bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCIDOT-19. A MECHANICALLY-ENGINEERED SPRAY TO INCREASE BRAIN PENETRATION OF CHEMOTHERAPEUTIC NANOPARTICLES IN THE TREATMENT OF HIGH-GRADE GLIOMAS
Authors: McCrorie Phoebe , Taresco Vincenzo , Xu Zeyuan , Ritchie Alison , A Clarke Philip , Marlow Maria , Rahman Ruman 
Published: November 2019

Abstract
Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.
SCIDOT-28. TARGETED NANOPARTICLES FOR IMPROVED DRUG DELIVERY TO MEDULLOBLASTOMA
Authors: Straehla Joelle P , Boehnke Natalie , Dacoba Tamara G , Hammond Paula T 
Published: November 2019

Abstract
Platinum-based agents remain a key component of therapy for children with medulloblastoma, despite significant systemic side effects and only modest blood-brain barrier (BBB) penetration. Cisplatin has a cerebrospinal fluid-to-plasma ratio <5% and dose-limiting side effects of nephrotoxicity, ototoxicity, and myelosuppression. Improving delivery of cisplatin across the BBB and selectively accumulating in tumors could improve its therapeutic index. To this end, we are leveraging chemical engineering techniques to rationally design cisplatin nanoparticles (NPs) to cross the BBB and preferentially enter medulloblastoma tumor cells. Using the layer-by-layer (LbL) platform to ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we screened six negatively charged polypeptide and polysaccharide outer layers in medulloblastoma cell lines. Poly-L-aspartic acid (PLD) layered NPs had significant accumulation in tumor cells after 24 hours incubation, with an uptake index of 18±4 over unlayered control NPs. Next, we generated propargyl-functionalized PLD and used click chemistry to covalently conjugate the BBB shuttle ligands glutathione, angiopep-2, and transferrin, which have been shown to mediate transcytosis across brain endothelial cells. PLD layered NPs functionalized with angiopep-2 and transferrin had enhanced uptake in medulloblastoma tumor cells and NPs functionalized with glutathione were non-inferior to PLD layered NPs. After incubation with endothelial cells in vitro, all three BBB shuttle ligands enhanced uptake of PLD layered NPs over unlayered and non-functionalized control NPs. We then incorporated cisplatin into the nanoparticle core of this platform. Cisplatin-loaded NPs with PLD layering and ligand functionalization were more effective than free cisplatin as measured by IC50 over 72 hours in culture, and led to faster apoptosis as assessed by flow cytometry with annexin V and propidium iodide staining. In summary, functionalized nanoparticles are a promising platform to modulate drug delivery to medulloblastoma. In vivo studies using an orthotopic xenograft model are underway to investigate biodistribution, efficacy, and toxicity.
ANGI-06. FUNCTION OF FORMIN-LIKE 1 (FMNL1) IN GLIOBLASTOMA MULTIFORME
Authors: Higa Nayuta , Shinsato Yoshinari , Takajyo Tomoko , Yonezawa Hajime , Uchida Hiroyuki , Furukawa Tatsuhiko , Yoshimoto Koji 
Published: November 2019

Abstract

INTRODUCTION
Glioblastoma multiforme is the most common primary malignant brain tumour in adults. It is characterised by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in cancer progression, invasion, and migration. However, the role of FMNL1 in cancer remains unclear. We are the first to investigate FMNL1 in GBM.

METHODS
Clinical specimens were obtained from tumours surgically removed and pathologically confirmed as GBM from 217 GBM patients treated from 2000 to 2015 at the Department of Neurosurgery, Kagoshima University Hospital. We studied the expression of FMNL1 in glioblastoma samples by immunohistochemistry to analyse the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from TCGA and analysed using Gene Set Enrichment Analysis (GSEA).

RESULTS
FMNL1 was found to be a predictor of poor prognosis in a cohort of 217 cases (P < 0.001). GSEA showed that upregulation and downregulation of FMNL1 were associated with mesenchymal and proneural markers, respectively. Contrarily, downregulation of FMNL1 suppressed migration and invasion of glioblastoma multiforme cells via DIAPH1 and GOLGA2, respectively. Downregulation of FMNL1 also suppressed assembly of actin fibres, induced morphological changes, and diminished filamentous actin.

CONCLUSION
Our studies show that abundant FMNL1 expression in GBM patients is correlated with an unfavourable prognosis. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.
SCIDOT-37. ASSESSING CEREBROSPINAL FLUID FLOW DYNAMICS IN PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Kramer Kim , Donzellie Maria , Nwora Emmanuela , Pandit-Taskar Neeta 
Published: November 2019

Abstract

BACKGROUND
The incidence of abnormal CSF flow dynamics in the pediatric population with CNS tumors prior to intraventricular therapy has not been described.

