bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMIC-52. REACTIVE ASTROCYTES AID THE EVOLUTION OF IMMUNOSUPPRESSIVE ENVIRONMENT AND DRIVE ONCOGENIC SIGNALING IN GLIOBLASTOMA
Authors: Heiland Dieter , Ravi Vidhya , Behringer Simon P , Wurm Julian , Beck Juergen , Schnell Oliver 
Published: November 2019

Abstract
Reactive astrocytes are caused by multiple pathologies of the central nervous system, whereby they undergo distinct transcriptomic re-programming. Although the role of reactive astrocytes in some inflammatory diseases has been investigated, many central questions regarding the immunoregulatory functions of tumor-associated astrocytes and their crosstalk to microglia remain poorly understood. In our presented study, we purified astrocytes from various pathologies and different brain tumors to map the transcriptional landscape of reactive astrocytes. We identified the marker genes CHI3L1 and CD274 highly enriched in reactive astrocytes of the marginal astrogliosis scar at the tumor boarder. Human neocortical slices along with a microglia loss-of-function model were used to explore the crosstalk of microglia and reactive astrocytes within the tumor environment. Our results revealed that the reactive phenotype mutually arises from both, microglia and tumor cells. This interaction caused JAK/STAT signalling in reactive astrocytes along with a large release of anti-inflammatory cytokines such as TGFß and IL10. Additionally, inhibition of the JAK/STAT pathway recovered the release of anti-inflammatory cytokines and resulted in a pro-inflammatory environment. Besides the immunosuppressive properties, we found evidence that reactive astrocytes drove AKT and MAPK signaling in the tumor through astrocytic released CHI3L1 and consequential binding to IL13RA2. Our findings revealed increased malignant properties arising from astrocytic-tumor interaction, which were rescued by IL13RA2 inhibition. In a nutshell, reactive astrocytes have decisive regulatory tasks in the microenvironment of CNS tumors. Along with microglia, reactive astrocytes cause the evolution of an immunosuppressive environment and support malignant properties of the tumor.
TMIC-56. ROLE OF HUMAN BRAIN TUMOR STEM CELLS-DERIVED EXTRACELLULAR VESICLES ON THE PHENOTYPIC TRANSDIFFERENTIATION OF HUMAN NEURAL PROGENITOR CELLS
Authors: Zarco Natanael , Norton Emily , Lara-Velazquez Montserrat , Carrano Anna , Quinones-Hinojosa Alfredo , Guerrero-Cazares Hugo 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.
TMIC-61. ROLE OF CX3CR1 SIGNALING IN MALIGNANT TRANSFORMATION OF GLIOMAS
Authors: Lee Sungho , Latha Khatri , Rao Ganesh 
Published: November 2019

Abstract
High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating data suggest that chemokine signaling directly contributes to malignant transformation of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in the malignant transformation of LGGs. First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, a genetically-engineered murine model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. Our data demonstrate that heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism was associated with significantly better median overall survival in patients with LGGs that have transformed to HGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204 positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival. Taken together, our results show that CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated M2 macrophages and microglia and increased angiogenesis.
ACTR-69. FEASIBILITY STUDY OF THE EMULATE THERAPEUTICS™ VOYAGER SYSTEM IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Barkhoudarian Garni , Blondin Nicholas , Chowdhary Sajeel , Fonkem Ekokobe , Vaillant Brian , Kesari Santosh 
Published: November 2019

Abstract

BACKGROUND
The EMulate Therapeutics Voyager system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of brain cancer.

METHODS
This open-label, multi-center study (NAT-109) enrolled adults newly diagnosed with GBM. Following surgical debulking, patients were enrolled and treated concurrently with temozolomide, radiotherapy, and Voyager. The objective of the study is to assess if the Voyager is a safe and feasible treatment for newly diagnosed GBM when combined with standard of care. The primary outcome measure is safety, assessed by the incidence and evaluation of any adverse events (AEs) associated with the Voyager. The secondary outcome measure is clinical utility, assessed by progression-free survival and overall survival.

RESULTS
Enrollment is closed, and treatment and long-term follow-up is ongoing. A total of 37 patients were enrolled and treated. 27 patients reported 282 AEs, none of which required withdrawal from the study. One AE was reported as probably related to the device - i.e., mild dysesthesia, which resolved without interruption or cessation of treatment with the device. 15 patients reported 28 SAEs, and none were reported as related to the device. 56% of patients were progression-free at 6 months, and 43% were progression-free at 12 months. 89% of patients were still alive after 6 months, 71% were still alive after 12 months.

