bluuebunny/crossref_metadata_2025_split huggingface dataset:
RTID-07. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS (CYNK-001) FOR TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Majd Nazanin , Rizk Maha , Ericson Solveig , Grzegorzewski Kris , Koppisetti Sharmila , Zhu Junhong , Kang Lin , He Shawn , Mahlakoiv Tanel , van Der Touw William , Zhang Xiaokui , Habboubi Nassir , Hariri Robert , Hunter Kathy , Alfaro-Munoz Kristin , Heimberger Amy , de Groot John , Chi Linda , Srour Samer 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor with dismal prognosis. Recent advances of immunotherapy in cancer have sparked interest in the use of cell therapy for treatment of GBM. Active transfer of Natural Killer (NK) cells is of particular interest in GBM because NK cells are capable of exerting anti-tumor cytotoxicity without the need for antigen presentation and sensitization, processes that are impaired in GBM. CYNK-001 is an allogeneic, off-the-shelf product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells manufactured by Celularity. Here, we demonstrate in vitro cytotoxicity of CYNK-001 against several GBM lines and its in vivo anti-tumor activity in a U87MG orthotopic mouse model via intracranial administration resulting in 94.5% maximum reduction in tumor volume. We have developed a phase I window-of-opportunity trial of CYNK-001 in recurrent GBM via intravenous (IV) and intratumoral (IT) routes. In the IV cohort, subjects receive cyclophosphamide for lymphodepletion followed by 3-doses of IV CYNK-001 weekly. In the IT cohort, subjects undergo placement of an IT catheter with an ommaya reservoir followed by 3-doses of IT CYNK-001 weekly. Patients are monitored for 28-days after last infusion for toxicity. Once maximum safe dose (MSD) is determined, patients undergo IV or IT treatments at MSD followed by surgical resection and the tumor tissue will be analyzed for NK cell engraftment and persistence. We will utilize a 3 + 3 dose de-escalation design (maximum n=36). Primary endpoint is safety and feasibility. Secondary endpoints are overall response rate, duration of response, time to progression, progression free survival and overall survival. Main eligibility criteria include age ≥18, KPS ≥60, GBM at first or second relapse with a measurable lesion on ≤2mg dexamethasone. This is the first clinical trial to investigate CYNK-001 in GBM and will lay the foundation for future NK cell therapy in solid tumors.
STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA
Authors: Nikolic Ana , Bobyn Anna , Ellestad Katrina , Lun Xueqing , Johnston Michael , Gafuik Christopher , Zemp Franz , Ninkovic Nicoletta , Berger Daniel , Brownsey Duncan , Dirks Peter , Derksen Darren , Senger Donna , Chan Jennifer , Mahoney Douglas , Gallo Marco 
Published: December 2020

Abstract
Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.
SURG-09. EXTRAOPERATIVE CORTICAL MAPPING VIA IMPLANTED SUBDURAL AND DEPTH ELECTRODES FOR MAXIMIZING ELOQUENT AREA GLIOMA RESECTION
Authors: Fountas Konstantinos , Paschalis Thanasis , Kapsalaki Eftychia 
Published: December 2020

Abstract

OBJECTIVE
Aggressive, even supramarginal, resection without compromising the neurological status of the patient remains a great challenge in the management of glioma cases. Accurate cortical and subcortical functional mapping allows more radical glioma resection. Numerous imaging, electrophysiological, and hybrid methodologies have been employed in the cortical mapping of patients with gliomas in eloquent areas. Despite the recent advances of these non-invasive modalities, direct electrical cortical and subcortical stimulation and mapping through an awake craniotomy remains the gold standard for maximal glioma resection and preservation of eloquent cortex functions. Extraoperative stimulation and mapping via implanted subdural and/or depth electrodes may be a valid alternative mapping method in these cases that an awake procedure is not feasible. The role of this mapping method is examined in our current study.

MATERIAL & METHODS
In a retrospective study, 51 patients undergoing extraoperative stimulation and mapping for glioma resection were included. The demographic data, the clinical characteristics, the stimulation parameters and complications, the extent of resection, the perioperative complications, and the tumor histological grade were analyzed. Shapiro-Wilk test, as well as uni- and multi-variate regression analysis was used for our statistical analysis.

