bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOS-01. MANAGEMENT OF OPTIC PATHWAY GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Yousefi Omid , Azami Pouria , Sabahi Mohammadmahdi , Adada Badih , Borghei-Razavi Hamid 
Published: November 2022

Abstract
In the current study, we systematically review the literature regarding the management of optic pathway glioma (OPG). This review will analyze demographics, information regarding the type of treatment, radiological and clinical (visual) outcomes, and also complications. Article selection was performed by searching PubMed, Web of Science, and Cochrane databases. Of the 105 eligible studies, a total of 4177 patients underwent different therapeutic modalities including surgery, radiotherapy, and chemotherapy. The mean age was 8.17 years and the gender ratio was 97 males per 100 females. Based on the available data, the mean follow-up was 98.6 months and 48.7% of the patients were known cases of the neurofibromatosis type1. According to the Dodge classification 1104, 941, and 1353 tumors were D1, D2, and D3, respectively. The toxicity induced by either chemo- or radiotherapy was the most common complication, followed by the ophthalmologic complications rather than visual acuity exacerbation. The pooled mortality rate was 0.12 (95%CI 0.09–0.14). Due to the unrepresentative data, improved and not changed outcomes were classified as the favorable outcome and worsened as an unfavorable. Meta-analyses were performed to determine the rate of clinical and radiological favorable outcomes. In terms of visual assessment, the pooled rate of a favorable outcome in chemotherapy, radiotherapy, and surgery was 0.74, 0.81, and 0.65, respectively and the overall pooled rate of the favorable outcome is 0.75 (95%CI 0.70–0.80). In terms of radiological assessment, the rate of a favorable outcome following chemotherapy, radiotherapy, and surgery was 0.71, 0.74, and 0.67, respectively and the overall pooled rate of the favorable outcome is 0.71 (95%CI 0.65–0.76). The subgroup analysis revealed no significant difference in the rate of clinical and radiological favorable outcomes between the different treatment modalities (P &gt; 0.05). Our analyses showed that each therapeutic modality represents viable treatment options to achieve remission for these patients.
CNSC-05. ELECTROPHYSIOLOGICAL PATTERNS OF GLIOMA-INDUCED NEURONAL NETWORK REMODELING ARE CONSERVED ACROSS TUMOR SUBTYPE
Authors: Aabedi Alexander , Lipkin Benjamin , Young Jacob S , Hinkley Leighton , Findlay Anne , Daniel Andy , Krishna Saritha , Umbach Gray , Kaur Jasleen , Berger Mitchel S , Molinaro Annette , Brang David , Nagarajan Srikantan , Hervey-Jumper Shawn L 
Published: November 2022

Abstract
Recent evidence indicates that diffuse gliomas engage with neurons at the single-unit and circuit level through differing mechanisms. Certain malignant gliomas form glioma-neuron excitatory glutamatergic synapses and modulate neuron-neuron synapses through activity-dependent paracrine signaling, while others establish glioma-glioma connections via tumor microtubes. It is therefore possible that diffuse gliomas remodel neuronal circuits in a defined and predictable manner and demonstrate distinct electrophysiological profiles with prognostic and therapeutic significance. Here we apply machine learning principles in 140 patients across glioma subtypes to uncover unique electrophysiological features non-invasively via magnetoencephalography (discovery dataset) followed by feature validation using subdural electrocorticography (validation dataset). Following spatial-temporal registration, we fit an elastic net logistic regression classifier to distinguish between power spectra arising from glioma-remodeled cortex and within-subject control conditions. Model significance was determined non-parametrically by re-training each model 1,000 times with randomly permuted class labels and testing the true phi coefficient against the null distribution. In the discovery dataset, we were able to classify glioma infiltration based on tumor intrinsic neuronal activity (p &lt; 0.05) in 127 patients (90.7%). We identified 30 electrophysiological features which revealed increased power in the delta range (1-4 Hz) and decreased power in the beta range (12-20 Hz) as a unique signature of glioma remodeling (p &lt; 0.05) which was preserved in the validation dataset as well as across WHO 2021 diffuse glioma subtypes. In order to identify gene expression programs and signaling mechanisms that may contribute to glioma-induced remodeling but are potentially not identified in the current clinical classification scheme, we assessed targeted, next generation sequencing and DNA mutations as covariates, which again demonstrated the significance of the delta-beta spectral features. These data support converging mechanisms of glioma-induced neuronal network remodeling across tumor subtypes, setting the stage for novel therapies such as neuromodulation.
CNSC-07. MECHANISMS OF GLIOBLASTOMA-INDUCED CORTICAL REMODELING IDENTIFY THERAPEUTIC VULNERABILITIES
Authors: Krishna Saritha , Choudhury Abrar , Keough Michael , Ni Lijun , Seo Kyounghee , Aabedi Alexander , Popova Galina , Kakaizada Sofia , Findlay Anne , Lee Anthony , Gonzales Cesar , Sudharshan Rasika , Cao Caroline , Venkatesh Humsa , Almeida Nyle , Nagarajan Srikantan , Berger Mitchel S , Raleigh David , Brang David , Monje Michelle , Hervey-Jumper Shawn L 
Published: November 2022