CONCLUSIONS
The Voyager system appears to be safe and feasible for the treatment of newly diagnosed GBM. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is planned.
TMOD-07. IN SITU MICROSCOPY OF DRUG AND IMMUNE CELL INTERACTIONS AGAINST BIOFABRICATED TUMOR MODELS
Authors: McGhee Eric , Uruena Juan , Levings Padraic , van Meter Kylie , Smolchek Ryan , Hood Derek , Flores Catherine , Mitchell Duane , Gregory Sawyer W 
Published: November 2019

Abstract

BACKGROUND & SIGNIFICANCE
Cancer is a disease in 3-dimensions and there is a desperate need for infrastructure and models to study immuno-oncology treatment strategies in 3D. A new culture system for long-duration maturation of patient derived microtumors has been developed. This system enables in situconfocal imaging and movies of T-cells and tumor model interactions, including measurements of T-cell migration, infiltration, and killing. HYPOTHESIS: Biofabrication of 3D microtumors using bioprinting in transparent soft granular gel media can facilitate the precise arrangement and stability of extra-cellular matrix components, tumor, and immune cells while maintaining continuous liquid perfusion.

METHODS
The design, development, and validation of a modular negative pressure perfusion system controls the transport of liquid growth medium, drugs, antibodies, growth factors, and metabolic waste management in 3D. In situ confocal fluorescent microscopy measures cell positions, velocities, and viability during experiments. Steady perfusion velocities are controlled through negative pressure, and velocities from 1–100 nm/s can be achieved.

RESULTS
Cell motility, adhesion, and dynamic rearrangement of fibroblasts and endothelial cells within a 3D co-culture of microtumors evolved dramatically over the first 72 hours. Tracking of activated CD8+ T-cells revealed super-diffusive motion in the presence of 3D tumors with a range of 250 µm. Activated T-cell migration speeds have been measured to be between 1.3–2.0 um/min in the 3D media, and preliminary estimates of T cell migration forces are on the order of 1 nN. Arrival of CD8+ T-cells to the tumors within the first 30 minutes revealed cell killing which continued for over 3-hours and resulted in a 2-fold reduction in tumor cell numbers.

CONCLUSIONS
This integrated system of 3D bioprinting, perfusion culture plates, and confocal microscopy enables in situ3D studies of cancer biology, immunotherapy, and drug treatment regimens and provides unique insights and measurements of immune cell invasion dynamics in 3D microtumors.
TMOD-08. SERUM ESTABLISHED CANCER STEM CELL CULTURES REPRESENT UNIQUE MODELS OF GLIOBLASTOMA INTER-TUMOR HETEROGENEITY
Authors: Maturi Nagaprathyusha , Tan E-Jean , Xie Yuan , Sundström Anders , Bergström Tobias , Casar-Borota Olivera , Jiang Yiwen , Uhrbom Lene 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most frequent primary malignant brain tumor. The invasive and heterogeneous nature of GBM stem cells (GSCs) provide the basis for extreme therapy resistance of GBM and the majority of patients survive less than one year from diagnosis. Relevant models of GBM are important for basic research and drug screening and development, and the current consensus in the field is that GSCs are most faithfully maintained under serum-free neural stem cell (NSC) conditions. We have used serum-free NSC media to explant 230 patient-derived GBM samples, and have in parallel also explanted the same samples in regular serum-containing media. We found, accordingly, that serum-free media was most effective in generating sustainable cultures (137/230, 60%), called serum-free (SF) cultures. Interestingly, we also found that that there was a subgroup of GBM specimens that could only be established in serum-containing media (31/230, 13%), called exclusive serum-containing (eSC) cultures. We characterized a number of the eSC cultures and found that they expressed typical GSC markers such as MSI-1, BMI-1, nestin, CD44 and SOX2. They also displayed all functional characteristics of GSCs, i.e. extended proliferation, sustained self-renewal and orthotopic tumor initiation. Molecular analyses showed that the eSC cultures were most closely related to but separated from mesenchymal subtype GBM. In summary we have established GSC cultures that would have evaded modeling under serum-free conditions, representing unique cell models of GBM inter-tumor heterogeneity. Key words: Glioblastoma, serum cultures, stem-like cells, GBM heterogeneity
TMOD-09. MODELING TERT PROMOTER MUTATION IN ISOGENIC NEXT GENERATION GBM MODELS
Authors: Miki Shunichiro , Koga Tomoyuki , Parisian Alison , Furnari Frank 
Published: November 2019

