bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-05. IN VIVO REPROGRAMMING OF POSTMITOTIC NEURONS INDUCES MEDULLOBLASTOMA
Authors: Aiello Giuseppe , Tiberi Luca 
Published: November 2019

Abstract
It is widely accepted that the “cell of origin” of tumors has to possess a proliferative capacity. Particularly for brain cancer, the transition of neural progenitors to differentiated postmitotic neurons is considered irreversible in physiological and pathological conditions. Therefore, postmitotic neurons have not been considered as suitable cell-of-origin for brain cancer. Here, we show that neurons reprograming may occur upon Shh activation and it leads to medulloblastoma (MB) formation in vivo. Shh MB is a cerebellar tumor, found in infants and adults that is thought to originate from cerebellar granule neuron progenitors. More recently, it was discovered that the two different forms of SHH MB are distinguished by different transcriptome/methylome levels suggesting that the adult SHH MB may originate from a different cell-of-origin. Relying on these data, we take advantage of a conditional Cre-Lox recombination system to recapitulate the human adult medulloblastoma pathogenesis in mice and demonstrate that post-migratory mature granule neurons can be reprogrammed in vivo. Furthermore, to define the contribution of chromatin changes in granule neurons dedifferentiation in response to Shh activation, we profiled changes in chromatin accessibility by ATAC-seq both in mouse tissue samples and also in human neurons. Upon Shh pathway activation we detected the presence of hyper-accessible chromatin regions corresponding to cis-regulatory elements specifically favouring activation of enhancers and super-enhancers. Our novel model of cancer development could explain the human SHH medulloblastoma onset in adult individuals where granule neuron progenitors are no more present. We strongly believe that our model represents an important starting point to study other tissues where postmitotic cells might originate cancer and therefore open a new field in cancer and stem cell biology.
TMOD-12. THE ROLE OF INTEGRIN α V AND CD44 IN GBM MIGRATION USING HUMAN ORGANOTYPIC SLICES
Authors: Binder Zev , Hyun Ji Kim Sarah , Wu Pei-Hsun , Giri Anjil , Gallia Gary , Pardo-Villamizar Carlos , Wirtz Denis 
Published: November 2019

Abstract
Current model systems used for GBM research include traditional in vitro cell line-based assays and in vivo animal studies. In vitro model systems offer the advantages of being easy to use, relatively inexpensive, and fast growing. However, these models lack key elements of the pathology they are attempting to model, including the biochemical and biophysical microenvironment and three-dimensional structure inherent to human brain tissue. In vivo model systems address these limitations, but have restrictions of their own. Species differences may result in non-applicable results and animal experiments are often not designed like clinical trials. Evidence of the limitations of current GBM models is found in the disparity between basic research findings and successful new treatments for GBMs in the clinic. Here we present an alternative model system for the study of human GBM cell motility and invasion, which features advantages of both in vitro and in vivo model systems. Using human organotypic brain slices as scaffolding for tumor growth, we explored the dynamic process of GBM cell invasion within human brain tissue. To demonstrate the utility of the model system, we investigated the effects of depletion of integrin α V (ITGAV) and CD44 on GBM cell motility. These two cell-surface proteins have been identified to have key functions in GBM cell motility. However, knockdown of ITGAV had little effect on tumor cell motility in organotypics while CD44 knockdown significantly reduced cell movement. Finally, we compare motility results from cells in human brain slices to those from cells growing on standard Matrigel and in mouse brain organotypics. We found significant differences in motility depending on the substrate in which the cells were moving. Our findings highlight the physiologic characteristics of human brain organotypics and demonstrate the use of real-time imaging in the ex vivo system.
TMOD-14. RADIOGRAPHIC, STIMULATED RAMAN HISTOLOGIC, AND MULTIPLEXED RNA-SEQUENCING ANALYSIS OF POST-TREATMENT RECURRENT HIGH-GRADE GLIOMAS
Authors: Save Akshay , Hollon Todd , Farooq Zia , Boyett Deborah , Hawkins-Daarud Andrea , Yoon Hyunsoo , Singleton Kyle , Clark-Swanson Kamala , Li Jing , Swanson Kristin , Freudiger Christian , Orringer Daniel , Lassman Andrew , Sims Peter , Grinband Jack , Canoll Peter , Bruce Jeffrey 
Published: November 2019

