tbuckley/cabot-search huggingface dataset:
DRES-18. EZH2/PRC2-MEDIATED EPIGENETIC PLASTICITY PROMOTES THERAPEUTIC RESISTANCE BY REGULATING STAT3 ACTIVATION GENE NETWORK IN THE GLIOMA STEM CELLS
Authors: Cheol Park, Fatemeh Atashi, Seamus Caragher, Shivani Baisiwala, Maciej S Lesniak, C David James, Atique Ahmed
Journal: Neuro-Oncology (2017)

Glioma stem cells (GSCs), a rare population of GBM cells capable of self-renewal, are known to underlie therapeutic resistance in Glioblastoma. Previously, we have shown that treatment with temozolomide (TMZ) initiates remarkable plasticity in glioma cells and promotes the conversion of differentiated glioma cells to GSCs. Our initial investigation indicated that Polycomb group protein EZH2 is critical for this therapy-induced cellular plasticity. We have demonstrated that chemical inhibition and shRNA-mediated knockdown of EZH2 activity prevent the cellular plasticity-mediated conversion of non-GSCs to GSCs. To elucidate the molecular mechanisms by which EZH2 enables cellular plasticity and expands the GSC population after therapy, we performed genome-wide chromatin immunoprecipitation (ChIP) in parallel with DNA sequencing analyses (ChIP-seq) during exposure a patient-derived xenograft (PDX) line to a physiological dose of TMZ (50µM). This ChIP-seq mapping revealed 1449 distinct regions enriched for EZH2 binding. Of these sites, 82% were in intronic regions, 14% occurred in exon areas, and 4% were located in promoter regions. Utilizing pathway Enrichr analysis, we found that post-TMZ EZH2 binding was enriched at the promoter regions of several key genes including PTPRT, CDK5R2, and Siglec6. Gene expression microarray analysis showed that this binding decreased cognate gene expression in an effort to activate the master transcription factor STAT3, a key molecular factor in promoting the GSC niche. Western blot and flow cytometry analysis revealed that, following therapy, EZH2 positive GSCs expressed a higher level of p-(Ser722)-STAT3 (10-fold increase in MFI, p>0.005) and p-(Tyr705)-STAT3 (3-fold increase in MFI, p>0.005). Given this increase after TMZ, we hypothesized that blocking STAT3 would inhibit chemotherapy resistance in GSCs. Indeed, STAT3 inhibitor sensitized GSCs to TMZ therapy. These findings provide new insight into the molecular mechanisms by which epigenetic plasticity regulates the GSC niche and improve our understanding of how GBM cells resist current treatment modalities.
EPID-02. SURVIVAL BENEFIT OF GLIOBLASTOMA PATIENTS AFTER FDA APPROVAL OF BEVACIZUMAB, A POPULATION-BASED STUDY USING SEER, TCR, AND NCDB DATABASES
Authors: Ping Zhu, Xianglin Du, Guangrong Lu, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2017)