Abstract
Prior work demonstrated synaptic integration of malignant gliomas into neural circuits induces local hyperexcitability and tumor proliferation. However, prognostication and therapeutic vulnerabilities are lacking from preclinical models. Here, we integrate in vivo and in vitro neurophysiology spatially matched with gene expression programs and protein signaling mechanisms across 66 IDH WT glioblastoma patients to identify thrombospondin-1 (TSP-1) as a molecular driver of glioma-induced network remodeling. Bulk and single cell RNA-sequencing of 11 intratumoral regions maintaining functional connectivity (13,730 cells analyzed) revealed a distinct neurogenic signature enriched for the synaptogenic factor TSP-1. Mechanistic and functional studies validating therapeutic vulnerabilities to TSP-1 silencing by shRNA knockdown and FDA-approved inhibitors (Gabapentin and LSKL) of excitatory synapse formation through the gabapentin a2d-1 receptor was performed in vitro and in vivo. Glioma-neuron co-culture of TSP-1 overexpressing cells demonstrated increased Ki67 proliferation and tumor microtube (TMT) formation when cultured in the presence of neurons. Pharmacological inhibition of TSP-1 using gabapentin or TSP-1 shRNA inhibited the proliferation and TMT-mediated expansion. Hippocampal xenografted mice with TSP-1 over expressing primary patient cultures demonstrated shorter survival and gabapentin treatment of xenografted mice significantly reduced the proliferation of TSP-1 overexpressing cells in vivo. Electrophysiological properties of glioma-neuron co-cultures analyzed using multi-electrode array (MEA) demonstrated increased neuronal spiking activity and network burst synchrony in the presence of TSP-1 over expressing cells. Strikingly, these increases were eliminated in the presence of gabapentin. We modeled survival risk in patients incorporating the effects of glioma intrinsic neuronal activity, molecular, therapeutic, and clinical factors on overall survival by recursive partitioning. Three risk groups were identified based on tumor intrinsic neuronal activity, pre- and post-operative tumor volume with shortest overall survival in patients with glioma intrinsic neuronal activity. These data identify glioma-induced secretion of TSP-1 as a key contributor of tumor proliferation shedding light on new therapies.
TMET-05. MAGMAS FACILITATES METABOLIC CHANGES INDUCED BY STRESSORS IN GLIOBLASTOMA
Authors: Lepe Javier , Lomeli Naomi , Douglas Chris , Di Kaijun , Bota Daniela 
Published: November 2022

Abstract
The dynamic nature of tumor microenvironments contributes to tumor heterogeneity generating subpopulations of cells that are resistant to treatment in glioblastoma (GBM). The high recurrent rate of GBM tumors in patients can partially be explained by the presence of glioma stem cells (GSCs), which are thought to give rise to resistant clones against chemotherapy. As solid tumors expand, cancer cells can disrupt the tumor microenviroment by disrupting the blood brain barrier. Pericytes and astrocytes detach from the vascular endothelial cells, forming leaky vessels, which leads to thrombosis and eventually necrosis. Necrosis is a hallmark signature of GBM, as oxygen and nutrient supply runs low which can be observed through contrast imaging. Cancer cells go through a phenotypic change by upregulating stemness genes and glycolytic metabolism. Cells migrate away from hypoxic and nutrient deprived regions forming pseudopalisading cells which are an indication of cells becoming more invasive and malignant. Mitochondrial protein trafficking is a tightly regulated mechanism which selectively allows specific peptides carrying a mitochondrial targeting sequence (MTS) to be transported through the TOM40 and TIM23 complexes. Magmas, a TIM23 subunit, negatively regulates DNAJC19 by inhibiting its stimulatory activity on Hsp70 in the mitochondrial matrix. The regulation of the ATPase activity on Hsp70 is critical for processing pre-cursor proteins through the TIM23 complex into the mitochondrial matrix. Our laboratory has uncovered a novel role of Magmas activity in GBM cells under serum starved conditions in vitro. Magmas is downregulated in serum starved cells which allows for an increase of mitochondrial matrix proteins, which include key subunits important for forming electron transport chain complexes. This influx of ETC proteins can explain how cells are able to reduce aerobic glycolysis and increase oxidative phosphorylation (OXPHOS), a mechanism that can be exploited for potential therapeutic treatment in patients with GBM.
TMET-07. MOLECULAR MECHANISM OF EXQUISITE SENSITIVITY OF DIFFUSE MIDLINE GLIOMA TO DE NOVO PYRIMIDINE BIOSYNTHESIS
Authors: Pal Sharmistha , Savani Milan , Kaplan Jakub , Stopka Sylwia Sylwia A , Nguyen Huy , Regan Michael , Agar Nathalie , McBrayer Samuel , Haas-Kogan Daphne 
Published: November 2022