Abstract
High-grade gliomas (HGGs) nearly always recur after standard initial treatment, and the resulting mixture of recurrent tumor and treatment-induced reactive changes presents major diagnostic challenges. Anatomical imaging, such as MRI, cannot adequately distinguish progressive disease from treatment effect (pseudo-progression). Furthermore, there is marked intra-tumoral heterogeneity, such that some areas of a tumor may demonstrate necrotic treatment effect and others frank recurrence. Due to this difficulty reliably differentiating between these two clinical findings, analytic methods using multiple modalities are necessary to further our understanding of this disease process. To this end, we sought to correlate radiographic, histopathologic and molecular features of surgically sampled post-treatment suspected recurrence to identify markers distinguishing tumor growth from treatment effect. We performed Stimulated Raman Histology (SRH) imaging and highly multiplexed RNA-sequencing (PLATE-seq) on 84 MRI-localized biopsies from 39 patients with clinically suspected recurrent HGG. The SRH images were classified as recurrent tumor or gliotic/reactive tissue using a convolutional neural network trained on an independent cohort including a large set of recurrent HGG, and an automated cell-counting algorithm was used to quantify cellularity from the SRH image of each sample. Differential gene expression analysis of the PLATE-seq data was used to identify gene sets that distinguish recurrent tumor from treatment effect, and single sample gene set variation analysis (GSVA) was used to further assess the molecular and cellular composition of each MRI-localized sample. The histopathologic and molecular features of each sample were also correlated with the MRI features of the corresponding biopsy sites, and this data is currently being used to train machine learning models that predict the distribution of recurrent tumor and treatment-induced reactive changes within a patient’s radiographic lesion. These predictive radiomic models will help to guide neurosurgical sampling, and improve our ability to monitor glioma progression and response to therapy.
TMOD-16. MULTIFUNCTIONAL NANOPARTICLES USED FOR MAGNETIC RESONANCE/NIR FLUORESCENCE DUAL-MODAL IMAGING AND CHEMOTHERAPY OF GLIOMA
Authors: Zhao Shiguang 
Published: November 2019

Abstract

PURPOSE
Glioma is the most common malignant brain tumor and infamous for its high invasiveness and lethality. Therefore, plenty of techniques like intraoperative MRI (iMRI) and fluorescence-guided surgery were performed to improve the surgical resection rate of glioma. In addition, the chemotherapy effect of glioma was severely restricted because of the low blood-brain barrier (BBB) permeability of traditional therapeutic drugs. Doxorubicin (DOX) is a widely used antineoplastic drug, but its application in glioma therapy is prevented by the BBB. Thus, it is urgent to develop novel diagnostic methods and drug delivery systems to improve glioma treatment effect.

MATERIALS AND METHODS
In this study, we constructed a multifunctional nanotheranostic agent which integrated MR imaging, fluorescence imaging and targeting chemotherapy for glioma by encapsulating iron oxide nanoparticles, DOX and indocyanine green (ICG) with PEGylated phospholipid.

RESULTS
The obtained multifunctional were proved with an average diameter of 22.9 nm. In vitro cell experiments demonstrated that the nanoparticle effectively enhanced cellular uptake of DOX compared with that of free DOX. In vivo MR and fluorescence imaging not only demonstrated that the nanotheranostic agent effectively crossed the BBB and selectively accumulated at the tumor area, but also easily monitored the real-time therapeutic outcome. Among all treatment groups, C6 glioma-bearing rats treated with nanoparticles exhibited the maximal degree of efficacy, including the longest survival times and smallest tumor volume.

CONCLUSION
All these results suggested that the multifunctional nanoparticles could be simultaneously used for iMRI and fluorescence-guided surgery to increase the resection rates, as well as delivering chemotheraputic drugs to tumor site to improve therapeutic effect. We believe that this multifunctional nanoparticle might serve as a potential theranostic treatment for glioma in the near future.
TMOD-19. ELUCIDATING THE RESISTANCE TO IMMUNOTHERAPY IN BRAIN TUMORS USING A HUMANIZED MICROBIOME MOUSE MODEL
Authors: Dees Kory , Koo Hyunmin , Hakim Joseph , Fraser Humphreys J , Crossman David , Crowley Michael , Nabors Louis , Benveniste Etty , Morrow Casey , McFarland Braden 
Published: November 2019