The nationwide studies on survival change in GBM patients treated with bevacizumab (BEV) after Food and Drug Administration (FDA) approval in May 2009 were limited. We investigated the impacts of BEV on survival in general GBM patient population by conducting a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER), Texas Cancer Registry Limited-Use datasets (TCR), and National Cancer Database (NCDB). The adult patients diagnosed with GBM between 2005 and 2013 were included from SEER (N=14827), TCR (N=2709), and NCDB (N=32731). Patients were categorized into two calendar periods based on date of GBM diagnosis: pre-BEV (2005–2008, P1), and post-BEV (2010–2013, P2). The association between calendar periods and GBM survival was analyzed in SEER, TCR, and NCDB separately, by applying the Kaplan-Meier method and Cox proportional hazards model. A significant increase in median overall survival (OS) was observed from P1 to P2 in SEER (P1: 10, P2: 11, months; P<0.001), TCR (P1: 9.97, P2: 12.00, months; P<0.001), and NCDB (P1: 10.71, P2: 12.25, months; P<0.001). One-year survival rate was remarkably increased during P2 in SEER (P1: 41.9%, P2: 45.4%; P<0.001) and NCDB (P1: 45.1%, P2: 50.8%; P<0.001). In NCDB, 2-year survival rate was improved by 23.1% after BEV approval (P1: 18.6%, P2: 22.9%, P<0.001). No significant change of 1-year and 2-year survival rate was detected between P1 and P2 in TCR. After controlling different sets of covariates, including demographics, clinical characteristics, and treatments in multivariate analysis, the risk of death was significantly reduced by 9%, 28%, and 11% in SEER, TCR, and NCDB, respectively. Comparison and validation analysis were performed in the combined dataset (SEER+TCR), and consistent results were observed. Therefore, the administrations of BEV for recurrent GBM after FDA approval may contribute to the improvement of OS, 1-year and 2-year survival rate in GBM patients.
Les recommandations BICHAT sur la prise en charge clinique lors d'un acte de bioterrorisme
Authors: P Bossi, F van Loock, A Tegnell, G Gouvras
Journal: Eurosurveillance (2004)

L’emission deliberee de charbon aux Etats-Unis, peu apres les attaques terroristes du 11 septembre 2001, a radicalement modifie la perception du risque bioterroriste. Ces evenements, contrairement aux actes bioterroristes anterieurs, ont eu un impact
Fattibilità della sorveglianza della resistenza ai farmaci antitubercolari: Europa, 1997
Authors: V Schwoebel, D Antoine, J Veen
Journal: Eurosurveillance (2000)

Sono stati raccolti dati sulla suscettibilita ai farmaci antitubercolari di una percentuale di isolati dal 28 al 100%, provenienti da dieci paesi partecipanti al network EuroTB. La resistenza ai farmaci e stata piu comune tra i pazienti nati all’estero e in generale tra i pazienti che erano stati precedentemente trattati per la tubercolosi.
CSIG-37. TGF-β PROMOTES MEMBRANE TUBE FORMATION IN GLIOBLASTOMA THAT CONTRIBUTES TO INVASION AND THERAPY RESISTANCE
Authors: Justin Joseph, Julia Grosch, Tushar Tomar, Barbara Klink, Thomas Daubon, Lalit Rane, Gergely Solecki, Mahdi Hasan-Olive, Jubayer Hossain, Abdul Latif, Sandra Ninzima, Linda Bergersen, Saverio Tardito, Frank Kruyt, Rolf Bjerkvig, Frank Winkler, Hrvoje Miletic
Journal: Neuro-Oncology (2017)

Transforming growth factor-β (TGF-β) is a cytokine with a key role in tissue homeostasis and cancer. TGF-β signalling is highly active in glioblastomas (GBM) and elevated TGF-β activity has been associated with poor clinical outcome. Here we report the role of TGF-β in mediating the formation of membrane tubes (MTs), which are tubular cytoplasmic extensions forming important communication structures. We observed that TGF-β stimulation promotes enhanced MT formation both in vitro and in vivo. Blockade of the TGF-β pathway using a selective inhibitor (A8301) or the administration of Cytochalasin-D, a potent inhibitor of actin polymerization could significantly reduce the MT formation and associated invasion. Further we found that the cells connected through MTs sustained lesser amount of DNA double strand breaks post administration of TMZ in comparison to the non-connected cells. We also observed shuttling of mitochondria through the MTs and an elevation of mitochondrial biogenesis post TGF-β administration. The role of TGF-β in MT formation was further evident in a TGF-β responsive and non-responsive patient derived cell lines. The non-responsive cell line was found to lack the TGF-β receptor 2 and stimulation of this cell line with TGF-β did not show an elevation in MT formation. Interestingly the non-responsive cell line generated a small and well circumscribed tumour upon intracranial implantation that remained confined to the site of injection and showed poor MT formation and weak pSMAD2 staining. However, the responsive cell line on the other hand presented a highly invasive tumour with intense pSMAD2 staining and abundant MTs connecting the cells inside the tumour. Similar observation was also made on the corresponding patient samples from which these cell lines where derived. Taken together it is compelling to speculate that targeting TGF-β pathway or its downstream components could potentially break the complex MT driven invasion/ resistance network in GBM.
Response by Mehra et al to Letter Regarding Article, “Hemocompatibility-Related Outcomes in the MOMENTUM 3 Trial at 6 Months: A Randomized Controlled Study of a Fully Magnetically Levitated Pump in Advanced Heart Failure”
Authors: Mandeep R. Mehra, Kartik S. Sundareswaran, Nir Uriel
Journal: Circulation (2017)
IMMU-51. ASSESSING AND AUGMENTING THE IMMUNE RESPONSE TO GLIOBLASTOMA USING REPURPOSED PHARMACEUTICALS
Authors: Breanna Brenneman, Desiree Floyd, Aizhen Xiao, Alisa Malyakvo, Tajie Harris, Benjamin Purow
Journal: Neuro-Oncology (2017)

