bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXPLORING LOW-DENSITY LIPOPROTEIN RECEPTOR (LDLR) FAMILY IN GLIOBLASTOMA
Authors: Huyton Mr Jack , Smith Dr Christopher George Severin , Alder Dr Jane 
Published: October 2024

Abstract

AIMS
Cancer and neurodegenerative disease are unlikely to co-exist in the same patient. As glioblastoma is the most prevalent primary brain cancer, our research group is exploring how GBM is affected by genes implicated in Alzheimer’s disease. SorL1 has been established to be an important risk factor for Alzheimer’s disease and our group have shown it to be upregulated in patient derived GBM cells and it contributes to GBM cell migration and proliferation. SorL1 is part of a wider family of low-density lipoprotein receptor (LDLR) family and so my project was to explore the wider family as a potential target for investigation.

METHOD
The LDLR family were initially investigated using the bioinformatic data bases Xena browser and ivy Glioblastoma Atlas Project (ivyGAP). Xena browser reports RNA expression between healthy tissue samples (GTEX study) and from low grade glioma and glioblastoma and survival analysis while ivyGAP reports gene expression in the different anatomical regions of glioblastoma tumours.

RESULTS
Following bioinformatics and literature review: LRP1B, LRP5, LRP10 and Sortilin were chosen for further investigation. Western blot and immunocytochemistry were used to explore expression in cell lines SVGP12, U87MG and 1321N1. Sortilin and LRP10 were shown to be down regulated whilst LRP5 showed no signiﬁcant differences between cell lines.

CONCLUSION
The next step in this project is to explore expression of the LRP family in patient derived cells and normal human astrocytes. As the expression of the LDLR family was region speciﬁc across the tumour (ivyGAP data) future work in the project will explore expression in 3D spheroids and organotypic brain slice cultures, to create a model that better recapitulates the tumour microenvironment to better understand these proteins and their roles in GBM
DIFFERENTIAL CELL SURFACE PROTEOMICS OF FLOTILLIN-1, HMGB1 AND AMINOPEPTIDASE N IN H3 MUTATED PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Fairley Ms Hannah , Walugembe Ms Chloe , Sulman Mr Joshua , Haque Dr Farhana 
Published: October 2024

Abstract

AIMS
High-grade gliomas (HGG) are central nervous system tumour in children, where treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identiﬁed as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adult gliomas. Our previous proteomic research on cell membrane protein through protein MS data analyses have identiﬁed different signatures of differentially expressed cell membrane proteins in H3-G34R/V mutated pHGG cells, in comparison to H3 wild type tumour cells in culture. Among these proteins we have identiﬁed ﬂotillin-1, HMGB1 (High mobility group box 1) and aminopeptidase N. Flotillin-1 is associated with numerous malignancies and HMGB1 also functions as an oncogene and aminopeptidase N is a cell surface metalloprotease involved in tumour progression. Our aim is to study the expression and localisation of these cell surface proteins in H3 mutated and wild type tumour cells, to validate them as targets for developing novel therapeutics.

METHOD
Expression and localisation of ﬂotillin-1, HMGB1 and aminopeptidase N in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma and control cells was analysed, using different protein expression assays including immunoﬂuorescence microscopy and western blotting.

RESULTS
Results showed statistically signiﬁcant differential protein expression and localisation of these proteins. Flotillin-1 had increased cell membrane localization in H3 mutated cells. HMGB1 expression was increased, while aminopeptidase N expression was decreased in the H3 mutated cells in comparison to wildtype pHGG.

CONCLUSION
This new knowledge of the cell membrane proteomics of H3 mutated pHGG may help us utilise Flotillin- 1,HMGB1 and aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.
THE EPIGENETIC REGULATORY PROTEIN CBX2 AS A NOVEL THERAPEUTIC TARGET FOR GLIOBLASTOMA
Authors: Marsh Ms Danielle , Greenman Prof John , Wade Dr Mark 
Published: October 2024

Abstract

AIMS
Glioblastoma (GBM) is the deadliest and most common form of brain tumour. The average length of survival for GBM patients remains low, in part, due to a lack of targeted therapeutics. Identiﬁcation and validation of novel therapeutic targets is therefore crucial. Chomobox 2 (CBX2; a component of polycomb repressive complex 1 (PRC1)), represses gene expression and has a pro-oncogenic role in several aggressive cancer subtypes. CBX2 expression is elevated in GBM, however, very little is known about its role in this deadly disease. We aim to assess the phenotypic and gene expression effects of preventing CBX2-chromatin interaction in patient-derived GBM cell models, and to determine the functional mechanisms by which CBX2 promotes GBM progression; thereby determining its potential as a novel therapeutic target.