Abstract
Although the immunotherapy anti-PD-1 works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated a similar efficacy in patient clinical trials. Recent studies have linked the gut microbe composition to tumor growth and response to immunotherapy in some cancers. To date, all GBM pre-clinical studies have been done in mouse models using mouse gut microbiomes. There are significant differences between mouse and human microbial gut compositions, with up to 85% of gut bacteria found in laboratory mice not found in humans. Because it is known that the gut microbe composition can impact the immune system, we hypothesize that the non-responsiveness of GBM patients to immunotherapy may be due to the composition of the gut microbiome. Therefore, we have generated a humanized microbiome mouse model in which mice have been colonized by human donor microbes in their GI tract (two different healthy human donors (HuM1 and HuM2)). In preliminary results, we have found that HuM1 mice are resistant to anti-PD-1, while HuM2 mice are responders to anti-PD-1 in the GL261 syngeneic intracranial model. These mice are genetically identical and only differ in gut microbiome composition. Furthermore, we found that HuM2 mice exhibited a significant increase in cytotoxic CD8+T-cells producing IFN-γ and significant increased CD8+/Treg ratio in the spleen following anti-PD-1 treatment, which was not observed in the HuM1 mice. When testing the efficacy of standard of care temozolomide (TMZ) in our humanized mice, we found that TMZ significantly prolonged survival of both HuM1 and HuM2 mice with intracranial tumors. However, HuM2 mice exhibited superior efficacy (p< 0.001; 57% survival), compared to HuM1 mice (p< 0.01; 0% survival). We are extending these studies to analyze additional humanized microbiome lines as well as GBM patient donor lines to more accurately understand individual responses to tumor growth and responsiveness to therapies.
TMOD-27. A NEURAL CREST CELL SUBPOPULATION UNDERLIES INTRATUMOR HETEROGENEITY IN MENINGIOMA
Authors: Magill Stephen , Vasudevan Harish , Seo Kyounghee , John Liu S , Hilz Stephanie , Villanueva-Meyer Javier , Choudhury Abrar , Demaree Benjamin , Lim Daniel , Braunstein Steve , Ann Oberheim-Bush Nancy , Ullian Erik , Aghi Manish , Theodosopoulos Philip , Sneed Patricia , Abate Adam , Berger Mitchel , McDermott Mike , Costello Joseph , Raleigh David 
Published: November 2019

Abstract

BACKGROUND
Meningiomas are the most common primary intracranial tumor, and high grade meningiomas are resistant to most cancer therapies. Intratumor heterogeneity is a recognized source of resistance to treatment in numerous malignancies. Thus, we hypothesized that investigating molecular heterogeneity in meningiomas would elucidate biologic drivers and shed light on tumor evolution and mechanisms of resistance.

METHODS
We collected 86 spatially distinct samples at the time of resection from 13 meningiomas. Seven meningiomas were WHO grade I (46 samples), three were grade II (22 samples), and three were grade III (18 samples). Seven meningiomas were sampled at the time of salvage surgery (48 samples), and 6 were sampled at the time of initial diagnosis (38 samples). We performed multiplatform molecular profiling of these samples to identify drivers of intratumor heterogeneity, and validated our results using meningioma cells co-cultured with human cerebral organoids and RNA sequencing of paired primary and recurrent meningiomas.

RESULTS
Using bulk RNA sequencing, DNA methylation profiling and phylogenetic analysis of spatially distinct samples, we discovered significant transcriptomic, epigenomic and genomic heterogeneity in meningioma. In particular, we identified chromosomal structural alterations and differences in immune and neuronal signaling that underlie clonal evolution in high grade tumors. Using MRI-stratified bulk RNA sequencing, single nuclear RNA sequencing, RNA sequencing of paired primary and recurrent meningiomas, and live cell microscopy and single cell RNA sequencing of meningioma cells in co-culture with human cerebral organoids, we revealed a rare meningioma cell subpopulation with strong transcriptional concordance to the neural crest, a multipotent embryonic tissue that forms the meninges in development.

CONCLUSIONS
These data suggest that misactivation of a developmental cell population underlies intratumor heterogeneity in meningioma and that expression of neural crest and immediate early genes are an important step in meningeal oncogenesis.
TMOD-29. A MOUSE MODEL OF FGFR3-TACC3 UNCOVERS MECHANISMS OF GLIOMAGENESIS AND MAINTENANCE
Authors: Fnu Tala , Shi Peiguo , Zhang Jing , Iavarone Antonio , Lasorella Anna 
Published: November 2019