In order to improve the therapeutic responses to immunotherapies in glioblastoma patients, a known pharmaceutical, ritanserin, was repurposed to augment cytotoxic T cell responses and suppress tumor growth. Ritanserin is able to inhibit the activity of diacylglycerol kinase alpha (DGKA), which converts diacylglycerol to phosphatidic acid, and inhibit tumor growth in mice. In addition, DGKA is expressed in T cells, and is more highly expressed in those that have entered an unresponsive (anergic) state. To determine the kinetics of the immune response to GBM, the transplantable syngeneic glioma cell line GL261 was used in C57BL/6 mice to assess the tumor immune response in the brain, spleen, and cervical lymph node via flow cytometry weekly for one month. After identifying the optimal T cell response temporally, mice with established tumors were treated with 50 mg/kg of ritanserin for one week and harvested post treatment. To determine if ritanserin can counteract T cell anergy, T cell responses were determined by assessment of T cell number by subset, by activation, and by tumor-specific response to ovalbumin-expressing GL261 tumor cells in the brain and spleen. In comparison to mock-injected mice, tumor-bearing mice showed a robust T cell response to tumors in the brain, peaking at days 21 and 28 post injection. Treatment with ritanserin resulted in a trend toward increased number and activation of T cells in the brain and increased IFNγ-producing T cells in the spleen compared to vehicle-treated mice. In conclusion, T cells respond robustly to brain tumors in mice, and ritanserin treatment appears to increase this response by increased activation and priming of tumor-specific T cells. This indicates that ritanserin may be able to boost T cell responses in the brain. Future experiments will focus on further characterizing ritanserin’s effect on T cells in in vitro anergy models and subcutaneous models.
NIMG-70. THE EFFECT OF PATIENT AGE AT GLIOMA PRESENTATION ON MRI PHENOTYPE: A COMPREHENSIVE ANALYSIS OF VASARI-BASED FEATURE-SET CRITERIA IN 711 PATIENTS
Authors: Devsmita Das, Byung Yoon, Louis Golden, Peyman Samghabadi, Hannes Vogel, Kristen Yeom, Michael Iv, Tarik Massoud
Journal: Neuro-Oncology (2017)

