bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-07. IDENTIFICATION OF A NOVEL CSC SIGNALING AXIS CONTAINING JAM-A/SERPINB3/TGF-BETA
Authors: Lauko Adam , Turaga Soumya , Volovetz Josephine , Bayik Defne , Naik Ulhas , Lathia Justin 
Published: December 2020

Abstract
Despite therapeutic interventions including surgery, radiation, and chemotherapy, multiple clones of treatment resistant cells repopulate the tumor, resulting in recurrence and a high rate of mortality in glioblastoma. Effective targeting of these cancer stem cells (CSCs) has been limited by our incomplete understanding of the intracellular signaling mechanisms maintaining the CSC state. Our laboratory previously identified junctional adhesion molecule-A (JAM-A) on CSCs and, through functional studies, demonstrated that JAM-A is both necessary and sufficient for self-renewal and tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription factor activity; however, the intermediate signaling network is yet to be fully elucidated. Therefore, our goal was to delineate the pathway downstream of JAM-A. To achieve this, we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry leading to the identification of the serine/cysteine protease inhibitor SerpinB3. While SerpinB3 has a functional role in lung adenocarcinoma, breast, pancreas, as well as in hepatocellular carcinoma, there is limited information in GBM or CSCs, and its relationship to JAM-A is yet to be elucidated. Using in vitro CSC functional assays, we observed that SerpinB3 is necessary for the maintenance of CSCs. Additionally, in an intracranial implantation model of GBM the knockdown of SerpinB3 extended the survival of mice. Knockdown of SerpinB3 in multiple GBM CSCs models also led to decreased expression of TGF-β, a known regulator of the CSC state. We also observed that SerpinB3 stabilizes JAM-A expression and further studies are investigating the mechanism of this stabilization, identifying the specific interaction sites of JAM-A and Serpin B3, and determining how TGF-β alters the association through positive and negative feedback mechanisms. Taken together, these data highlight the role of SerpinB3 in GBM CSCs and provides a novel target to inhibit the JAM-A-mediated CSC maintenance as a next-generation GBM therapy.
STEM-08. PLATELETS DRIVES GLIOBLASTOMA ONCOGENESIS BY ENHANCING THE GLIOMA STEM CELL PHENOTYPE
Authors: Sloan Anthony , Lee-Poturalski Christine , Elder Theresa , Harris Peggy , Kerstetter-Fogle Amber , Cioffi Gino , Raghavan Alankrita , Willis John , Rich Jeremy , Barnholtz-Sloan Jill S , Jankowsky Eckhard , Sloan Andrew E 
Published: December 2020

Abstract
Glioblastoma (GBM) is recognized as one of the deadliest forms of cancer, despite aggressive therapy consisting of maximal surgical resection followed by concurrent radiation and chemotherapy, the median survival remains ~15 months. Glioma stem cells (GSCs) possess potent tumor-initiating properties and comprise a cellular hierarchy that is responsible for treatment resistance and progression. Specifically targeting GSCs has been considered a promising therapeutic approach, however no clear method has been identified. Histologically, it is known that GSCs are found in perivascular and pseudsopalisading regions of GBM. Similarly, platelet aggregates are often found in pseudsopalisading necrotic regions, suggesting a potential interaction between platelets and GSCs due to their spatial locations. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Our work aimed to understand the crosstalk between GSCs and platelets within GBM solid tumors that work to enhance disease progression and treatment resistance. Our clinical studies suggest elevated platelet counts positively correlate with tumor growth and negatively correlate to overall patient survival. We found platelets and GSC co-localization in GBM solid tissue; platelet exposure to GSCs results in increased proliferation of GSCs specifically, by increasing the self-renewing capacity of GSCs in a dose dependent manner, and resulted in an increased “Stem-like” transcriptional pattern. Consequently, inhibiting the GSC-platelet interaction results in a decrease in GSC renewal and stemness. These results introduce a novel interaction between GSCs and platelets and elucidate a novel therapeutic approach specifically targeting GSCs by disrupting the GSC-platelet interaction.
STEM-09. INTRINSIC INTERFERON SIGNALING REGULATES THE CELL DEATH OF GLIOBLASTOMA STEM CELLS
Authors: Khan Khan Sabbi , Martinez-Ledesma Emmanuel , Mittal Sandeep , Gandy Kaitlin , Alfaro-Munoz Kristin , Majd Nazanin , Balasubramaniyan Veerakumar , de Groot John 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most common, highly aggressive, and lethal primary brain tumor in adults. Interferon (IFN)-mediated signal transducer and activator of transcription 1 (STAT1) signaling contributes to various aspects of stemness, cell death, cytokine signaling in immune and non-immune cells. However, the role of IFN/STAT1 signaling in stemness, cell death and treatment resistance in GBM is unclear. This study aimed to investigate the cancer cell-intrinsic IFN/STAT1 signaling and its role in cell proliferation, stemness, and apoptosis. By using the metagene scores for type I and type II IFN-responsive genes, we evaluated basal IFN/STAT1 signaling in The Cancer Genome Atlas (TCGA) and in patient-derived cohorts of stem-like cells (GSCs) RNA expression datasets. In-silico analyses were further validated for the constitutive IFN signaling in a subset of GSCs using qPCR, WB and ELISA assays. We employed pharmacological activators and/or inhibitors of IFN/STAT1 signaling in GSCs to study its role in stemness and cell death. We found differential cell-intrinsic type I and type II IFN-signaling markers in GSCs and GBM tumors. High IFN-signaling is associated with mesenchymal phenotype and poor survival outcomes. Acute and chronic GSC exposure to recombinant IFNs reversibly activated both type I and II IFN-signaling in GSCs. IFN-β exposure induced apoptosis in intrinsically high IFN/STAT1-signaling GSCs, but not in the low IFN/STAT1-signaling GSCs. In summary, our findings demonstrate that GBM exhibit differential cell-intrinsic IFN-signaling, and basal IFN/STAT1 is a key factor for IFN-β-mediated cell death in GSCs. However, further mechanistic investigation of intrinsic IFN signaling in GBM, particularly in the stem cell compartment is needed.
STEM-17. NOT ALL GBM STEM CELLS ARE EQUAL: IMPLICATIONS FOR RESEARCH AND THERAPY
Authors: Galdieri Luciano , Jash Arijita , Malkova Olga , Mao Diane , Campian Jian , Brennan Cameron , Oh Stephen , Kim Albert , Chheda Milan 
Published: December 2020