METHODS
We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003–2018 (15 years).. Patients underwent 111-indium diethylene triamine pentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 minutes, 4, 24, and 48 hours (if required). CSF flow was classified as normal, delayed, asymmetric or obstructed.

RESULTS
278 CSF flow studies were performed in 224 patients, 202(90%) <18 years of age. 116(52%) patients had metastatic CNS neuroblastoma, 57(25%) had medulloblastoma, and 51(23%) had other CNS histologies. Of the 278 studies, 237(85%) were normal, 9(3%) required neurosurgical intervention, 25(9%) were delayed, and 7(3%) were asymmetric.

CONCLUSIONS
Abnormal CSF flow and necessity of neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.
SCIDOT-47. EFFECT OF ulRFE COGNATES EMULATING BIOACTIVE SUBSTANCES ON ANIMAL BEHAVIOR
Authors: Figueroa Xavier , Butters Mike , Donnell Scott 
Published: November 2019

Abstract

BACKGROUND
The EMulate Therapeutics Voyager system produces a magnetic field obtained from the magnetic fluctuations produced by molecules in solution. These recordings, ultra-low radio frequency energy (ulRFE®) cognates, are intended to emulate the effects of the molecule.

METHODS
Mice were treated with cognates for up to 120 min on the first day, then 24 h/day for the next 15 days.

RESULTS
All ulRFE cognates were well tolerated. Body weights remained stable. Animals exposed to signals derived from melatonin, THC (tetrahydrocannabinol), scotch, and ethanol showed signs of mild hypo-activity, while cognates derived from CBD (cannabidiol), Everclear, nicotine, and white wine showed mild signs of somnolence. Caffeine exposure initially caused mild hyperactivity, which returned to normal after the 120 minutes. The espresso cognate induced signs of mild hyperactivity during the initial 20-minute exposure. After 40 minutes, mild head convulsions and normal activity levels were noted. After 120 minutes, signs of hypoactivity were seen. Animals exposed to caffeine ulRFE showed signs of mild hyperactivity for the duration of the 15-day exposure, and animals exposed to nicotine, melatonin, THC, CBD, Everclear, scotch, and white wine cognates experienced mild hypo-activity. Animals exposed to espresso or 100% ethanol ulRFE remained normal during the 15-day exposure.

CONCLUSIONS
Mice displayed altered behavior when exposed to the magnetic field produced by the cognates, which, at least in part, were consistent with some effects that would be anticipated for the molecules used to create the cognates. The ulRFE technology offers potential to emulate the effects of bioactive substances across the blood:brain barrier.
CBMT-07. BIOMARKERS OF AGGRESSIVENESS IN IDH MUTANT GLIOMA
Authors: Yamasaki Tomohiro , Lita Adrian , Dowdy Tyrone , Gilbert Mark , Larion Mioara 
Published: November 2019

Abstract

BACKGROUND
Gliomas with isocitrate dehydrogenase (IDH) mutations in adults evolve from lower-grade gliomas to secondary glioblastomas (GBM), a fatal disease with fast progression. IDH mutation occurs early in tumorigenesis, and persistently contribute to the reprograming of glucose, lipid and amino acid metabolism. This offer a plethora of potential biomarkers of progression. However, because it is extremely difficult to detect the distribution and transfer of metabolites changing in every moment in a single cell, the involvement of metabolites produced by mutant IDH in malignant progression remains understudied.

MATERIALS AND METHODS
Raman imaging spectroscopy, which can image chemical bonds and concentration of molecules at submicron spatial resolution, enables detection of spatiotemporal changes of metabolomes in live cells. We developed the software called Biomolecular Component Analysis (BCAbox) to deconvolute the recorded raw Raman spectra, leading to detection of unique spectral features of different classes of biomolecules.

RESULTS AND CONCLUSIONS
We applied Raman imaging spectroscopy to GBM cell lines that were transfected with IDH1 mutant gene. Our results indicated that lipid metabolism has a unique profile in IDH1 mutant gliomas. Subsequent mass spectrometry analysis of extracted organelle revealed the exact classes of lipids altered in the IDH mutant glioma and suggested biomarkers unique to IDH1 mutant. We will report our validation studies of the biomarkers in patient-derived IDH mutant glioma cell lines and patients derived-orthotopic xenograft mouse models with different degrees of aggressiveness and in matched primary versus recurrent gliomas. The results of the present study may provide novel insights into the discovery of metabolic biomarkers for the malignant progression in IDH mutant gliomas.
CBMT-14. THE DIELECTRIC PROPERTIES OF BRAIN TUMOR TISSUE
Authors: Proescholdt Martin , Haj Amer , Doenitz Christian , Brawanski Alexander , Bomzon Ze’ev , Sara Hershkovich Hadas 
Published: November 2019

Abstract

INTRODUCTION
Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed GBM. One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dielectric properties of brain tumors by analyzing resected tissue following a fast acquisition protocol. To account for the intratumoral heterogeneity, different regions of the tumor were analyzed separately.

