bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-58. COLD ATMOSPHERIC PLASMA (CAP) CAUSES SELECTIVE TUMOR CELL DEATH VIA APOPTOSIS AND FERROPTOSIS IN MALIGNANT GLIOMA CELLS
Authors: Peeters Sophie , Kim Wi , Armellini Amber , Haist Blake , Ge Weihong , Ayad George , Chen Zhitong , Obenchain Richard , Yilgor Can , Owens Geoffrey , Tamayo Andrea , Nathanson David , Prins Robert , Bhaduri Aparna , Wirz Richard , Wang Anthony 
Published: November 2024

Abstract

BACKGROUND
High-grade gliomas (HGGs) are primary brain tumors associated with significant morbidity and mortality, and despite advances in neuro-oncology, the prognosis remains poor. Cold atmospheric plasma, a novel experimental anti-cancer therapeutic tool, is a near-room temperature ionized gas generated at atmospheric pressure. It has many promising results in vitro and in vivo with a variety of cancers. CAP cytotoxicity appears to be selective to cancer cells without significant damage to surrounding healthy tissues. We aim to evaluate the efficacy of CAP in generating tumor-selective cytotoxicity against high-grade glioma.

METHODS
B16, U87, GL261, patient derived high grade glioma, human neural stem cells (LM-NSC008) and astrocytes (NHA hTERT) were treated with CAP. Proliferation and propidium iodide (PI)/annexin V flow cytometry assays were employed to quantify cytotoxicity, cell cycle phases and apoptosis. Cells were pre-treated with ferroptosis inhibitors Ferrostatin-1 and Deferoxamine (DFO) in rescue assays. Cerebral organoids were transplanted with fluorescent tumor cell lines and stained with cleaved caspase-3, ki67 and transferrin receptor.

RESULTS
CAP induces dose dependent cell death in all glioma cell lines tested. CAP induces an accumulation of intracellular ROS, most prominent in glioma cells. CAP-mediated cell death involves apoptosis and ferroptosis. CAP selectively leads to apoptosis in tumor implanted organoids and leads to decreased proliferation in malignant and non-malignant cells. CAP leads to a shift into G0 phase of all treated cells, malignant and non-malignant.

CONCLUSIONS
CAP treatment induces dose-dependent increases in ROS and apoptosis in HGG lines tested more significantly than in NHAs and hNSCs. CAP induces decreased proliferation and G0 phase cell cycle arrest in all CAP-treated cells. CAP-mediated cytotoxicity was significantly mitigated with DFO pre-treatment in HGG cells, suggesting that ferroptosis plays a critical role in the mechanism of CAP treatment in HGG. CAP led to selective glioma cell death in tumor implanted cerebral organoids.
SURG-59. A RARE CASE OF COMBINED OCCURRENCE OF GLIOBLASTOMA MULTIFORME AND PHEOCHROMOCYTOMA: A CASE REPORT AND LITERATURE REVIEW
Authors: Lin YaJui 
Published: November 2024

Abstract
Glioblastoma is most common and malignant primary brain tumors. However, combined other solid organ malignancies sometimes occurred. To our knowledge, the combination of glioblastoma multiforme and pheochromocytoma is an exceedingly rare occurrence. As a result, we present the case of a 61-year-old male patient who suffered from slurred speech and unsteady gait due to left frontal glioblastoma with concurrent pheochromocytoma. The clinical course was retrospectively collected from medical records, including the lab data, imaging, surgical procedure and neurological examination results. We also provide a comprehensive review and discussion of the association between pheochromocytoma and glioblastoma, including genetic disorder the management strategy. The fluctuated blood pressure during brain surgery implied suspicious concurrent endocrine tumor in this patient. The patient was ultimately diagnosed with adrenal pheochromocytoma after left adrenalectomy and radical nephrectomy by urologist. No other malignancies or genetic disorders were found in this patient. Subsequently, this patient recovered well without any neurologic deficit and with effectively controlled blood pressure. The presence of a concomitant pheochromocytoma may precipitate paroxysmal catecholamine surges, fluctuations in cerebral perfusion, and an elevated risk of significant intra-cranial blood loss during neurosurgery. Once patient of brain tumors presented with uncontrolled or fluctuated blood pressure occurred, concurrent endocrine tumor should be considered.
TMET-04. METABOLOMICS ANALYSIS IN FUNCTIONING AND SILENT CORTICOTROPH ADENOMAS USING A TWO-DIMENSIONAL NANOMATERIAL HIGH-THROUGHPUT PLATFORM
Authors: Guo Xiaopeng , Liang Weiqiang , Ma Chunxia , Zhao Yuanli , Xing Bing 
Published: November 2024