Abstract
Glioblastoma harboring Fibroblast Growth Factor Receptor 3 (FGFR3)-Transforming Acidic Coiled-Coil containing 3 (TACC-3) (FGFR3-TACC3) fusion is a distinct molecular subclass of tumors that can be targeted by FGFR kinase inhibitors. We generated a knock-in mouse in which the expression of FGFR3-TACC3 is doxycycline inducible and reversible. The tetO-FGFR3-TACC3-IRES-GFP cassette was placed into the Rosa26 locus and the FGFR3-TACC3 knock-in strain was intercrossed with GFAP-rtTA*M2 mice to trigger expression of the tetracycline transactivator (and the fusion gene) from the GFAP promoter. To recapitulate the genetic lesions that are more frequently associated with FGFR3-TACC3 in human glioblastoma, we also intercrossed the tetO-FGFR3-TACC3-IRES-GFP;GFAP-rtTA*M2 mice with TP53+/-or Ink4A+/-mouse strains. Both strains developed aggressive and infiltrating gliomas within 90 days after induction of FGFR3-TACC3 by doxycycline containing diet. Tumors occurred with a prevalence of ~50% and were found almost exclusively at two brain locations: the lateral septum and the neuro-epithelium adjacent to the fimbria of the hippocampus, thus recapitulating the restricted expression of endogenous FGFR3 in the ventral telencephalon and ganglionic eminence during development. The FGFR3-TACC3-positive glioma resembled human glioblastoma as they exhibited marked invasiveness and vascularization, elevated proliferative index and positivity for Nestin and GFAP. Rapid tumor progression caused appearance of neurological symptoms and death within few weeks. Doxycycline withdrawal from the diet of mice diagnosed with brain tumors by MRI resulted in rapid loss of FGFR3-TACC3 from glioma cells, marked inhibition of tumor growth with essentially complete glioma regression in some cases and recovery of general and neurological clinical symptoms. Our findings validate FGFR3-TACC3 as powerful oncogene that drives development of high-grade glioma from distinct areas of the brain. They also provide an accurate pre-clinical model in which glioma maintenance requires continuous expression of the fusion gene, thus supporting therapeutic targeting of the fusion protein in patients with FGFR3-TACC3-positive glioblastoma.
TMOD-30. CHARACTERIZATION OF AN ALTERNATIVELY SPLICED NTRK2 VARIANT IN GLIOMAS
Authors: Pattwell Siobhan , Arora Sonali , Cimino P J , Szulzewsky Frank , Hoellerbauer Pia , Hoffstrom Benjamin , Boiani Norman , Ozawa Tatsuya , Bolouri Hamid , Correnti Colin , Silber John , Paddison Patrick , Holland Eric 
Published: November 2019

Abstract
Recent work has uncovered oncogenic TRK fusions in a wide range of cancer types, including adult and pediatric gliomas. With some exceptions, many of these fusions tend to occur at very low frequencies below 1–2%, with unclear clinical significance, yet they highlight a potentially important and rapidly evolving role for NTRK1, NTRK2, NTRK3 in glioma biology. Basic scientific and clinical investigation surrounding TRKs’ role in cancer has often been hindered due to the nonspecific nature of antibodies and kinase inhibitors, combined with a lack of precise exon-specific expression data from patient populations. Tropomyosin receptor B (TrkB), encoded by the NTRK2 gene, is most known for its established roles in neuronal survival, proliferation, differentiation, apoptosis, learning, and memory. TrkB exerts diverse effects on cellular outcomes through interactions with downstream signaling cascades and has been shown to exhibit complex alternative splicing patterns. Here we show a novel role for a TrkB splice variant in human gliomas via NTRK2 transcript analyses in normal human brain and gliomas using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx). Using a novel antibody designed against this splice variant, immunostaining shows altered receptor localization within human gliomas compared to normal human brain. This NTRK2 splice variant enhances PDGF-driven gliomas in vivo in an RCAS-TVA mouse model and augments PDGF-induced signaling in vitro. Through the lens of NTRK2, these results highlight the importance of expanding upon whole gene-level and kinase-fusion analyses to explore TRK splicing in basic and translational research.
TMOD-33. AN INTEGRATED APPROACH COMBINING MATHEMATICAL AND GENOMIC METHODS TO REVEAL THE OPTIMAL TIMING OF THERAPEUTIC INTERVENTION IN WHO GRADE II DIFFUSE GLIOMA
Authors: Aoki Kosuke , Yamamoto Takashi , Suzuki Hiromichi , Maeda Sachi , Ranjit Melissa , Motomura Kazuya , Nakamura Hideo , Narita Yoshitaka , Nakada Mitsutoshi , Deguchi Shoichi , Mizoguchi Masahiro , Momii Yasutomo , Muragaki Yoshihiro , Abe Tatsuya , Akimoto Jiro , Wakabayashi Toshihiko , Haeno Hiroshi , Natsume Atsushi 
Published: November 2019