Abstract
Diffuse midline glioma (DMG) is a lethal pediatric brain cancer in dire need for therapeutic breakthroughs. To identify intrinsic addictions and therapeutic targets for DMG, we conducted a genome-wide k¬¬¬¬nockout CRISPR screen that identified de novo pyrimidine biosynthesis pathway as a targetable dependency. Since pyrimidine nucleotides can be synthesized by salvage and de novo pathways, identification of the latter as a dependency indicated a prominent role of de novo pathway in establishing the pyrimidine nucleotide pool in DMG. We investigated the molecular mechanism underlying this dependency using metabolic tracing of 15N-glutamine and genetic approaches. We report that DMG cells derive the majority of UMP (70%) through de novo synthesis, along with significantly elevated flux through the pyrimidine degradation pathway. High flux of 15N- labeled UMP through pyrimidine degradation in DMGs suggests that substrates (uridine and uracil) required for pyrimidine nucleotide salvage are limited, thus enhancing the dependency on de novo biosynthesis. To further confirm the causal role of pyrimidine degradation in driving de novo pathway dependency in DMG, we knocked down DPYD, the enzyme catalyzing the first committed step in pyrimidine degradation, using inducible shRNAs. Knockdown of DPYD diminished sensitivity of DMGs to de novo pathway inhibition as it rescued UMP pools and resultant DNA damage. Conversely, overexpression of DPYD in adult glioblastomas enhanced their sensitivity to de novo pyrimidine synthesis inhibition which was accompanied by greater depletion of UMP and induction of DNA damage. Consistent with this mechanism, we observed downregulation of DPYD in DMGs that acquired resistance to antagonists of de novo pyrimidine synthesis. Taken together, we have uncovered DPYD as a predictive biomarker of sensitivity to de novo pyrimidine synthesis inhibitors.
TMET-14. TUMOR-ASSOCIATED MYELOID CELL-DERIVED CREATINE PROMOTES GLIOBLASTOMA GROWTH IN HYPOXIC NICHES AND PSEUDOPALISADING TUMOR REGIONS
Authors: Zolp Andrew , Rashidi Aida , Chia Tzu-Yi , Dmello Crismita , Arrieta Victor , Zhao Junfei , Castro Brandyn , Markwell Steven , Heiland Deiter Henrik , Brat Daniel , Chandel Navdeep , Lesniak Maciej , Lee-Chang Catalina , Miska Jason 
Published: November 2022

Abstract
Glioblastoma (GBM) consists of a unique tumor microenvironment (TME) dominated by infiltrating tumor-associated myeloid cells (TAMCs). TAMCs are central to tumor growth and understanding how they support tumor progression is critical to identifying new therapeutic modalities. Examination of the metabolic and genetic phenotypes of TAMCs revealed that the de-novo creatine phenotype is central to their identity. Immunohistochemistry and multiplex fluorescence in GBM patient-derived tissue showed TAMC infiltration localizing to hypoxic pseudopalisading regions. Furthermore, single-cell RNAseq analysis of human and mouse models of GBM identified that the transporter of creatine, Slc6a8, is located on tumor cells within these regions. Spatial transcriptomics confirmed this transporter-synthesis gene compartmentalization is specific to hypoxic pseudopalisading regions, and further elucidated a radial glial cell gene signature for tumor cells expressing Slc6a8. Murine models recapitulated the TAMC de-novo creatine metabolic phenotype both ex-vivo and in-vitro. Metabolomics showed that TAMC-derived creatine can transfer to tumor cells in-vitro and is enhanced under hypoxic conditions. β-guanidinopropionic acid (β-GPA) is a creatine analog proposed to block Slc6a8 function and effectively blocked TAMC-derived creatine transfer to tumor cells in-vitro. Furthermore, β-GPA inhibited both the viability and size of spheres for tumor cells grown in stem-cell conditions. Lastly, inhibition of creatine transport using clinically relevant inhibitors enhanced survival following tumor implantation in murine models. This work highlights the key role of creatine in the pseudopalisading and hypoxic niche in GBM, offering evidence for a potential benefit in targeting this axis for GBM therapy regimens.
CNSC-21. CHARACTERIZATION OF NEURON-TUMOR INTERACTIONS USING HUMAN CO-CULTURES
Authors: Tetzlaff Svenja , Campos Joaquín , Nguyen Linh , Strahle Christopher , Wick Wolfgang , Kuner Thomas , Winkler Frank , Acuna Claudio , Venkataramani Varun 
Published: November 2022