Abstract
Telomere reverse transcriptase (TERT) promotor mutations increase TERT expression and are known to be the most common single genetic abnormality in Glioblastoma (GBM). Recent studies have revealed this mutation to be an early event in gliomagenesis but it is detected subclonally in a considerable number of cases. Due to the long telomere length and TERT expression in somatic cells of mice, genetically engineered mouse models of GBM do not address the function of this mutation and thus an ideal heterozygous TERT promotor mutation model is yet to be established. Recently, our lab established strategies for generating GBM models using neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) that have been CRISPR/Cas9 engineered with different combinations of authentic GBM-related genetic drivers which can be used for introduction of mutant TERT promotor (MTP) sequence and examination of its function. We obtained multiple heterozygous MTP hiPS clones in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, using a two-step targeting approach. Two single-strand guide RNAs (sgRNAs) were used to delete the TERT promotor and a portion of exon 1 followed by repair of the locus with wild type TERT promoter (WTP) and MTP sequence. Following promoter reconstitution, TERT promotor function was tested in iPSCs, NPCs, and astrocytes. This analysis revealed successful TERT expression silencing in WTP astrocytes. Furthermore, orthotopic injection of WTP and MTP NPCs into immunodeficient mice formed pathologically similar GBM-like tumors in same period of time. TERT expression was only detected in cell lines derived from MTP tumors, indicating TERT promotor mutation has little impact in initiation of tumor formation from NPCs, explaining its subclonality in patient tumors. Our model enables further research on MTP function and dependency during gliomagenesis.
TMOD-15. IDENTIFYING THE SPATIAL AND TEMPORAL DYNAMICS OF GLIOBLASTOMA SUBPOPULATIONS WITHIN INDIVIDUAL PATIENTS
Authors: Morris Bethan , Curtin Lee , Hawkins-Daarud Andrea , Bendok Bernard , Mrugala Maciej , Li Jing , Tran Nhan , Hu Leland , Rahman Ruman , Smith Stuart , Auer Dorothee , Hubbard Matthew , Owen Markus , Swanson Kristin 
Published: November 2019

Abstract
Glioblastomas (GBMs) are known to be complex tumors comprising multiple subpopulations of genetically-distinct cancer cells; it is thought that this genetic variation is a major factor in the lack of observed survival benefit of treatment regimes that target one of these subpopulations. The field of radiogenomics seeks to study correlations between MRI patterns and genetic features of GBM tumors. Spatial radiogenomic maps produced using machine-learning (ML) methods that are trained against information from image-localized patient biopsies identify regions where particular cancer sub-populations are predicted to occur within a GBM, thus non-invasively characterizing the regional genetic variability of these tumors. These tumor subpopulations may also interact with one another, in ways which may be of a competitive or cooperative nature to varying degrees. It is important to ascertain the nature of these interactions, as they may have implications for treatment response to targeted therapies, and characterization of the spatio-temporal dynamics of these co-evolving sub-populations will shed light on why some therapies fail. Here we combine mathematical modeling techniques and spatially-resolved radiogenomic maps to study the nature of these interactions between molecularly-distinct GBM subpopulations. We model the interactions between cell populations using a partial differential equation based formalism. The model is parameterized using radiogenomic ML maps from which we infer the nature of interactions between subpopulations. Furthermore, using maps as inputs, the model turns static maps into dynamic information, thus providing insight into how these subpopulations composing the tumor change over time and the effect this has on observed treatment response for individual patients.
TMOD-18. EXPLORING THE FACTORS LEAD TO SUCCESS OF CAR T-CELL THERAPY IN GLIOBLASTOMA WITH COMPUTATIONAL MODELING AND IN VITRO DATA
Authors: Sahoo Prativa , Yang Xin , Abler Daniel , Maestrini Davide , Adhikarla Vikram , Brown Christine E , Rockne Russell 
Published: November 2019

Abstract
Chimeric antigen receptor (CAR) T-cell therapy is an emerging targeted immunotherapy which has shown success in liquid cancers such as leukemias. CAR T-cells are also being used for the treatment of solid tumors such as glioblastoma, which is a primary brain tumor. Ongoing phase I trials have been designed to evaluate CAR T-cell dosing, scheduling, and route of administration in order to understand and improve the efficacy of CAR T-cell therapy. A better understanding of factors leading to the success of CAR T-cell immunotherapy for solid tumors will be necessary to improve outcomes for patients with solid tumors and to advance the field of CAR T-cell immuno-oncology. Here we use mathematical model to explore factors in determining a successful response to CAR T-cell therapy: proliferation, persistence, and killing capacity of CAR T-cells. Using a novel in vitro experimental apparatus, we are able to measure the density of cancer cells over several days in 15 minute interval time resolution. This highly temporally resolved data provides a unique opportunity to confidently estimate parameters of the model and to provide insights into the dynamics of CAR T-cell proliferation, persistence, and killing capacity. Furthermore we explore the relationship between these factor with CAR T-cell dose level. We will show results from experiments using patient-derived cancer cell lines as well as cancer cells engineered to express specific levels of the target antigen (IL13Rα2) to quantitatively evaluate the roles of proliferation, persistence, and killing in cells with different levels of antigen expression. We will discuss the interpretation of the model parameters and demonstrate the clinical value of this analysis through an application of CAR T-cell treatment tailored to the dynamics of an individual patient’s cancer growth rate.
TMOD-20. COMBINING TARGETED INHIBITOR AND RADIOTHERAPY IN TREATING ANAPLASTIC MENINGIOMA
Authors: Wang Yufen , Horbinski Craig , James Charles , Sathiaseelan Vythialingam , Kalapurakal John 
Published: November 2019