Tumor morphological features affect patient survival after glioma diagnosis. VASARI-based feature-set criteria are used to characterize glioma MRI phenotypes. We examined whether a large panel of features, including aggressive glioma MRI biomarkers, were more pronounced at different ages. Establishing the role of age as a possible confounder serves as baseline for future more extensive radiogenomic correlations to account for worsening prognosis of glioblastoma with increasing age (>40yr). In this large retrospective single-center study, we analyzed initial-presentation MRI scans with suspected low- or high-grade gliomas in steroid-naïve patients (n = 711) of four age groups (0-18yrs, 19-40yr, 41-65yr, and >65yr). Three reviewers recorded 30 key imaging features based on VASARI feature-set criteria. We used a chi-square test of independence and a Kruskal-Wallis test to statistically examine the group-wise relation between age and categorical or ordinal VASARI features, respectively. Significance was at p<0.05. There was significant difference in short (p=0.006) and long axis (p<0.0001) size between groups, with highest tumor size in 40-65yr adults. Incidence of high-grade tumors (p<0.0001), presence of restricted diffusion (p=0.004), necrosis (p<0.0001), satellites (p<0.0001) and cortical involvement (p=0.0002) significantly increased with age, being lowest in the pediatric age group and highest in >65yr adults. Presence of tumor crossing midline (p=0.006), cysts (p=0.0001), and calvarial remodeling (p<0.0001) were more common in children. Old age was also significantly associated with greater edema (p<0.0001), proportions of enhancing tumor (p<0.0001), and restricted diffusion (p=0.004) as compared to other age groups. Similar to previous studies, age at diagnosis determines tumor size and degree of peritumoral edema or necrosis in gliomas. Cortical involvement is greatest in the elderly. Several MRI biomarker signatures are more significantly associated with pediatric glioma phenotypes. We will extend this MRI analysis to future correlations with underlying tumor biology and genomic composition to predict patient survival.
GENE-61. TEMOZOLOMIDE-INDUCED MISMATCH REPAIR INSUFFICIENCY AND HYPERMETHYLATION OF MGMT PROMOTER WITH HYPERMUTATION IN MALIGNANT GLIOMAS
Authors: Kuniaki Saito, Kaori Suzuki, Saki Shimizu, Keiichi Kobayashi, Daisuke Shimada, Satoshi Kume, Shohei Iijima, Tomohiro Chiba, Junji Shibahara, Yoshiaki Shiokawa, Motoo Nagane
Journal: Neuro-Oncology (2017)

that drive tumor growth.
P1.04-005 Phase 2 Study of Nivolumab and Metformin in Advanced Non-Small Cell Lung Cancer with and without Prior Treatment with PD-1/PD-L1 Inhibitors
Authors: Y. Chae, W. Iams, S. Pai, R. Costa, T. Taxter, N. Mohindra, V. Villaflor, B. Pro, F. Giles
Journal: Journal of Thoracic Oncology (2017)
P3.03-020 Unique Molecular Profile of NSCLC in Thai Population
Authors: N. Trachu, P. Incharoen, A. Jinawat, A. Charoenyingwattana, O. Trachoo, I. Senson, W. Pairoj, P. Janchompoo, C. Srichunrusami, S. Detarkom, S. Lukrak, E. Sirachainan, T. Sirisinha Dejthevaporn, R. Panvichien, W. Chantratita, P. Tienchainaanda, M. Ngodnbamthaweesuk, N. Prasongsook, S. Techasurungkul, N. Iemwimangsa, W. Klaisuban, T. Reungwetwattana
Journal: Journal of Thoracic Oncology (2017)
Development and psychometric testing of a measure of perception of care dependency in cancer patients
Authors: M. Piredda, G. Gambale, M.L. Candela, D. Mecugni, L. Rasero, L. Iacorossi, V. Rossi, J. Brice, M.T. Capuzzo, S. Migliore, T. Petitti, E. Pettinari, R. Barbetta, C. Fanni, M. Marcucci, A. Marchetti, M.G. De Marinis
Journal: Annals of Oncology (2017)
IMMU-34. CONTROLLED EXPRESSION OF IL-12 IMPROVES SURVIVAL IN GLIOMA BY ACTIVATING THE IMMUNE RESPONSE IN MICE AND HUMANS
Authors: John Barrett, Hongliang Cai, John Miao, Pranay Khare, Tim Chan, Laurence Cooper, Francois Lebel
Journal: Neuro-Oncology (2017)