Abstract
Glioblastoma are incurable brain tumors characterized by their colonization of the entire brain and their notorious therapeutic resistance. Recently, we discovered long membrane tubes called tumor microtubes contributing to invasion, network formation of tumor-tumor networks and therapeutic resistance. Subsequently, heterogeneous networks of neurons and glioblastoma cells were characterized, which can communicate by synaptic and perisynaptic contacts as well as by paracrine mechanisms. Currently used models of studying neuron-glioblastoma interactions are limited by the possibility to study glioblastoma in a defined human neuronal microenvironment. Here, we set out to derive excitatory and inhibitory neurons from embryonic stem cells via lentiviral reprogramming and co-cultured them with patient-derived glioblastoma cells. We could show that structural and functional neuron-glioblastoma synaptic contacts are formed. Functional communication between neurons and glioblastoma cells were characterized with calcium imaging, showing similar complex calcium dynamics previously characterized with in vivo imaging of patient-derived xenograft models. The single-cell glioblastoma morphology was morphometrically similar to that of human glioblastoma tissue. Tumor microtubes and the formation of tumor-tumor networks could be demonstrated. Additionally, glioblastoma invasion patterns in our human neuronal co-culture model resemble invasion patterns recently characterized with patient-derived xenograft models. Lastly, we investigated reciprocal neuron-glioblastoma interactions and longitudinally characterized neuronal activity with patch-clamp electrophysiology. In conclusion, we provide a novel human neuron-glioblastoma co-culture system allowing in-depth molecular and functional characterization for future Cancer Neuroscience studies.
TMET-18. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN GLIOBLASTOMA
Authors: Ohba Shigeo , Teranishi Takao , Hirose Yuichi 
Published: November 2022

Abstract
Tumor cells have different metabolism from normal cell, which is called as cancer metabolism. In normal cells, asparagine is provided by asparagine synthetase (ASNS) from aspartate. On the other hand, in tumor cells, asparagine is needed to be taken in from outside the cells in addition to synthesized by ASNS within the cells, because of rapid growth of the tumor cells. Glioblastoma is one of the aggressive brain tumors, and temozolomide is frequently used. After glioblastoma cells acquire the resistance to temozolomide, no effective chemotherapy remained. The object of this study is to evaluate whether cancer metabolism, especially asparagine, could be a new target of treatment in primary and recurrent glioblastoma. Temozolomide-sensitive glioblastoma cell lines (U251, and U87), and U251- or U87 derived temozolomide-resistant cells, which were obtained after long treatment of temozolomide to parental cells, were used for the experiments. Genetical inhibition of ASNS using siRNA suppressed the proliferation of temozolomide-sensitive glioblastoma cells, inducing apoptosis. Adding of asparagine in the medium reversed the effect of siRNA targeting ASNS. L-asparaginase, which converts asparagine into aspartate, reduced the colonogenicity of glioblastoma cells. L-asparaginase increased the expression of mRNA of ASNS, and inhibition of ASNS potentiated L-asparaginase-induced anti-tumor effect. For temozolomide-resistant U251- or U87-derived cells, inhibition of ASNS also suppressed the colonogenicity of the cells, and inhibition of ASNS enhanced anti-tumor effect by L-asparaginase. In conclusion, targeting asparagine metabolism will be a therapeutic option for temozolomide-sensitive and temozolomide-resistant glioblastoma.
TMET-24. MITOCHONDRIAL AND GENE EXPRESSION CHANGES IN BRAIN TUMOR CELLS GROWN IN Β-HYDROXYBUTYRATE
Authors: Almekkawi Ahmad Kareem , Sheets Rachelle , Werner Brianna , Perryman Richard , Singh Indrapal , Karim Mohammad , Frye Richard , Syed Nelofer , Scheck Adrienne 
Published: November 2022