Abstract
Glioblastoma (GBM) kills almost all patients within 2 years. A subpopulation of cells, GBM stem cells (GSCs), contributes to treatment resistance and recurrence. A major therapeutic goal is to kill GSCs, but no targeted therapy yet exists. Since their discovery, GSCs have been isolated using single surface markers, such as CD15, CD44, CD133, and a-6 integrin. It remains unknown how these single surface marker-defined GSC populations compare to each other in terms of signal transduction and function and whether expression of different combinations of these markers is associated with distinct phenotypes. Using mass cytometry and fresh operating room specimens, we found that 15 distinct GSC subpopulations exist in vivo and they differ in their MEK/ERK, WNT, and AKT pathway activation status. In culture, some subpopulations were lost and previously undetectable ones materialized. GSCs highly expressing all four surface markers had the greatest self-renewal capacity and in vivo tumorigenicity as well as the strongest WNT pathway activation. This work highlights the signaling and phenotypic diversity in GSC subpopulations, together suggesting that not all GSCs are equivalent. These observations should be considered when studying GSCs in the laboratory, with implications for the development of treatments that target GSCs and prevent tumor recurrence in patients.
STEM-19. THE ISOLATION AND IDENTIFICATION OF GLIOMA STEM CELLS AND MESENCHYMAL STEM CELLS FROM HUMAN GLIOMA SPECIMENS
Authors: Yu Yan-jiao , Jing Wang , Chen Zhong-ping 
Published: December 2020

Abstract

INTRODUCTION
Glioma is the primary malignancy with the highest incidence in central nervous system. Studies have shown that glioma stem cell (GSC) is the important origin for recurrence and closely associated with tumor microenvironment. Glioma-associated human mesenchymal stem cells (GA-hMSCs), as an important part of the tumor microenvironment, might promote proliferation and invasion of GSC. We try to isolate GSCs and GA-hMSCs through glioma primary culture, and investigate the relationship between GSC and GA-hMSCs, as well as their roles in the recurrences of glioma.

MATERIALS AND METHODS
Five surgical specimens from patients with human high-grade glioma were collected for primary culture. The surgical specimens were cut up and digested with Dispase II (collagenase), terminated by adding plenty of DNase II. Cell suspension was collected and resuspended in conditional medium for MSC or GSC. After being cultured for several passages, GSCs were identified by immunofluorescence, and GA-hMSCs were identified by flow cytometry and in vitro differentiation assays.

RESULTS
Cell cultures were observed with an inverted phase-contrast microscope after 24 hours. Adherent GA-hMSCs were collected and the supernatant was discarded with non-adherent cells. GSC was cultured as neurospheres. The single-cell suspension was prepared from spheres of GSC to identify their surface expression profile by immunofluorescence assays after several passages. The results confirmed that GSCs positively expressed CD133, Nestin and SOX2, but did not express GFAP and Tublin III. GA-hMSCs positively expressed CD105, CD73, CD90 and negatively expressed CD45 and CD34. GA-hMSCs could differentiate into adipocytes, chondrocytes and osteocytes.