Abstract
Functioning pituitary corticotroph adenomas (CAs) originated from T-PIT lineage with an ACTH-positive staining cause Cushing’s Disease. However, silent CAs (SCAs) baring the same histological features present clinically non-functioning with more aggressive courses. Metabolites within the tumor microenvironment play critical roles in regulating tumor behaviors and responses to therapy. Understanding their distribution and concentration provides valuable insights for diagnosis and treatment. This study investigated metabolite patterns in functioning and silent CAs. We developed a novel two-dimensional nanomaterial platform for enhanced surface-assisted laser desorption/ionization mass spectrometry. Utilizing this platform, we analyzed the metabolomes of three functioning CAs and three SCAs. Our platform exhibited exceptional sensitivity and stability in detecting metabolite molecules. Analysis of the metabolomes revealed distinct spatial distributions and peak intensity of various metabolites, including carbohydrates, amino acids, organic acids, nucleotides, and their precursors. Notably, certain metabolites such as tryptophol, clopidogrel carboxylic acid, DG(20:4(8Z,11Z,14Z,17Z)-2OH(5S,6R)/0:0/i-16:0), S-(-)-ureidoglycolate, and PC(20:4(5Z,7E,11Z,14Z)-OH(9)/14:1(9Z)) were significantly enriched in functioning CAs compared to SCAs, while others, including Cer(d18:1/16:0), Dihydrocytochalasin B, and LysoPC(O-18:0/0:0), exhibited higher peak intensity in SCAs. Overall, our findings underscored the existence of unique metabolomic signatures distinguishing functioning CAs and SCAs. Heterogeneous metabolite distributions among functioning CAs and SCAs were revealed by our novel nanomaterial high-throughput platform, and unique metabolic signatures were identified. Metabolomics analysis holds promise for precise biomedical diagnostics and individualized therapeutic strategies in functioning and silent CAs.
TMET-07. RADIORESISTANT GLIOBLASTOMA EVADES MITOCHONDRIAL LIPOTOXICITY THROUGH ALTERED DGKB AND DGAT1
Authors: Lee Haksoo , Kim Dahye , Kim Byeongsoo , Yoo Gaeun , Cha JiYong , Kang Hyunkoo , Jeon Jaewan , Youn HyeSook , Youn BuHyun 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a median survival of only 15 months despite multimodal therapy. Radiotherapy is a conventional therapy of GBM treatment, but the development of radioresistance often leads to tumor recurrence and treatment failure. To elucidate the molecular mechanisms underlying radioresistance in GBM, we established radioresistant GBM cell lines through repeated exposure to ionizing radiation. Transcriptomic analysis revealed that diacylglycerol kinase beta (DGKB), an enzyme that converts diacylglycerol (DAG) to phosphatidic acid, was significantly downregulated in radioresistant GBM cells. Functional studies demonstrated that knockdown of DGKB or expression of a kinase-dead DGKB mutant resulted in DAG accumulation and reduced fatty acid oxidation. Conversely, overexpression of DGKB activated fatty acid oxidation, increased reactive oxygen species (ROS) production, and sensitized GBM cells to radiation. Interestingly, we found that radiation upregulated the expression of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the conversion of DAG to triglycerides. Knockdown of DGAT1 using shRNA or miR-3918 mimic reduced lipid droplet formation and enhanced radiosensitivity both in vitro and in vivo. Furthermore, using Connectivity Map, we identified cladribine as a potential radiosensitizing agent that increases DGKB and decreases DGAT1. Cladribine effectively sensitized GBM cells to radiation and significantly prolonged the survival of mice bearing GBM xenografts. In conclusion, our study reveals a novel mechanism by which radioresistant GBM cells maintain lipid homeostasis through downregulation of DGKB and upregulation of DGAT1 to evade lethal mitochondrial lipotoxicity. Targeting the DGKB-DGAT1 axis represents a promising therapeutic strategy to overcome radioresistance and improve the outcomes of GBM patients.
TMET-20. A METABOLIC BIOMARKER IN GLIOBLASTOMA: A PROMISING APPLICATION OF CO-POLARIZED [1-13C]PYRUVATE AND [1-13C]DEHYDROASCORBATE
Authors: Coffee Elizabeth , Porcari Paola , Kim Nathaniel , Patel Saket , Berishaj Marjan , Deh Kofi , Rahimi-Keshari Kayvan 
Published: November 2024