RESULTS
The mean age of our participants was 58 (SD: 9.4) years. The location of the glioma was on the left side in 80.4%, while the frontal lobe was affected in 51.0%. Extraoperative cortical and subcortical stimulation and mapping was successful in 94.1%. The median stimulation procedure was 2.0 hours, while the median implantation time was 72 hours. Stimulation-induced seizures occurred in 13.7%, while CSF leakage in 5.9% of our cases. The mean extent of resection was 91.6%, while transient dysphasia occurred in 21.6%, and transient hemiparesis in 5.9% of our cases.

CONCLUSIONS
Extraoperative stimulation and mapping constitutes a valid alternative mapping option in glioma patients, who cannot undergo an awake craniotomy.
SURG-33. ROLE OF SURGERY IN TREATING EPSTEIN-BARR VIRUS-ASSOCIATED SMOOTH MUSCLE TUMOR (EBV-SMT) WITH CENTRAL NERVOUS SYSTEM INVASION: A SYSTEMIC REVIEW
Authors: Chen Ko-Ting , Lau Ka-Wei , Hsu Yu-Wei , Lin Yin-Ting 
Published: December 2020

Abstract
Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor that almost exclusively occurs in immunocompromised hosts. The term unknown malignant potential once used interchangeably to describe EBV-SMT and the less invasive clinical behavior than leiomyosarcoma indicate an indolent growth pattern of EBV-SMT. Nevertheless, an EBV-SMT with CNS invasion would result in neurological deficits which may jeopardize patients’ survival.We provide a systemic review of literature under PRISMA guideline on the clinical features, treatment modalities, role of surgery intervention and outcomes of all 65 reported EBV- SMTs with central nervous system (CNS) invasion. Over 95% of the reported cases were immunocompromised, while human immunodeficiency virus infection and post- organ transplantation being the most commonly associated underlying causes (near 90%). A 76.0% 1-year survival rate and 59.6% 5-year survival rate confirms the indolent and non-deadly nature of EBV-SMT even with CNS invasion. An immune survey and reconstruction should be conducted for every patient with CNS EBV-SMT. Surgical resection is mostly adopted as primary treatment to acquire diagnosis and relieve compressive effect. A total resection of tumor may be beneficial if tumor was symptomatic and had intracranial invasion
TAMI-23. NEUTROPHIL-TRIGGERED FERROPTOSIS PROMOTES TUMOR NECROSIS IN GLIOBLASTOMA PROGRESSION
Authors: Yee Patricia , Wei Yiju , Kim Soo Yeon , Lu Tong , Lawson Cynthia , Tang Miaolu , Liu Zhijun , Anderson Benjamin , Young Megan , Thamburaj Krishnamoorthy , Aregawi Dawit , Glantz Michael , Zacharia Brad , Specht Charles , Wang Hong-Gang , Li Wei 
Published: December 2020

Abstract
Tumor necrosis indicates poor prognoses in many cancers, including glioblastomas (GBMs). Although thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscured by lack of animal models recapitulating the extent of necrosis in human GBMs. The molecular and clinical heterogeneity of GBMs adds further complexity. Not all GBMs contain necrosis. Mesenchymal (MES)-GBM, the subtype correlated with worst prognosis and highest treatment resistance, is most closely associated with necrosis. MES-GBM exhibits hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in human GBMs predicts short survival. To elucidate mechanisms driving GBM necrosis, we devised a novel orthotopic mouse model recapitulating human MES-GBM phenotypically and histopathologically by expressing a constitutively-active TAZ mutant (TAZ4SA) in three human GBM cell lines (LN229, U87, and LN18) lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter than mice implanted with GBMvector or mutant TAZ unable to bind its downstream effector, TEAD (GBM4SA-S51A). Extensive (≥30% of tumor volume) necrosis was present in GBM4SA mice but not GBMvector or GBM4SA-S51A. In GBM4SA tumors, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse tumors killed co-cultured tumor cells. Neutrophils induce iron-dependent accumulation of lipid hydroperoxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibiting myeloperoxidase suppresses neutrophil-induced tumor cytotoxicity. Intratumoral glutathione peroxidase 4 (GPX4) overexpression or acyl-CoA synthetase 4 (ACSL4) depletion diminishes necrosis and aggressiveness of tumors. Human GBM analysis indicates neutrophils and ferroptosis are associated with necrosis and predict poor survival. Together, we propose that certain tumor damage(s) during early tumor progression (i.e. ischemia) recruits neutrophils to damaged tissue and results in a positive feedback loop, amplifying GBM necrosis development. We show GBM necrosis involves neutrophil-triggered ferroptosis and reveal an unprecedented pro-tumorigenic role of ferroptosis.
TAMI-31. MACROPHAGE M1 INVASION PREDICTS POOR PROGNOSIS OF GLIOMA AND REVEALS A STRATEGY FOR GLIOBLASTOMA THERAPY
Authors: Zhou Zhaoming , Wen Lei , Shan Changguo , Lai Mingyao , Zhou Cheng , Cai Linbo 
Published: December 2020