METHOD
Crucial to impactful target validation is the use of translationally relevant models, this study utilises a 3D spheroid model, using patient-derived cells, which more closely recapitulates the in vivo tumour microenvironment. GBM cell monolayers and spheroids were treated with SW2_152F, a selective CBX2 inhibitor. The phenotypic effects of CBX2 inhibition were assessed by cell count, CellTiter-Glo viability assays, ﬂuorescence microscopy, and ﬂow cytometry. Genes and biological pathways differentially regulated following CBX2 inhibition were assessed by RNA-sequencing and Gene Set Enrichment Analysis (GSEA).

RESULTS
Inhibition of CBX2 induced cell death and reduced cell viability in both 2D and 3D GBM cultures. RNA-seq and GSEA of SW2_152F-treated cells identiﬁed dysregulation of gene signatures involved in pro-oncogenic MYC and E2F signalling pathways, and dysregulation of genes associated with G2/M cell cycle progression.

CONCLUSION
Preventing CBX2-chromatin interaction induces GBM cell death. Further research will identify CBX2- chromatin binding sites to characterise the activity and direct regulatory role of CBX2 in GBM. Furthermore, we will assess the phenotypic and gene expression effects of CBX2 inhibition and depletion on ex vivo maintained GBM tissue biopsies.
QUALITY OF LIFE IN PATIENTS WITH SKULL BASE CHORDOMA AND CHONDROSARCOMA TREATED WITH PENCIL BEAM SCANNING PROTON THERAPY
Authors: Bryjova Dr Katarina , Mackeprang Dr Paul-Henry , Weber Prof Damien Charles 
Published: October 2024

Abstract

AIMS
The objective of this study is to assess the health-related quality of life (HRQoL) of skull base chor- doma/chondrosarcoma patients treated with proton therapy (PT).

METHOD
Seventy seven adult patients with skull base chordoma/chondrosarcoma completed the EORTC-QLQ-C30 and the BN20 Questionnaires prior to PT, Clinical outcome and therapy related acute and late toxicities have been recorded in course of the follow-up. The data was collected, categorized and analyzed, comparing the posttreatment scores to each patient’s baseline. In order to assess the impact of the clinical outcome and toxicities on HRQoL, the scores were correlated to collected clinical outcomes.

RESULTS
Median follow-up was 51 months. 6-year overall survival and local failure free survival rates observed were 85.1% and 80.3%. One G3 brain radiation necrosis and one G4 optic nerve disorder were documented during FU. HRQL deteriorated after the completion of proton therapy and returned to baseline values one year thereafter. After the second and third year, we observed further decrease in HRQL. This development was unrelated to tumor relapse. However, comparing the whole cohort over time, global QoL did not change substantially over the course of follow-up. GTR was correlated to better QoL at all time points. Disease progression was correlated with overall worse QoL and higher neurological symptoms already before PT, and higher symptom burden one year thereafter. Males had better QoL before and one year after PT than females.

CONCLUSION
PT achieves an excellent local and distant control in patients with skull base chordoma/chondrosarcoma. The HRQoL in these patients decreases immediately after the treatment completion, returns to the baseline from one year thereafter, and tends to deteriorate again with longer FU. The observed changes in global HRQoL were however not substantial in the whole cohort over the course of follow-up.
TARGETED THERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA: A COMPREHENSIVE REVIEW OF MONOCLONAL ANTIBODIES
Authors: Dib Ms Christie , Zaatar Mr Johnny , Sarouﬁne Ms Karmen , Elias Ms Linda , Alagha Mr Michel , Ghawi Ms Odette El , Khalil Ms Jana , Nakhle Mr Yves , Haidar Ms Elissa , Khoury Mr John-Victor El , Hawi Dr Jihad 
Published: October 2024

Abstract

AIMS
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor, marked by its poor prognosis and frequent recurrence despite conventional therapy. Our review examines the molecular landscape of DIPG, highlighting key factors driving tumor progression. We evaluate the therapeutic potential of various monoclonal antibodies (mAbs) targeting these factors, providing insights into their mechanisms and ongoing clinical trials. Our aim is to guide future investigations and immunotherapeutic strategies for DIPG.