CONCLUSION
We isolated and identified GSCs and GA-hMSCs from glioma primary culture. Our future work will focus on the relationship between the two types of cells and their roles in the process of tumor recurrence based on the successful isolation of GSC and GA-hMSCs. Keywords: Glioma; Mesenchymal stem cells; Glioma stem cells; Recurrence
STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM
Authors: Skirboll Stephen , Lucki Natasha , Villa Genaro , Vergani Naja , Bollong Michael , Beyer Brittney , Lee Jae Wook , Anglin Justin , Spangenberg Stephan , Chin Emily , Sharma Amandeep , Johnson Kevin , Sander Phillipp , Gordon Perry , Wurdak Heiko , Schultz Peter , Mischel Paul , Lairson Luke 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner.

METHODS
A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation.

RESULTS
We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation.

CONCLUSIONS
Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.
STEM-27. miR-10b-5p MODULATES 5hmC EXPRESSION AND THE STEM-LIKE PHENOTYPE IN GBM
Authors: Khela Harmon , Sudhir Sweta , Lugo-Fagundo Maria , Lal Bachchu , Lopez-Bertoni Hernando , Laterra John 
Published: December 2020

Abstract
Epigenetic alterations such as DNA methylation and dysregulation of non-coding RNAs (e.g. miRNAs) are found in all types of cancer and are thought to play important roles in tumorigenesis. GBM is characterized by small subsets of cells, referred to as glioma stem cells (GSCs), that display stem-like properties implicated in tumor initiation, therapeutic resistance, and recurrence. DNA methylation patterns are altered in GBM and GSCs and are thought to play critical roles in tumor initiation and propagation. DNA methylation is a reversible process catalyzed, in part, by the ten-eleven translocation (TET) family of enzymes. These enzymes function as deoxygenases that catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients. However, the mechanisms leading to the loss of 5hmC in glioma and the role this phenomenon plays in gliomagenesis remains poorly understood. We found that Sox2 expression decreases TET2 expression and its product 5hmC in GSCs and identified miR-10b-5p as a molecular intermediary of this process. We show that miR-10b-5p expression is high in GBM compared to non-tumor in clinical specimens and high levels of this miRNA correlate with poor patient outcome. Expression of transgenic miR-10b-5p enhanced sphere formation capacity of GSCs and the expression of stem cell markers and drivers. Additionally, using a combination of molecular and biochemical endpoints, we show that miR-10b-5p modifies 5hmC levels by regulating TET2 in GSCs. Finally, we show that repression of miR-10b-5p increases 5hmC levels and inhibits tumor propagation in GBM xenograft models. Taken together, these results present a new molecular mechanism that controls 5hmC and the tumor propagating capacity of GSCs and suggests that miR-10b-5p inhibition and other strategies for enhancing TET2 function can be developed to treat GBM.
SURG-02. SURVIVAL PREDICTION AFTER NEUROSURGICAL RESECTION OF BRAIN METASTASES: A MACHINE LEARNING APPROACH
Authors: Hulsbergen Alexander , Lo Yu Tung , Kavouridis Vasileios , Phillips John , Smith Timothy , Verhoeff Joost , Yu Kun-Hsing , Broekman Marike , Arnaout Omar 
Published: December 2020

Abstract

INTRODUCTION
Survival prediction in brain metastases (BMs) remains challenging. Current prognostic models have been created and validated almost completely with data from patients receiving radiotherapy only, leaving uncertainty about surgical patients. Therefore, the aim of this study was to build and validate a model predicting 6-month survival after BM resection using different machine learning (ML) algorithms.

METHODS
An institutional database of 1062 patients who underwent resection for BM was split into a 80:20 training and testing set. Seven different ML algorithms were trained and assessed for performance. Moreover, an ensemble model was created incorporating random forest, adaptive boosting, gradient boosting, and logistic regression algorithms. Five-fold cross validation was used for hyperparameter tuning. Model performance was assessed using area under the receiver-operating curve (AUC) and calibration and was compared against the diagnosis-specific graded prognostic assessment (ds-GPA); the most established prognostic model in BMs.

RESULTS
The ensemble model showed superior performance with an AUC of 0.81 in the hold-out test set, a calibration slope of 1.14, and a calibration intercept of -0.08, outperforming the ds-GPA (AUC 0.68). Patients were stratified into high-, medium- and low-risk groups for death at 6 months; these strata strongly predicted both 6-months and longitudinal overall survival (p &lt; 0.001).