Abstract

BACKGROUND
In WHO grade II diffuse gliomas (low-grade gliomas, hereafter called LGGs), chemotherapy and radiotherapy contribute to prolonged survival but could induce somatic mutations. The optimal timing of treatment in LGGs remain poorly understood. To delineate this, we designed a mathematical model for tumor growth and investigate the association among the treatment, malignant transformation (MT), and the accumulation of somatic mutations revealed by whole exome sequencing (WES) in LGGs.

METHODS
Totally, 290 patients with LGGs between 1990 and 2018 were analyzed. We assessed the statuses of IDH mutation and 1p19q co-deletion in all tumors. Among all, 114 patients (39%) underwent MT during follow-up periods (mean: 82.6 months). Tumor volume was evaluated with FLAIR and/or T2-weighted MRI. MT was evaluated with contrast-enhanced MRI and/or pathological diagnosis. To investigate the number of somatic mutations in a cohort of LGGs and their patient matched recurrence, WES was performed on 88 serial samples collected at least two time-points from 39 patients.

RESULTS
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (OD) showed longer transformation-free survival compared to other subtypes. An exponential model was chosen to estimate growth rate in LGGs, since the exponential model provided a better fit to our data as compared to a linear model. The growth rate significantly decreased in the middle of chemotherapy and after radiotherapy. By contrast, these treatments increased the number of somatic mutations identified by WES and the rate of MT in each subtype. The increasing number of mutations in recurrent tumors showed strong correlation with the rise in MT rate. Based on the growth rate and the risk of MT, optimal timing of treatments could be calculated for each genetic subtype.

CONCLUSIONS
The mathematical model and WES analysis delineates the optimal timing of treatments in each subtype, which will help to decide the treatment for LGGs.
SCIDOT-08. CHILDREN’S BRAIN TUMOUR DRUG DELIVERY CONSORTIUM (CBTDDC)
Authors: Rahman Ruman , Campbell Emma , Brem Henry , Pearl Monica , Green Jordan , Janowski Miroslaw , Walczak Piotr , Tyler Betty , Warren Katherine , Singleton Will , Mullen Alexander , Boyd Marie , Veal Gareth , Hargrave Darren , van Vuurden Dannis , Powell Steven , Battaglia Giuseppe , Vivanco Igor , Al-Jamal Khuloud , Walker David 
Published: November 2019

Abstract

INTRODUCTION
The brain tumour community has seen significant progress in the discovery of new therapeutic targets and anticancer drugs. Unfortunately, advances in how to deliver drugs to the brain lag behind. The blood-brain barrier restricts the entry of many small-molecule drugs and nearly all large molecule drugs that have been developed to treat brain disorders.

METHODS
Following an international CNS drug delivery workshop in 2016, we were awarded funding from Children with Cancer UK to launch the Children’s Brain Tumour Drug Delivery Consortium (CBTDDC; www.cbtddc.org; @cbtddc).

RESULTS
The CBTDDC launched in 2017 (in Europe and the US) to raise awareness of the challenge of drug delivery in childhood brain tumours, and to initiate and strengthen research collaborations to accelerate the development of drug delivery systems. We ran a Workshop on Drug Delivery to the Brain, attracting 52 delegates from the UK, Belgium, Spain and Portugal. We liaised with UK-based funders over the drug delivery agenda, and with UK policy makers. In the US, we jointly organised the SIGN2019 meeting and we are currently liaising with the leads of Project ‘All In’ DIPG about how we can lend our support to this project. As of June 2019, 150 individuals have registered with the consortium, representing researchers, clinicians, charities, patient groups and industry. These stakeholders represent 70 research institutions, covering 15 countries (France, UK, Italy, Sweden, The Netherlands, USA, Greece, Germany, Belgium, Cuba, Denmark, Spain, Portugal, Israel and Egypt). We host a freely accessible online collaborative research database, containing the details of over 70 researchers.

CONCLUSION
We believe that collaboration between clinicians and multi-disciplinary researchers is vital to solving the brain tumour drug delivery challenge. We hope to raise awareness of the CBTDDC, and to extend our invitation for collaborators to join the consortium, through SCIDOT’s unrivalled drug delivery platform.