Modulating the tumor microenvironment with immuno-stimulatory therapy maybe an attractive approach for the treatment of glioma. We took advantage of IL-12 biology utilizing a replication-incompetent adenovirus (Ad) engineered to conditionally express mouse or human IL-12 (Ad-RTS-mIL-12 or Ad-RTS-hIL-12), via our RheoSwitch Therapeutic System® (RTS®) gene switch, tightly controlled by the oral activator ligand veledimex (V). Previous human and mouse studies demonstrated that V crosses the blood-brain-barrier (BBB), enabling controlled IL-12 expression. Ad-RTS-mIL-12 injected into orthotopic GL-261 glioma at the optimal dose of 5x109 viral particles (vp) +veledimex (Ad+V) elicited dose-related increases in local IL-12 and downstream IFN-gamma production. Cytokines within the tumor were ~20 times higher than serum and elicited sustained increases within glioma of cytotoxic T cells and macrophages concomitant with reduction in regulatory T cells (Tregs) resulting in enhanced survival where ~65% of mice receiving Ad+V 10-30mg/m2/day were tumor free 80 days after immunotherapy (end of study). Ad+V 10mg/m2/day was the optimal therapeutic index. Using allometric modeling, mouse Ad+V 10mg/m2/day translated into ~20mg V for a 70kg subject and supports Ad-RTS-hIL-12 up to 5x1012vp. Based on these results, a phase 1 trial in recurrent glioma studying local hIL-12 production using Ad-RTS-hIL-12 2x1011vp +V 10-40mg QDx14po. was initiated. Interim results demonstrated that V20mg elicited the optimal therapeutic index. Results at 20mg (N=15) demonstrated that V crossed the BBB with 35 ± 5% of plasma levels in tumor and peak serum levels of hIL-12 and IFN-gamma at 27 and 36pg/ml. Increase in circulating cytotoxic-T cell/Tregs ratio at days 14-28 correlated with an increase in the median overall survival of 12.5mo. Our working hypothesis tested in the mouse that IL-12 activates the immune response leading to mouse anti-tumor effects now appears to be validated in humans.
CBIO-03. CORTICOTROPIN RELEASING HORMONE CAN SELECTIVELY STIMULATE GLUCOSE UPTAKE IN CORTICOTROPINOMA VIA GLUCOSE TRANSPORTER 1
Authors: Alejandro Bugarini, Gregoire Chatain, Jie Lu, Blake Montgomery, Stuart Walbridge, Qi Zhang, Abhik Ray-Chaudhury, Russell Lonser, Prashant Chittiboina
Journal: Neuro-Oncology (2017)

Pre-operative detection of adrenocorticotropin (ACTH)-secreting microadenomas causing Cushing’s disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with 18F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased 18F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. Clinical data was analyzed for efficacy of CRH in improving 18FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p<0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4h (mean difference 341.2%, [95% CI 114.1–568.3], ANOVA p≤0.001). Similarly, a robust GLUT1 upregulation was seen with CRH (205.3 ± 30.8%, p=0.0004) and 8-Br-cAMP (1.8 ± 1.6%, p=0.25) while Immunocytochemistry revealed increased membrane translocation at 2 h. Fasentin suppressed baseline (mean difference 47.3% [95% CI 41.2–53.4], ANOVA p<0.0001) and CRH-mediated glucose uptake compared to controls (12.7%, [95% CI 6.591–18.7], ANOVA p<0.0001). Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression on immunohistochemistry. Lastly, human-derived corticotroph tumor cells utilized up to 70–80% of their glycolytic capacity but less than 15% of their glucose oxidation capacity. Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated 18F-FDG PET could improve microadenoma detection.
STEM-28. DOT1L EPIGENETICALLY REGULATES GBM BRAIN TUMOR STEM CELLS
Authors: Danielle Bozek, Alice Wang, Xiaoguang Hao, Michael Johnston, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2017)