Abstract

BACKGROUND
Noninvasive biomarkers for treatment response in glioblastoma are needed to improve patient outcomes. Our understanding of redox biology in treatment resistance is rapidly evolving, and interrogation of tumor metabolism represents an ideal opportunity to meet this need. In this study, the utility of co-hyperpolarized [1-13C]pyruvate and [1-13C]dehydroascorbate (HP PA/DHA) to simultaneously evaluate brain tumor metabolism and oxidative stress in orthotopically implanted mice is investigated.

METHODS
To characterize HP PA/DHA, mice were treated with 0-4mM diethyl maleate and 1D slab dynamic acquisitions were performed over the mouse brain. As an initial evaluation of the utility of HP DHA/PA in brain tumors, athymic nude mice (n=8) underwent orthotopic U87 glioblastoma implantation. After treatment with 8Gy in one fraction, mice were injected with HP DHA/PA dissolved in D2O. T2-weighted and 13C Chemical Shift Imaging sequences were obtained on a 3T MRI using a quadrature double-tuned 1H/13C volume coil.

RESULTS
HP DHA/PA detected differential lactate and vitamin C generation over the mouse brain. Treatment with diethyl maleate, which depletes the cofactor glutathione, diminished fractional vitamin C generation (0.1 vs 0.03, p=0.0009). Elevation in tumor lactate generation was seen in untreated (125.1±17.6µM, p=0.005) and radiated mice (149.4±32.6µM, p=0.01). Treatment with radiation generated higher vitamin C concentrations in tumors relative to contralateral brain (46.8±4.8µM, p=0.002). Radiated tumors were distinguished by higher ratio of lactate to vitamin C compared to untreated tumor controls (3.7 vs 2.5, p=0.07), and the same relationship was preserved between treated and untreated non-tumor brain.

CONCLUSION
The ratio of vitamin C/lactate detects the metabolic effects of radiation in brain tumors, inspiring its’ potential as a biomarker for treatment response. To further characterize these findings, examination of survival and modulation of radiosensitivity are ongoing.
TMET-22. OVERCOMING RESISTANCE: PANOBINOSTAT SENSITIZES 2DG-RESISTANT PEDIATRIC HIGH-GRADE GLIOMAS WITH H3.3 K27M/G34R MUTATIONS TO APOPTOSIS
Authors: Miller Tracy , Jane Esther , Gatesman Taylor , Halbert Matthew , Sneiderman Chiam , Raphael Itay , Mullett Steven , Gelhaus Stacy Lynn , Agnihotri Sameer , Steinman Richard , Premkumar Daniel , Pollack Ian 
Published: November 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas (pHGG) harboring H3.3 K27M/G34R mutations present formidable challenges in treatment due to their aggressiveness and resistance to standard chemotherapy. Our preliminary investigations have shown promising results, indicating that combining 2-deoxyglucose (2DG), a glycolytic inhibitor, with DNA-damaging agents synergistically inhibits pHGG growth. However, prolonged exposure to 2DG induces resistance, necessitating the exploration of alternative therapies. This study aims to investigate the potential of panobinostat, a histone deacetylase inhibitor, in sensitizing 2DG-resistant pHGG with H3.3 K27M/G34R mutations to apoptosis.