Abstract
Malignant brain tumors are devastating diseases with poor outcomes. The search for more effective therapeutic combinations has led to investigation of the use of a therapeutic ketogenic diet (KD) as an adjuvant therapy based on the metabolic dysregulation that is a hallmark of cancer. KD sometimes results in extended survival, but like all cancer therapies the tumor eventually becomes resistant. Resistance can arise due to the “metabolic remodeling” of resistant cells due to limitations in nutrient availability and other signals from the tumor microenvironment. We are investigating the molecular and mitochondrial changes of tumor cells grown in β-hydroxybutyrate (BHB), the main ketone produced when following a therapeutic KD, to partially recapitulate the long-term effects of the KD on patients. Murine malignant glioma cells (GL261-luc2) were cultured long term in 2, 5 or 10mM BHB. The Agilent XFe96 Seahorse Analyzer was used to measure changes in cell metabolism. Epigenetic changes that occur in the mitochondria were interrogated using DNA methylation assays. Finally, we implanted BHB resistant glioma cells intracranially in mice and carried out RNAseq to determine the mechanisms by which these cells adapt. Seahorse analyses of GL261-luc2 cells grown in BHB demonstrated changes in several respiratory parameters including maximal respiration and reserve capacity. In addition, there is a statistically significant decrease in mitochondrial DNA methylation with increasing concentrations of BHB. RNAseq analysis of BHB resistant GL261 tumors showed changes in pathways related to mitochondrial translation and the electron transport chain. Our preliminary results show that the heterogeneity seen in these tumors is recapitulated in the various mitochondrial respiration parameters. Further, these may be altered as a consequence of BHB therapy. An understanding of the genetic and mitochondrial changes that occur when cells become resistant will lead to a more effective use of the KD as an adjuvant therapy.
TMET-32. INTRAOPERATIVE MICRODIALYSIS FOR GLIOMA METABOLIC RECONNAISSANCE AND BIOMARKER DISCOVERY
Authors: Riviere-Cazaux Cecile , Carlstrom Lucas , Rajani Karishma , Munoz-Casabella Amanda , Rahman Masum , Burns Terry 
Published: November 2022

Abstract
Gliomas are genomically heterogeneous tumors that may harness a convergent and therapeutically targetable set of metabolic pathways. At present, the metabolic landscape of in situ human gliomas remains incompletely characterized, hampering translational progress. To that end, we are leveraging the previously untapped potential of high molecular weight microdialysis to determine the global extracellular metabolic profiles of live human gliomas. Under an investigational device exemption, HMW microdialysis (&lt; 100 kDa) was performed at 2.0 μL/min in an initial discovery cohort of five patients in glioma and adjacent brain during neurosurgical resection; a subsequent cohort of five patients was independently analyzed to critically evaluate results from the discovery group. Untargeted metabolomics via ultra-performance liquid chromatography-tandem mass spectrometry revealed over 300 named metabolites and five drugs from only 20 μL of microdialysate, representing a short and feasible 10 minutes of intraoperative collection time. Enrichment analysis of each patient’s tumor vs. brain ranked extracellular metabolome highlighted marked metabolic convergence within the most aggressive regions of molecular diverse tumors (FDR = 0). Pathway analysis revealed significant enrichment for large neutral amino acid pathways, including valine, leucine, and isoleucine biosynthesis (p=1.6E-9) and degradation (p=0.001) and glycine, serine, and threonine metabolism (p=4.7E-5). Notably, this amino acid signature was not as abundantly present in nonenhancing tumor when compared to enhancing tumor (Average tumor/brain: 1.9x vs. 4.3x, respectively), suggesting upregulation of neutral amino acid transporters in enhancing tumor or delivery from plasma into the CNS via a disrupted BBB. Interestingly, guanidinoacetate (GAA) was our most highly conserved and upregulated metabolite (128.9x in tumor vs. brain). Given its co-production with ornithine, the precursor to protumorigenic polyamines, we posit that GAA may serve as a biomarker of increased ODC activity in live human gliomas. In conclusion, intraoperative HMW microdialysis feasibly offers improved opportunities to perform glioma metabolic biomarker and therapeutic discovery.