METHOD
A narrative review was conducted using the PubMed database to identify relevant review articles, clinical trials, and observational studies published within the past 10 years, focusing on the use of mAbs in DIPG. The search terms “monoclonal antibodies”, “diffuse intrinsic pontine glioma”, and “targeted therapy” were employed. Additionally, a search was conducted on clinicaltrials.gov to gather information on ongoing and completed clinical trials.

RESULTS
Current human clinical trials on the checkpoint inhibitors anti-PD-1 (Nivolumab, Pembrolizumab, Balstilimab, Cemiplimab), anti-PD-L1 (Durvalumab), and anti-CTLA-4 (Ipilimumab, Zalifrelimab) have not demonstrated signiﬁcant improvement in overall patient survival. One major limitation has been the small sample size and limited expression of such markers in DIPG. Conversely, combination therapies involving anti-VEGF (Bevacizumab) and anti-EGFR (Nimotuzumab and Cetuximab) have shown promising results in small sample studies, but these results are not conclusive. Trials on anti-CD276 (Omburtamab) and CD40 agonist (APX005M) have shown no speciﬁc clinical or tumor outcomes in DIPG. Newer emerging agents like anti-TIM3 and anti-IL13Ra2 have shown very favorable results in in-vivo and in-vitro studies.

CONCLUSION
Current evidence is insuﬃcient to support the use of mAbs in DIPG. More large-size studies investigating the combinations of checkpoint inhibitors with different therapeutic agents are needed. Additionally, the promising results seen with anti-VEGF and anti-EGFR mAbs in their respective combination therapies warrant exploration in large-scale studies to draw more accurate conclusions. Furthermore, human trials should be conducted on anti-TIM3 and anti-IL13Ra2.
MULTI-OMIC INTEGRATION REVEAL INTRA-TUMOUR HETEROGENEITY AND IDENTIFY DISULﬁRAM AND COPPER AS A SYNERGISTIC THERAPY IN PAEDIATRIC EPENDYMOMA
Authors: Pandele Dr Alina , Whitby Dr Alison , Lankford Ms Sophie , Macarthur Mr Donald , Kamaly-Asl Mr Ian , Barrett Prof David , Grundy Prof Richard , Kim Dr Dong-Hyun , Rahman Dr Ruman 
Published: October 2024

Abstract

AIMS
Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a signiﬁcant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it diﬃcult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN.

METHOD
Surgical sampling of spatially-distinct regions was performed on eight PF-A patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method.

RESULTS
Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulﬁram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ signiﬁcantly sensitized cells to Disulﬁram, particularly under hypoxic conditions. This synergistic combination signiﬁcantly impaired invasion in both normoxia and hypoxia.

CONCLUSION
This is the ﬁrst instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.
VASARI-AUTO: PERFORMANT, EQUITABLE, EﬃCIENT, ECONOMIC, AND SURVIVAL PREDICTIVE FEATURISATION OF GLIOMA MRI
Authors: Ruﬄe Dr James , Mohinta Ms Samia , Baruteau Dr Kelly Pegoretti , Rajiah Dr Rebekah , Lee Ms Faith , Brandner Prof Sebastian , Nachev Prof Parashkev , Hyare Dr Harpreet 
Published: October 2024

Abstract

AIMS
The VASARI (Visually AcceSAble Rembrandt Images) MRI feature set is a quantitative system designed to standardize glioma imaging descriptions. Though effective, deriving VASARI is time-consuming and therefore seldom used in clinical practice. This is however a problem that performant machine-learning software could plausibly automate.