METHODS
Transcriptomic analysis via Illumina NovaSeq 6000 and metabolomic profiling employing Liquid Chromatography-High-Resolution Mass Spectrometry was used to delineate the molecular landscape of naive and 2DG-resistant pHGG cell lines. Functional assays, including the Agilent Seahorse Mito Stress Test and flow cytometry, assessed bioenergetics and mitochondrial dynamics. Intracellular NAD+ and NADH levels were quantified utilizing NAD+/NADH Glo assays, while apoptotic markers and metabolic stress were measured using the Annexin V-FITC Conjugates for Apoptosis Detection kit and western blot.

RESULTS
Comparative analysis revealed increased transketolase activity in 2DG-resistant cells, augmenting the interaction between the pentose phosphate pathway and glycolysis, resulting in elevated levels of NADPH and ATP. Additionally, these resistant cells displayed enhanced reliance on mitochondrial energy metabolism, as evidenced by substantial increases in mitochondrial membrane potential and mass, coupled with elevated NAD+ levels. Subsequent treatment with panobinostat induced a significant decrease in NAD+ biosynthesis and ATP generation. Furthermore, this intervention triggered the upregulation of pro-apoptotic BCL-2 family proteins, particularly BAX and BAK, concomitant with a notable reduction in mitochondrial membrane potential and the accumulation of reactive oxygen species. Consequently, heightened caspase-3 activity ensued, leading to significantly elevated cell death rates in 2DG-resistant gliomas.

CONCLUSION
Our findings highlight panobinostat as a promising therapy to resensitize 2DG-resistant pHGG cells to apoptosis, offering hope for treating these aggressive tumors with H3.3 K27M/G34R mutations.
TMET-23. MASS SPECTROMETRY-BASED METABOLIC PROFILING AND IMAGING OF ASTROCYTE AND GLIOBLASTOMA INVASIVE MARGIN CELLS
Authors: Kontrimaite Une , McCrorie Phoebe , Martinez-Jarquin Sandra , Porter Harry , Wong Kei F Carver , Smith Stuart , Kim Dong-Hyun , Rahman Ruman 
Published: November 2024