METHODS
A cohort of 84 patients with tumors of different histology have been recruited. Tissue probes were acquired from the vital tumor area and perinecrotic compartment. The tissue was measured immediately to avoid artifacts. A fragment was dissected from each tissue sample and was placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz using a software specifically developed for this study, which controls the LCR meter. The measured impedance was translated into dielectric properties of the sample (conductivity and relative permittivity) based on the parallel plate model, the recorded complex impedance and the geometry of the samples. Each tissue probe was fixed, H&E stained and histologically analyzed.

RESULTS
We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest conductivity (mean conductivity [S/m]: 0.193; range: 0.327 – 0.113) and GBM tissue exhibiting the highest conductivity values (mean conductivity [S/m]: 0.402; range: 0.893 – 0.157). Consistently, the perinecrotic areas displayed lower conductivity values compared to the solid tumor compartments. Also, we found a significant intratumoral heterogeneity in tumors of one specific histological diagnosis.

CONCLUSION
The dielectric properties of intracranial tumors appear to be depending on histological class and malignancy grade and show significant intratumoral heterogeneity. These results may allow a more precise modelling of electric field intensity distribution within the tumor.
CBMT-21. TERT PROMOTER-MUTANT GLIOBLASTOMAS EXHIBIT DEPENDENCY ON TELOMERASE
Authors: Aquilanti Elisa , Baird Duncan , Watson Jacqueline , Meyerson Matthew 
Published: November 2019

Abstract
TERT promoter mutations are among the most common somatic alterations in cancer and they occur in about 80% of IDH-wildtype glioblastomas. TERT promoter mutations were found to reactivate telomerase by providing a novel binding site for the GABP transcription factor. While the effects of telomerase ablation are well understood in mice and somatic human cells, these effects in cancer are yet to be fully elucidated. In this study, we used a genetic approach with CRISPR-interference to knock down telomerase in TERT promoter-mutant glioblastoma cell lines. We show that this leads to a gradual and significant reduction in proliferation. This phenotype ultimately culminates in telomere crisis, with telomere shortening, activation of the DNA damage response pathway and formation of chromatin bridges. These data suggest that anti-telomerase therapy is a potential effective approach for glioblastoma tumors.
CBMT-26. SERIAL CHARACTERIZATION OF HYPERPOLARIZED [1-13C]PYRUVATE METABOLISM IN PATIENTS WITH GLIOMA AND THE INFLUENCE OF BEVACIZUMAB
Authors: Autry Adam , Gordon Jeremy , Chen Hsin-Yu , Lafontaine Marisa , Villanueva-Meyer Javier , Chang Susan , Xu Duan , Larson Peder , Vigneron Daniel , Li Yan 
Published: November 2019

Abstract
Treatment-related changes often mimic or mask tumor on standard anatomic imaging, making it difficult to monitor disease recurrence. Hyperpolarized (HP) carbon-13 MR imaging allows for real-time non-invasive measurement of metabolism, which may improve patient surveillance. Here, we focused on characterizing serial HP scans in patients undergoing treatment compared to healthy controls. Serial dynamic HP C-13 MRI scans were performed on 5 patients with recurrent glioma (22 total) and 3 healthy controls (4 total) using an echo-planar imaging sequence (2.88-8cm3 spatial resolution, 3s temporal resolution, 60s), following injection of 0.43mL/kg of 250mM HP [1-13C]pyruvate. Apparent rate constants were modeled for enzymatic conversion of pyruvate-to-lactate (kPL) via cytosolic lactate dehydrogenase and pyruvate-to-bicarbonate (kPB) via mitochondrial pyruvate dehydrogenase and carbonic anhydrase. Regions of interest included normal-appearing white matter (NAWM) and T2-hyperintense lesions (T2L), which were segmented from H-1 MR images and then aligned to the HP data. Carbon voxels containing >30% of NAWM or T2L were included in the analysis. Healthy controls demonstrated consistent kPL and kPB values over 4 scans in NAWM with SD/Mean of 5% and 12%, respectively. Compared to the median kPL-NAWM of 0.022s-1 in controls, the 5 patients had median serial kPL-NAWM values of 0.023, 0.023, 0.023, 0.029, and 0.015s-1, and mean serial ratios of kPL between T2L and NAWM (kPL-T2L/kPL-NAWM) of 1.22, 1.27, 1.05, 1.32, and 1.37s-1, indicating higher values in putative tumor. Median kPB-NAWM in controls was 0.004s-1 and ranged in patients 0.003-0.006s-1. Two patients with >4 serial scans, showed consistent kPL-NAWM over standard-of-care treatment and elevated kPL-T2L within new lesions, but up to 85% increase in kPL-NAWM with bevacizumab, which may be attributed to reduced BBB permeability. Stable patients generally demonstrated consistent kPL-T2L values that were lower compared to progressive patients. Future studies will include multi-parametric 1H imaging analysis in a larger patient population.
CBMT-39. TARGETING METABOLIC PATHWAYS IN HYPOXIA FOR GLIOBLASTOMA
Authors: Gruslova Aleksandra , Lodi Alessia , Li Mengxing , Zhou Mei , Garcia Michael , Tiziani Stefano , Brenner Andrew , Caflisch Laura 
Published: November 2019