METHOD
In 100 patients, two consultant neuroradiologists independently quantiﬁed VASARI features. In parallel, we developed VASARI-auto, an automated VASARI-labelling software applied to both open-source hand-segmented lesion masks and our openly available tumour segmentation model. We quantiﬁed: 1) agreement across neuroradiologists and VASARI-auto; 2) calibration of patient equity; 3) an economic workforce analysis; and 4) ﬁdelity in predicting patient overall survival. Neuroradiologists were blinded to VASARI-auto software development and evaluations, and software developers were blinded to neuroradiologist labelling.

RESULTS
Segmentation and VASARI-auto were equally performant regardless of age or sex (mean segmentation Dice coeﬃcient 0.947). A modest inter-rater variability between neuroradiologists (mean Cohen’s Kappa 0.49) was comparable between neuroradiologists and VASARI-auto (mean Cohen’s Kappa 0.41), with higher agreement across VASARI-auto methods (mean Cohen’s Kappa 0.94). The time taken for neuroradiologists to derive VASARI features was substantially higher than VASARI-auto (mean time per case 317 vs. 3 seconds, p&lt;0.0001). A hospital workforce analysis of our centre forecast that three years of VASARI glioma featurisation would demand 771 consultant neuroradiologist workforce hours (£40,789) or 8.6 hours of computing time (£3.76 of power) with VASARI-auto. The best-performing survival model utilised VASARI-auto features (R2 0.25), opposed to those derived by consultant neuroradiologists (R2 0.21).

CONCLUSION
VASARI-auto is a highly eﬃcient automated labelling system for VASARI featurisation with equitable performance regardless of patient age or sex, a favourable economic proﬁle if used as a decision support tool, and with non-inferior ﬁdelity in downstream patient survival prediction. Future work should integrate such tools to enhance patient care.
INTEGRATING TRANSCRIPTOMICS WITH SPATIAL RADIOGRAPHIC ATLASES FOR GLIOMA ANALYSIS
Authors: Li Mr Yonghao , Wan Mr Yizhou , Price Prof Stephen 
Published: October 2024

Abstract

AIMS
The localization of gliomas in the brain is a critical prognostic factor, reﬂecting the genetic makeup of their originating cells. Variations in transcriptomic proﬁles across different regions and subtypes may further shed light on the mechanisms driving tumor development. Our research delves into the complex interplay between glioma locations and their transcriptomic signatures, seeking to dissect the spatial and genetic intricacies contributing to glioma diversity.

METHOD
In this study, we conducted a comprehensive analysis of preoperative anatomical MRI and transcriptomic data from 242 glioma patients to investigate the relationship between spatial distribution and tumor transcriptomic proﬁles. The MRI data were standardized by registration to the MNI-152 brain space. Tumors were segmented, and the brain was partitioned into 84 discrete subregions for detailed examination. Transcriptomic data underwent preprocessing, with principal component analysis employed to reduce dimensionality. Statistical analyses were used to assess the relationship between glioma description across different subtypes and PCA results. Additionally, we identify differentially expressed genes and common genes across regions for various glioma subtypes. Comparative analyses with the Allen Brain Atlas (divided into 84 subregions with expression data) were also performed to discern transcriptional differences between healthy individuals and glioma patients, further enhancing our understanding of glioma biology at the molecular level.

RESULTS
We generated 21 frequency maps detailing regional glioma occurrences, categorized by biomarkers, subtypes, and grades. Notably, some of these maps showed signiﬁcant correlations with expression principal component analyses (PCAs). Our ﬁndings include a set of genes consistently expressed across subregions, alongside region speciﬁc differentially expressed genes. Additionally, we identiﬁed distinct gene expression patterns when comparing glioma patients to healthy controls in the Allen Brain Atlas, highlighting potential molecular underpinnings of glioma heterogeneity.