Abstract
Despite multimodal treatment, 90% of patients diagnosed with isocitrate dehydrogenase (IDH) wild-type glioblastoma experience tumour recurrence within 5 years. Poor prognosis is in considerable part attributed to the ability of cancer cells to infiltrate a healthy brain. We hypothesise that metabolic changes underpinning cellular crosstalk between astrocytes and glioblastoma cells isolated from the invasive margin within a physiologically representative in-vitro tumour microenvironment may reveal therapeutic targets to prevent or delay glioblastoma recurrence. This study used advanced analytical techniques to establish baseline metabolomic profiles for eGFP-tagged primary glioblastoma cells isolated from the invasive margin and healthy human cortical astrocytes. Liquid chromatography-mass spectrometry (LC-MS) enabled detailed analysis of biochemical pathways, and Atmospheric Pressure-Matrix Assisted Laser Desorption/Ionisation (AP-MALDI) imaging offered spatial localization of metabolites, critical for mapping their distribution within tumour microenvironments. Metabolites were extracted using a biphasic method (methanol:chloroform:water) for LC-MS analysis, and metabolic profiling was conducted using a ZIC-pHILIC column coupled with a Q-Exactive Orbitrap Mass Spectrometer. Additionally, AP-MALDI imaging facilitated the generation of high-resolution spatial distribution maps of selected metabolites, achieving a resolution of 10 µm. Both multivariate and univariate statistical analyses were applied to identify significant metabolic alterations. Metabolic profiling identified distinct pathways altered in glioblastoma cells compared to astrocytes, including alterations in aspartate, glycine and serine, and lipid metabolism. High-resolution imaging outlined the spatial distribution of metabolites involved in these pathways, revealing regions of metabolic heterogeneity. Furthermore, this methodology facilitated an expanded identification range of essential biomolecules, notably lipids and amino acids, thereby augmenting our understanding of their dynamic functions across diverse cellular contexts. By leveraging the complementary strengths of LC-MS and AP-MALDI imaging, this research enhances our understanding of spatial metabolite distribution in glioblastoma cells isolated from the invasive margin and suggests potential applications in patient tissue, offering a deeper exploration of disease mechanisms.
TMIC-07. TRIPLE COCKTAIL IMMUNOMODULATION OF TUMOR DRAINING LYMPH NODES RESULTS IN SYNERGISTIC REVERSAL OF IMMUNOSUPPRESSION AND IMPROVED OVERALL SURVIVAL IN A MURINE GLIOBLASTOMA MODEL
Authors: Choi John , Klich John , Kim Lily , Schonfeld Ethan , Verma Rohit , Cho Kwang Bog , Li Gordon , Appel Eric , Lim Michael 
Published: November 2024

Abstract
Clinical trials involving anti-PD-1 fail to improve survival compared to standard of care in glioblastoma (GBM). Despite the advent of newer immunotherapies such as STING agonists and anti-CSF-1R, combination of these strategies is limited by necessitation of intracranial delivery (STING) or off-target side effects with systemic exposure (anti-CSF-1R + anti-PD-1). We have previously shown that delivery of anti-PD-1 to tumor draining lymph nodes via hydrogels decreases systemic exposure of anti-PD-1 and results in improved therapeutic response compared to systemic delivery. This study assesses the efficacy of combining STING agonist (STING), anti-CSF-1R (aCSF1r), and anti-PD-1 (aPD1) into a hydrogel nanoparticle that targets different components of immunosuppression in tumor draining lymph nodes. CT-2A murine glioma cells were orthotopically implanted into C57BL/6J mice with treatment on day 7 via deep cervical injection of hydrogel polymers loaded with either PBS (control), STING, aCSF1r, aPD1, or a combination of all three immunomodulators. Flow cytometry was used for immunophenotyping and Kaplan-Meier survival curves were generated to assess therapeutic efficacy. Each treatment strategy targeted a different component of immunosuppression. Compared to controls, aCSF1r resulted in the greatest decrease of immunosuppressive myeloid cells in the brain (P=0.0017) and cervical lymph nodes (P=0.0008); STING resulted in the greatest activation of intracranial dendritic cells (P=0.0001); and aPD1 resulted in the highest level of T cell activation of the monotherapies (P=0.0008) but also caused compensatory upregulation of regulatory T cells in the brain (P=0.0176). Combination therapy resulted in the greatest decrease in immunosuppression with increased T cell IFN-y production and dendritic cell activation, with resultant improvement in median and overall survival (P=0.0006). Triple combination therapy to tumor draining lymph nodes that specifically targets multiple components of immunosuppression is a safe and efficacious treatment that can be translated to clinical application.
TMIC-08. PATTERNS OF PSTAT3 EXPRESSION IN REACTIVE ASTROCYTES OF BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER AND CORRELATIONS WITH OUTCOME
Authors: Pellerino Alessia , Wasilewski David , Bertero Luca , Ricci Alessia Andrea , Mangherini Luca , Bianconi Andrea , Garbossa Diego , Cassoni Paola , Priego Neibla , Valiente Manuel , Soffietti Riccardo , Rudà Roberta 
Published: November 2024

Abstract

BACKGROUND
pSTAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer may favor a pro-metastatic environment and negatively affect the intracranial progression-free survival (i-PFS) (Pellerino, 2023). We aim to evaluate whether pSTAT3 plays the same role also in BM from NSCLC.

