixed pattern. Taken together our data suggest that IDHwt tumors tend to develop centrally, whereas IDHmut tumors preferably develop outward. Our data could aid in tailoring localized treatment based on projected growth patterns.
CNSC-56. DIVERSE, FUNCTIONAL NEUROTRANSMITTER RECEPTOR EXPRESSION ON GLIOBLASTOMA CELLS ENABLES EXTENSIVE NEURON-TO-GLIOMA COMMUNICATION
Authors: Wagner Julia , Tetzlaff Svenja , Reyhan Ekin , Venkataramani Varun 
Published: November 2024

Abstract
Glioblastomas are invasive yet incurable brain tumors. Recent data have shown that glutamatergic neuron-to-glioma synapses drive glioblastoma proliferation and invasion. In this study, we set out to investigate whether glioblastoma could communicate with neurons via various neuron-derived neurotransmitters through a functional neurotransmitter receptor screening. For this purpose, we stably transduced glioblastoma cells with a genetically encoded calcium indicator and sequentially and locally applied eight different neurotransmitters to glioblastoma cells in neuron-glioma co-cultures. These neurotransmitters included acetylcholine, ATP, dopamine, glutamate, GABA, adrenaline, serotonin, and glycine. We observed functional responses to acetylcholine, glutamate, ATP, dopamine, indicating a potential role for diverse neuron-to-glioma communication. Further, we investigated in patient-derived xenograft models and human tissues the existence of putative neuron-to-glioma synapses that could signal via acetlycholine, ATP and dopamine. In conclusion, this study reveals that glioblastoma cells express a heterogeneous set of functional neurotransmitter receptors, which may facilitate neuron-to-tumor communication across broad neuronal populations and warrant further investigation into their role for tumor biology.
CNSC-66. STRUCTURAL AND ELECTROPHYSIOLOGICAL CONNECTIVITY IN GLIOBLASTOMA IS MEDIATED BY TUMOR AND IMMUNE DERIVED CYTOKINES
Authors: Picart Thiebaud , Krishna Saritha , Daniel Andy , Dada Abraham , Oten Sena , Jeanette Hyer , Hervey-Jumper Shawn 
Published: November 2024

Abstract

BACKGROUND
In glioblastomas (GBM), the pleiotropic cytokine interleukin-6 (IL-6) upregulates PD-L1 expression. This results in local immunosuppression favorable to tumor progression, and may account for the limited efficacy of immune checkpoint inhibition. Additionally, IL-6 increases synaptogenesis during development, and contributes to neuronal network remodeling following focal brain or spinal cord injury. Therefore, the aim was to determine whether IL-6 contributes to GBM-induced circuit remodeling from a structural and electrophysiological perspective.

METHODS
In magnetoencephalography (MEG)-based intratumoral regions of High- (HFC) and Low-Functional Connectivity (LFC) from GBM patients, the expression of IL-6 and GAP43 was compared using bulk and single-cell RNA sequencing and immunofluorescence staining in biological replicates (n=44). In mouse postnatal cortical neurons and primary patient-derived GBM cell cocultures, the expression of Ki67, GAP43, tumor connectivity and neuronal activity were monitored after exogenous application of recombinant human IL-6 (rIL-6) or microglial depletion using PLX5622. Results. IL-6 and GAP43 were overexpressed in HFC compared to LFC regions. In neuron-GBM cocultures, the tumour proliferation index was significantly increased by rIL-6 and decreased by PLX5622. Morphologically, the number of microtubes per tumor cell was significantly increased by rIL-6 and decreased by PLX5622. The expression of GAP43 was inconstantly increased by rIL-6, suggesting the regulation of other pathways involved in tumour microtube formation. Multielectrode array recordings showed a significant increase or decrease in the neuronal activity, following the addition of rIL-6 or microglial depletion, respectively.

CONCLUSIONS
IL-6-signaling increases proliferation, structural and electrophysiological connectivity in gliomas and may contribute to neuronal network hyper-excitability and synchrony. Microglial depletion provided opposite effects. Additional experiments are mandatory to determine whether the effects of IL-6 on GBM cells depend on the presence of microglial cells or not. These data will be critical to design new therapeutic options, likely to improve the oncological and functional outcomes of patients treated for GBM.