Abstract

BACKGROUND
Glioma is one of the most malignant tumors in the central neural system, due to a lack of efficient immune therapy targets. Here we explored the transcriptional information of gliomas with the aim to discover novel biomarkers for glioma classifying in the aspects of prognosis and immune therapy targets prediction.

METHODS
We explored the gene expression data from the Chinese Glioma Genome Atlas (CGGA). The extracellular matrix (ECM) and immune cells abundance of gliomas were evaluated on the transcriptional level by the ECM score and cell infiltration enrichment score.

RESULTS
Based on top differentially expressed genes (DEGs), ECM scores showed significantly differences between various grades (WHO II, III, and IV) of gliomas (p values &lt; 0.0001). Cell infiltration enrichment scores of macrophages, macrophages M1, and monocytes showed positively correlated with the ECM scores by the linear regression analysis (r = 0.51, 0.54, and 0.62, respectively; p values &lt; 0.0001). Variation-partitioning analysis indicated that macrophages, macrophages M1, and monocytes played dominant roles in the variances between WHO II, WHO III, and WHO IV gliomas. Survival association analysis showed that patients with higher infiltration of macrophages, macrophages M1, and monocytes shared shorter overall survival (OS). OS of glioblastoma (GBM) were determined to be shorter in high macrophages M1 enrichment group (p &lt; 0.0001). Univariate and multivariate analysis of clinical characteristics with OS in GBM cohort demonstrated that macrophages M1 enrichment score was an independent survival risk factor for GBM patients. Further subgroup survival association analysis showed that the higher M1 macrophages enrichment score was associated with higher OS in IDH wildtype GBM patients (p = 0.011).

CONCLUSIONS
This study demonstrates Macrophages M1 infiltration level as a poor prognostic factor for glioma and suggests macrophages M1 could be the potential immune therapy targets for IDH-wild-type GBM patients.
TAMI-62. ANGIOGENESIS INHIBITORS STRONGLY SYNERGIZE WITH THERAPEUTICS TARGETING TUMOR METABOLISM
Authors: Khadka Sunada , Lin Yu-Hsi , Ackroyd Jeffrey , Arthur Kenisha , Barekatain Yasaman , Poral Anton , Tran Theresa , Georgiou Dimitra , de Groot John , Huse Jason , Asara John , Muller Florian 
Published: December 2020

Abstract
Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates as state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that Angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.
TMOD-19. INDIVIDUAL SPECIFIC HUMAN GUT MICROBE COMMUNITIES INFLUENCE RESPONSE TO IMMUNOTHERAPY IN A HUMANIZED MICROBIOME MOUSE MODEL OF GLIOMA
Authors: Dees Kory , Koo Hyunmin , Humphreys J Fraser , Hakim Joseph , Crossman David , Crowley Michael , Nabors Louis , Benveniste Etty , Morrow Casey , McFarland Braden 
Published: December 2020