CONCLUSION
Our analysis revealed notable correlations between glioma subtype locations and transcriptomic proﬁles, underscoring the role of transcriptomic signatures in explaining regional variations in glioma incidence.
SURGICAL OUTCOMES OF TUBULAR RETRACTOR SYSTEMS IN THE MANAGEMENT OF BRAIN TUMOURS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Fard Mr Amir Rafati , Mowforth Mr Oliver , Hibberd Dr Owen , Akinduro Mr Isaac , Smith Mr Kieran , Patel Dr Reece , Bhatti Mrs Zainab , Karmarkar Mrs Sejal , Hill Mr Ciaran 
Published: October 2024

Abstract

AIMS
Retraction is a critical step in surgical removal of brain tumours, enabling visualisation and resection. Conventional retraction applies focal pressure to overlying tissue, potentially resulting in retraction-induced injury. Tubular retractors (minimally invasive parafascicular surgery) circumferentially distribute pressure to theoretically minimise injury. Whilst previous reviews have provided insight into their potential, the literature has since signiﬁcantly expanded, necessitating an update. The objective was to synthesise all current evidence regarding surgical outcomes of tubular retractors in resection of brain tumours.

METHOD
Studies reporting on use of tubular retractors to resect brain tumours in adult patients were eligible. PRISMA guidelines were followed. MEDLINE, Embase and the Cochrane Library were searched to 18th October 2023. Duplicate title/abstract screening, data extraction and risk of bias assessments were conducted.

RESULTS
Of the 2453 studies screened, 49 were included in the ﬁnal synthesis, involving 690 patients. Tubular retractor systems assessed were: BrainPath (n=199), VBAS (n=198), METRx (n=63) and other (n=230). Pooled estimate of gross total resection rate was 75% (95% CI 0.65-0.84; I2=83%), whilst pooled estimate of complication rate was 17% (95% CI 0.11-0.24; I2=75%). Sub-group analysis of gross total resection rate was conducted for: glioma (150 patients, pooled prevalence 47%, 95% CI 0.36-0.57; I2=29%), colloid cyst (121 patients, pooled prevalence 100%, CI 0.99-1.00; I2=0%), and metastasis (114 patients, pooled prevalence 82%, 95% CI 0.67-0.94; I2=64%). There was no signiﬁcant difference between tubular retractor systems with regards to gross total resection or complication rate (p&gt;0.05).

CONCLUSION
There is mounting evidence for the utility of tubular retractors in resection of brain tumours. However, this evidence remains largely in the form of low-quality case-series, providing proof-of-concept, but limited in its ability to draw more robust comparisons to conventional retraction. Future studies with greater sample sizes and inclusion of control groups are now needed to consolidate the position of tubular retractors in neuro-oncology.
DESIGN AND SET UP OF A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: Short Prof Susan , Mant Dr Rhys , Savage Dr Josh , Patel Dr Amit , Billingham Prof Lucinda , Meade Dr Sarah , Buckle Mr Peter , Collinson Dr Fiona , Boele Dr Florien 
Published: October 2024

Abstract

AIMS
ARISTOCRAT is a unique, randomised, double-blind, placebo-controlled phase II trial of cannabinoids (nabixo- mols) alongside temozolomide in patients with MGMT-methylated recurrent GBM and is open to recruitment in 12 centres across the UK. It was rapidly funded through a crowdfunding campaign organised by The Brain Tumour Charity during the COVID-19 pandemic.

METHOD
This pragmatic phase II randomised trial was designed and set up by a multi-disciplinary team of co-applicants and trial management group (TMG) members comprising of clinicians, statisticians, trialists, Patient & Public Involvement (PPI), pharmacists and quality of life (QoL) researchers. The protocol randomises on a 2:1 ratio between nabiximols or matched placebo with standard dose temozolomide in patients at ﬁrst recurrence of IDH wild-type GBM. Unique aspects include self-titration of nabiximols based on individual tolerance, and fully blinded randomisation with matched placebo. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. Intermediate assessment of feasibility to conﬁrm safety, compliance and achievability of recruitment will be undertaken after 40 patients are randomised. PPI input has been critical in the trial and patient-facing information design.

RESULTS
The trial has promoted a high level of patient and public interest, including press coverage. The trial aims to recruit a total of 234 patients over an 18 month period.

CONCLUSION
ARISTOCRAT will provide unique, robust clinical data on the role of nabiximols (combined with temozolomide) in improving overall survival and the impact on QoL for patients with recurrent GBM and is the ﬁrst of its kind in cancer patients.