The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo- therapies. Recurrence results from the invasion of GBM cancer cells away from the initial cancerous mass and may be due to brain tumor stem cells (BTSCs) that are resistant to therapy and capable of tumor initiation. Recently, epigenetic-based therapies have become of great interest given that, unlike genomic mutations, epigenetic alterations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. Long term treatment with the DOT1L inhibitor EPZ-5676 decreased H3K79me2 levels in BTSCs and altered BTSC sphere morphology, sphere initiating frequency, proliferation, migration and invasion. To investigate the mechanism by which DOT1L may regulate GBM tumorigenesis and growth we performed qPCR, flow cytometry, RNA-sequencing and H3K79me2 ChIP-sequencing of BTSC lines, following treatment with EPZ-5676. We found that DOT1L inhibition decreases the expression of GBM stem and progenitor cell genes and increases the expression of genes associated with neuronal and astrocytic differentiation. Furthermore, H3K79me2 ChIP sequencing revealed that DOT1L histone methylation was reduced within the gene body of stem and progenitor cell genes. Flank xenograft studies, of mice treated with EPZ-5676, revealed that DOT1L inhibition promotes neuronal and astrocytic differentiation in tumors. Ongoing pre-clinical studies are assessing the effect of DOT1L inhibition on survival in an orthotopic xenograft model of GBM and investigating rational combinatorial targeting strategies, with a long-term aim of preventing GBM recurrence and improving overall patient survival.
P2.03-025 Prevalence of EGFR T790M Mutation in NSCLC Patients after Afatinib Failure, and Subsequent Response to Osimertinib
Authors: M. Hochmair, S. Schwab, O. Burghuber, R. Koger, U. Setinek, A. Cseh, R. Fritz, A. Buder, M. Filipits
Journal: Journal of Thoracic Oncology (2017)
P3.13-015 18F-FDG-PET/CT after Induction Chemotherapy for Prediction of Survival after Radical Chemo-Radiotherapy in Locally Advanced NSCLC Patients
Authors: J. Fledelius, A.A. Khalil, K. Hjorthaug, O. Hansen, J. Frøkiær
Journal: Journal of Thoracic Oncology (2017)
P1.05-007 A Retrospective Study to Compare Resection Rate and Survival Rate in Operable Stage I to III NSCLC After Introduction of Lung Cancer MDT
Authors: Y.Y. Sum, C.S. Kan, S.Y. Soon, S. Eunice Ong, K.M. Adeline Lau, P.J. Voon
Journal: Journal of Thoracic Oncology (2017)
P1.01-012 Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis
Authors: A. Shaw, D. Kim, B. Solomon, E. Felip, G. Riely, M. Schuler, D. Tan, L. Chow, D.R. Camidge, P. Urban, C. Ortmann, I. Malet, R. Mehra
Journal: Journal of Thoracic Oncology (2017)
STEM-26. HYPOXIA REGULATES NOTCH TURNOVER IN GLIOMA STEM-LIKE CELLS
Authors: Jennifer Yu
Journal: Neuro-Oncology (2017)

Tumor hypoxia selects for highly malignant cells and is associated with poor patient survival. Glioblastoma is an incurable brain cancer characterized by regions of hypoxia. The Notch pathway is implicated in maintaining glioma stem-like cells (GSCs) in the hypoxic niche, but the underlying mechanisms are unclear. We have identified Vasorin as a critical link between hypoxia and Notch signaling in GSCs. Vasorin is preferentially induced in GSCs by hypoxia through a HIF1a/STAT3 co-activator complex. Vasorin binds to and stabilizes Notch1 at the cell membrane by reducing its lysosomal degradation. Vasorin therefore acts as a switch to augment Notch signaling under hypoxic conditions. In mouse models of glioblastoma, Vasorin promotes tumor growth and reduces animal survival. In human IDH1 wt gliomas, Vasorin expression inversely correlates with patient survival. We provide mechanistic insight into hypoxic regulation of membranous Notch1 turnover in GSCs and identify Vasorin as a prognostic marker and potential therapeutic target.