Abstract
Although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in GBM patients. Since recent studies have linked the gut microbial composition to the success with immunotherapy for other cancers, we utilized a novel humanized microbiome (HuM) model in order to study the response to immunotherapy in a pre-clinical mouse model of GBM. We used five healthy human donors for fecal transplantation of gnotobiotic mice since it is now recognized that microbe strain level differences render individual humans with a unique microbial community composition. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (humanized microbiome HuM1-HuM5). Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome composition with significant differences in diversity and microbial composition among HuM1-HuM5 lines. We next analyzed the growth of intracranial glioma cells in the HuM lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19-26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are non-responders to anti-PD-1 resulting in the death of the mice from the intracranial tumors, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that HuM2 and HuM3 were closely related. Detailed taxonomic comparison analysis at the top 5 across all HuM mouse lines revealed that Bacteroides cellulosilyticus was commonly found between HuM2 and HuM3 with high abundances. The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbe communities needed for effective immunotherapy against GBM.
TMOD-26. ESTABLISHING A PATIENT-DERIVED, IN-VITRO ORGANOTYPIC SLICE CULTURE MODEL OF GBM
Authors: Rappoldt Liam , Weeks Adrienne , Ouellete Rodney , Roy Jeremy , Taylor Catherine , McCormick Craig , Attwood Kathleen , Kim Inhwa 
Published: December 2020

Abstract
Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumour. This tumour is universally fatal with a median survival of 15 months. Driving this pathology is an extremely heterogeneic tumour and complex tumour microenvironment. GBM research is primarily conducted using immortalized or primary cell lines due to their practicality and reproducibility. However, these cell lines do not effectively recapitulate the tumour microenvironment. Mouse models address these shortcomings but are laborious and expensive. We propose to utilize a patient derived organotypic culture model of GBM as an intermediary. We have utilized this model to test genetic manipulation via lentiviral transduction and the feasibility of utilizing this model to understand patient derived extracellular vesicles (EVs). We have sectioned and cultured patient derived organotypic models for 14 days without loss of viability. To determine if these organotypic cultures are amenable to lentiviral manipulation, tissue sections were transduced with far-red fluorescent lentivirus and efficiency determined by confocal laser scanning microscopy (CLSM) and flow cytometry (FC). To determine feasibility as a model for EVs, media obtained from patient-derived organotypic cultures was analyzed by western blot, nanoparticle tracking analysis (NTA), and nanoFlow Cytometry (nFC). In the future these EVs will be compared to those found in patient serum. The model of GBM has been lentivirally transduced to express a far-red fluorescent vector in approximately 15% of the slice, quantified by CLSM and FC. EV-sized particles positive for canonical EV markers have been identified in the media by NTA, nFC and western blot. Using lentiviral-mediated genetic engineering and emerging EV science, this organotypic slice culture models yields exciting utility in GBM research. The established organotypic slice culture model will likely be a valuable tool in the study of GBM biology and EV dynamics.
ATRT-06. SMARCB1 LOSS DRIVEN NON-CANONICAL PRC1 ACTIVITY REGULATES DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS (ATRT)
Authors: Alimova Irina , Danis Etienne , Weetall Marla , Pierce Angela M , Wang Dong , Serkova Natalie , Balakrishnan Ilango , Madhavan Krishna , Sanford Bridget , Michel Cole , Foreman Nicholas K , Baird John , Venkataraman Sujatha , Vibhakar Rajeev 
Published: December 2020

Abstract
Loss of SMARCB1 is the hallmark genetic event that characterizes ATRT. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. To identify co-operating epigenetic factors, we performed an unbiased shRNA screen targeting 408 epigenetic/chromatin molecules in patient-derived ATRT cell lines and identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability. Genetic and Chemical inhibition of BMI1 inhibited clonogenic potential and induced apoptosis in vitro. In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors as evaluated by T2 MRI imaging and significantly prolonged survival compared to control animals. Using RNA-seq and ChIP-Seq our studies show that BMI1 co-operates with SMARCB1 loss to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We then used a doxycycline-inducible SMARCB1 expression system and performed Immunoprecipitation for BMI1, followed by and mass spectrometry analysis. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. Re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. CBX4 is implicated DNA damage response, tumor angiogenesis and self-renewal. CBX8 activates lineage-specific genes during differentiation of ESC. Our data suggest that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex. These studies identify the mechanistic basis of BMI1 co-operation with SMARCB1 loss in ATRT and establish BMI1 inhibition as a novel therapeutic approach in ATRT.