Abstract

BACKGROUND
Metabolic adaptation to hypoxia is a crucial consideration in combating anti-angiogenic resistance. We previously explored the potential of targeting the peroxisomal fatty acid oxidation (FAO) pathway and observed higher potency to peroxisomal FAO inhibitor thioridazine in hypoxia in vitro. In this study we further examine the effects of peroxisomal FAO enzyme ACOX1, looking at differences in mitochondrial and peroxisomal FAO in hypoxia between subtypes, and explore additional metabolic pathways that can be potentially further studied.

METHODS
We utilized a CRISPR doxycycline-inducible U251 knockout cell line for the peroxisomal FAO gene ACOX1 and examined growth and viability in 2 weeks hypoxia (2% O2). We analyzed the gene expression of 13 peroxisomal and mitochondrial FAO enzymes in six different patient-derived cell lines. Finally, we characterized serum metabolites that are associated with tumor hypoxic volume, progression-free survival, and overall survival in patients undergoing clinical trial for TH302 and bevacizumab with bevacizumab refractory tumors.

RESULTS
We observed decreased cell growth and viability (p < .03) specifically in hypoxia but not normoxia with ACOX1 knock out. We saw some changes in gene expression (|ΔΔCt| >1) in hypoxia for all genes, which differed between cell lines. ACOX1 and CPT1A expression were strongly decreased (|ΔΔCt| >2) while ACADSB expression was strongly increased for the proneural cell line. ACOX1 expression was strongly decreased in our most thioridazine-sensitive cell line. ACOX2, ACADVL, CPT1A, CPT1C, and DECR2 expression were strongly increased in one of the proneural cell lines. Twelve polar metabolites were positively or negatively correlated (|r| >.4) with both hypoxic volume and either overall survival or progression-free survival.

CONCLUSION
Peroxisomal FAO and other metabolic pathways may be essential to target in order combat metabolic resistance during anti-angiogenic therapy. Better understanding differences in metabolism in different tumor environments will help determine which targets will be most therapeutically useful.
CSIG-05. TRPM7 INDUCES MECHANISTIC TARGET OF Rap1b THROUGH DOWNREGULATION OF miR-28-5p IN GLIOMA PROLIFERATION AND INVASION
Authors: Wan Jingwei , Guo Alyssa , Liu Mingli 
Published: November 2019

Abstract
Our previous findings demonstrate that TRPM7 is critical in regulating human glioma tumorigenesis. miRNA participate in complex regulatory networks that may affect almost every cellular and molecular processes in glioma formation and progression, because a specific miRNA may simultaneously regulate many targets; While, a single protein target can be regulated by different miRNAs. Here, we explored the role of miRNAs in the progression of human gliomas by comparing miRNA expression profiles due to differentially expressed TRPM7. We determined 1) miRNA targets of TRPM7 by miroRNA microarray analysis upon TRPM7 silencing in glioma cell lines. 2) whether TRPM7 regulates glioma cell proliferation (MTT) and migration/invasion (transwell invasion assay) through different functional domains by transfecting wild-type human TRPM7 (wtTRPM7) or constructs with the α-kinase domain deleted (Δkinase) or with a point mutation within the ATP binding site of the α-kinase domain (K1648R-KR) into glioma cells. 3) the roles of miR-28-5p in glioma tumorigenesis by over- or under-expressing miR-28-5p in vitro. 4) whether Rap1b is a target of miR28-5p and the role of Rap1b in glioma tumorigenesis. 5) whether Rap1b can counteract the miR28-5p function on glioma tumorigenesis. We found 1) a list of 16 downregulated and 10 upregulated miRNAs that are statistically significant with fold changes greater than 2 by TRPM7 knock-down by miRNA microarray, and miR-28-5p as a promising candidate for functional analyses. 2) cell invasion was significantly reduced in Δkinase or K1648R transfectants, indicating that TRPM7 kinase activity is required for glioma cell migration/invasion. 3) overexpression of miR-28-5p caused a significant decrease in cell proliferation and migration by targeting Rap1b. 4) Co-transfection with siRap1b with miR28-5p inhibitor reduced the glioma cell proliferation and invasion caused by the latter. In summary, TRPM7 induces mechanistic target of Rap1b through downregulation of miR-28-5p in glioma proliferation and invasion.