CONCLUSIONS
We developed and internally validated an ensemble ML model that accurately predicts 6-month survival after neurosurgical resection for BM, outperforms the most established model in the literature, and allows for meaningful risk stratification. Future efforts should focus on external validation of our model.
SURG-05. IDEAL TREATMENT REGIMEN FOR PATIENTS WITH ≥1 BRAIN METASTASIS FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Authors: Brar Karanbir , Ellenbogen Yosef , Sadeghirad Behnam , Deng Jiawen , Hou Winston , Wang Xiaoqin , Taslimi Shervin , Mansouri Alireza 
Published: December 2020

Abstract

BACKGROUND
Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). The aim of this study was to assess the comparative effectiveness of treatments for BM from NSCLC.

METHODS
We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published until October 2018. We also searched the Chinese databases Wanfang Data, Wanfang Med Online, China National Knowledge Infrastructure, and Chongqing VIP Information for RCTs published until September 2019. Trials including &gt; 10 patients were selected. The primary outcomes were overall survival (OS) and intracranial progression-free survival (PFS). We used a frequentist random-effects model for network meta-analysis and assessed the certainty of evidence using the GRADE approach.

RESULTS
Among 8798 abstracts, 106 RCTs (9452 patients) met inclusion criteria. Median sample size was 67 (range 25-554). All trials included adult patients with histologically proven NSCLC and &gt;1 BM proven on CT/MRI. Of trials that reported performance status (e.g. ECOG or KPS, n=67), 63/67 excluded patients with non-favorable performance status. Interventions assessed included surgery, WBRT, SRS, targeted therapies (i.e. EGFR/ALK inhibitors), and chemotherapy. Compared to WBRT alone, several interventions demonstrated a statistically significant increase in median OS, including non-targeted chemotherapy + surgery (MD: 415.3 days, 95% CI: 31.3-799.4), WBRT + EGFRi (MD: 200.2 days, 95% CI:146.3-254.1), and EGFRi alone (MD: 169.7 days, 95% CI: 49.7-289.7). Among all interventions, only WBRT + EGFRi showed a significant improvement in median PFS (MD: 108.0 days, 95%CI: 48.5-167.5).

CONCLUSIONS
Our preliminary analyses indicate an OS and PFS benefit on the addition of EGFR inhibitors to WBRT for the treatment of BMs from NSCLC. Further analyses of hazard ratios for OS/PFS are underway, and subgroup analyses are planned. These data support the growing role of targeted therapies in the treatment of BMs, particularly in susceptible mutant tumours.
SURG-10. PROGNOSTIC IMPORTANCE OF THE EXTENT OF RESECTION IN IDH-WILD TYPE GRADE II ASTROCYTOMAS ACCORDING TO PTERT MUTATION
Authors: Pellerino Alessia , Bruno Francesco , Silvani Antonio , Ius Tamara , Bello Lorenzo , Minniti Giuseppe , Pace Andrea , Lombardi Giuseppe , Soffietti Riccardo , Rudà Roberta 
Published: December 2020

Abstract

BACKGROUND
IDH-wild type diffuse astrocytomas with pTERT mutation have been suggested by cIMPACT-NOW update 3 to share a poor prognosis with glioblastoma (GBM). In a previous series of the Italian Association of Neuro-Oncology, we reported that IDH-wild type grade II astrocytomas benefit from gross total resection. However, the impact of surgery in the pTERT-mutated subgroup has not been addressed so far. Here, we present our preliminary data about the impact of the extent surgery according to pTERT status.

MATERIAL AND METHODS
We re-analysed a national database of 122 patients with grade II IDH-wild type astrocytoma. P-TERT mutation was evaluated by gene sequencing. Kaplan-Meier curves were used for the analysis of progression-free and overall survival (PFS and OS).

RESULTS
Median follow-up was 33.0 months. P-TERT status was available in 40 cases and the mutation was found in 27 cases (67.5%). Patients with pTERT mutation had a significantly shorter PFS (9.4 vs 147.7 months, P &lt; 0.001) and OS (NR vs 36.6 months, P = 0.012). Furthermore, the OS of patients with pTERT mutation, who underwent gross total resection, was significantly longer than in patients with subtotal / partial resection (37.0 vs 32.0 months, P = 0.018). Thus far, the OS of patients without pTERT mutation was not reached with either subtotal / partial or gross total resection.

CONCLUSIONS
IDH-wild type astrocytomas may be stratified into classes with different outcome based on the pTERT mutation. As far as we know, this is the first study that specifically investigated the importance of a gross total resection according to pTERT status in IDH-wild type grade II astrocytomas.
SURG-13. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: A REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED SURGICAL COHORT
Authors: Fadel Hassan , Haider Sameah , Pawloski Jacob , Zakaria Hesham , Chaudhry Farhan , Bartlett Seamus , Bazydlo Michael , Kalkanis Steven , Lee Ian 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection.

METHODS
A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints.

RESULTS
A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p&lt; 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p&lt; 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort.

CONCLUSION
After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.