MATERIAL AND METHODS
Seventy-two BM specimens from NSCLC were identified from the biobank of Pathology Unit of University of Turin and Berlin. STAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical and molecular data, and i-PFS were retrospectively retrieved.

RESULTS
Median age was 64 years (IC95% 59-67). Immunohistochemistry for GFAP and pSTAT3 was feasible in 66/72 (91,6%). 42/66 (63,6%) had BM with druggable mutations, while 24/66 (36,4%) did not show any actionable mutations. Druggable mutations were as follows: 8/42 (19,1%) KRAS G12C, 6/42 (14,3%) EGFR, 5/42 (11,9%) ALK, 1/42 (2,4%) BRAFv600E, 31/42 (73,8%) PDL1 expression. Overall, 53/66 (80,3%) showed positive staining of pSTAT3: 22/66 (33,3%) with score 3, 21/66 (31,8%) with 2, 10/66 (15,1%) with 1, and 12/66 (19.8%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 32/42 (76,2%) BM with actionable mutations and in 12/24 (50%) without actionable mutations (p 0,031). PDL1 expression was significantly correlated with high pSTAT3 expression (29/31, 93,5%), while most of BM without PDL1 (20/35 – 57,1%) had low or absent pSTAT3 (score 0-1) (p&lt;0,0001). Median i-PFS was 12 months (IC95% 8-23): low pSTAT3 BM had a median i-PFS of 18 months (IC95% 14-28) versus 9 months (IC95% 8-12) for high pSTAT3 BM (HR 5,3;p 0,0001).

CONCLUSION
pSTAT3 overexpression in RA is associated with PDL1 expression and may negatively impact the i-PFS in BM from NSCLC. These data support the investigation of STAT3 inhibitor silibinin in preventing intracranial recurrence in a clinical trial (NCT05689619).
TMIC-10. GENETIC LANDSCAPE OF BRAIN METASTASIS IN TRIPLE-NEGATIVE-BREAST CANCER: COMPARISON OF PAIRED PRIMARY AND METASTATIC TUMOR USING SPATIAL TRANSCRIPTOMIC ANALYSIS
Authors: Yoo Jihwan 
Published: November 2024

Abstract
The survival rate of individuals diagnosed with breast cancer has shown improvement over time, primarily attributed to advancements in early detection methods and the implementation of proactive treatment strategies. However, it is concerning that the incidence of breast cancer continues to rise, thereby leading to a corresponding increase in mortality rates among female breast cancer patients. Among these, the presence of brain metastasis is associated with a worse prognosis in individuals with breast cancer. Notably, triple-negative breast cancer exhibits a heightened propensity for the development of brain metastasis. Furthermore, there has been a notable rise in the duration of breast cancer survival, leading to a concomitant increase in the occurrence of metastatic cancer throughout the course of the disease. Presently, a greater number of patients are experiencing brain metastases, surpassing the figures reported in current statistical data. In instances of metastatic cancer, a distinct microenvironment that is particular to the tumor is formed in a distant location. The comprehension of the molecular genetic and immunological mechanisms involved in the several phases of brain metastasis, including tumor cell invasion, engraftment, and proliferation, has significant importance in the context of patient treatment and prognosis prediction. However, it is worth noting that a well-defined scientific foundation in this area is currently absent. The objective of this study was to analyze the molecular genetic characteristics of triple-negative breast cancer primary tumors and brain metastasis tumors. This was achieved by utilizing spatial transcriptome analysis technology to compare the differences in genetic profiles between the tumor cells and the surrounding tumor microenvironment. The findings of this study allowed for a comprehensive comparison of the tumor microenvironment at each site. In order to validate alterations in gene expression of various constituents and elucidate the mechanisms behind metastasis, it is imperative to conduct spatial confirmation.