Abstract

BACKGROUND
Anaplastic meningiomas pose a serious health concern due to their propensity for recurrence and brain invasion. Five-year overall survival of patients with anaplastic meningiomas is less than 10%, similar to that of glioblastoma patients. Standard treatment of recurrent anaplastic meningioma is radiotherapy (RT), but radioresistance is common. New therapeutic strategies, used singularly or in combination with RT, are urgently needed. Since deletion of the gene encoding the p16 cell cycle checkpoint protein is common in anaplastic meningioma, we hypothesized that such tumors would be sensitive to Palbociclib, a cdk4/6 inhibitor, and that Palbociclib could enhance RT efficacy.

METHODS
CH157 anaplastic meningioma cells were used in vitro for investigating tumor cell proliferation response to RT and Palbociclib, either alone or in combination, and as indicated by MTT assay results. CH157 cells were also used to establish intracranial xenografts in mice treated with RT or Palbociclib. Accuracy of RT dose was verified with calibrated MOSFET\OSLD dosimeters. Mice were monitored for intracranial tumor growth and response to treatment, as indicated by bioluminescence imaging. Length of survival data was collected and analyzed by log-rank test.

RESULTS
At two days post RT, the in vitro anti-proliferative effect of 2, 6, and 10 Gy radiation was significantly enhanced with concurrent 1mM Palbociclib (p < 0.001). Daily administration of Palbociclib (150 mg/kg) for 1 week significantly extended the survival of mice with intracranial CH157 xenografts (group mean value of 18.4 vs. 13.6 days with vehicle control, p < 0.001). A single dose of 10 Gy RT was superior to 6 Gy administered 1x and 2Gy/day administered on 5 consecutive days (group mean values of 37.4 vs. 24.0 vs. 24.6, respectively: p < 0.001).

CONCLUSIONS
These data support further investigation of RT + Palbociclib for treating p16-deficient anaplastic meningiomas.
TMOD-21. TARGETING ANAPLASTIC MENINGIOMA WITH PANOBINOSTAT IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODELS DERIVED FROM A MATCHING PAIR OF PRIMARY AND RECURRENT TUMORS
Authors: Zhang Huiyuan , Qi Lin , Du Yuchen , Braun Frank , Kogiso Mari , Huang Lei , Klisch Tiemo , Zhao Yanling , Guo Lei , Li Can , Zhao Sibo , Lindsay Holly B , Injac Sarah , Baxter Patricia , Su Jack , Stephan Clifford , Keller Charles , Yang Jianhua , Li Xiao-Nan , Patel Akash 
Published: November 2019

Abstract

BACKGROUND
Meningioma is the most common brain tumor in adults. Despite the overall benign nature of meningioma, skull base tumors can be difficult to completely resect while others exhibit progression and aggressive profiles. The lack of clinically relevant animal models is blocking the development of novel therapies.

MATERIAL AND METHODS
Twelve surgical specimens (1 × 105) from 11 adult meningioma patients were implanted into the frontal cranial-base of the brain of SCID mice. Mice were then followed and assessed for tumor formation. Tumor growth was confirmed by small animal MRI. Pathologic features of the PDOX models and the matched patient tumors were compared with standard H&E and immunohistochemical staining. RNAseq was performed to examine the molecular fidelity of PDOX tumors and to identify new therapeutic targets. A panel of 60 clinically-relevant drugs was developed for screening drug sensitivity. In vivo examination of therapeutic efficacy of Panobinostat was performed in two models by treating preformed PDOX tumors with i.p. injection (10 mg/kg), 5 days on, 5 days off for 2 cycles.

RESULTS
Intracranial xenograft formation was confirmed in two samples derived from the same patient, the first an atypical meningioma (K029MEN-P) and the second, which progressed to anaplastic meningioma at recurrence (K029MEN-R). MRI scanning revealed that the PDOX tumors grew from the skull base. These patient tumor cells can be cryopreserved for long-term maintenance of tumorigenicity. The xenograft tumors replicated histopathological features of parental tumors. Overall gene expression profiles of PDOX were similar to the original patient tumors. Using MEN primary culture cells, we screened 60 drugs and identified 12 (20%) active compounds. Panobinostat also significantly prolonged survival of mice bearing orthotopic meningiomas.

CONCLUSION
A set of meningioma PDOX models derived from primary and recurrent tumor was established. Our data further demonstrate that panobinostat exerts potent antitumor activity against high-grade meningioma.