Saudi Cultural Missions Theses & Dissertations
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Item Restricted Pathways Regulated by Glucocorticoids in Glioblastoma and Crosstalk with the Microenvironment(University of Leeds, 2024) Qashqari, Hanadi; Matthews, Laura; Cook, GrahamGlioblastoma (GBM) is the most aggressive brain tumour in adults, with an average survival of just 18 months. Current treatment includes surgery in combination with radiotherapy and chemotherapy. Oncolytic viruses (OVs) are emerging to supplement standard cancer therapies as they kill tumour cells directly and activate immune surveillance. Most GBM patients are prescribed Dexamethasone (Dex), a synthetic glucocorticoid and potent anti-inflammatory drug that reduces brain inflammation, thereby limiting deleterious symptoms of GBM. While essential as part of standard therapy, it remains unclear how Dex might influence the efficacy of emerging immunotherapies such as OVs in GBM. In silico analysis of public RNA-seq data predicted potential crosstalk between glucocorticoids and reovirus in IL-6, AP-1 and TNF pathways. In vitro studies showed that Dex impairs direct GBM killing by reovirus. Dex did not influence virus entry or replication within GBM cells, suggesting that Dex alters GBM response to the virus. To elucidate the pathways involved, the effect of Dex on GBM cell infection by reovirus was explored by RNA-seq analysis. Gene ontology analysis demonstrated that Dex reduced pro-inflammatory signals, dysregulated activation of interferon response, and affected anti-apoptotic genes as well as cell cycle and ER stress response. A GBM-immune coculture model was used to investigate the effect of Dex on the ability of reovirus to activate immune cells and target GBM cells for destruction. Dex also impaired killing of GBM cells by immune cells. Dex altered expression of NK cell ligands on the surface of GBM cells which is predicted to reduce recruitment of NK cells. Dex significantly reduced NK cell number and activation in the presence of reovirus to reduce NK cells cytotoxic function. Consistent with this, the inhibitory effect of Dex was lost following NK cell depletion. This study elucidates the potential pathways of Dex treatment during virus immunotherapy and emphasizes the importance of careful consideration for Dex management during immunotherapy to enhance treatment outcomes for GBM patients.21 0Item Restricted Stiffness-induced EMT and Cancer Stemness in Glioblastoma Using Polyacrylamide Hydrogels(University of Glasgow, 2024) Alotaibi, Mohammed; Salmeron-Sanchez, ManuelGliomas are the most common type of brain and are considered one of the most fatal cancer forms due to their detrimental and aggressive behaviour. Amongst these types of brain cancer is glioblastoma (GBM), classified by the World Health Organization (WHO) as grade IV, known to have characteristics like high malignancy, rapid growth and aggressiveness. As these tumours progress, the extracellular matrix (ECM) stiffness increases, influencing their growth, survivability and treatment outcomes. The induction of Epithelial to Mesenchymal transition (EMT) was associated with the production of Cancer stem-like cells (CSCs), a small subpopulation with self renewal capabilities that generates phenotypic heterogeneity comparable to the original tumour. CSCs are responsible for sustaining tumour growth and metastasis formation to other body tissues. The main focus of this study was assessing the role of brain tissue mechanical stiffness in promoting EMT and cancer of glioblastoma cells. The surface of PAAm hydrogels was modified to overcome the non-adhesiveness via covalently linked to collagen type I to facilitate the attachment of glioblastoma cells. The stiffness of Polyacrylamide Hydrogels (PAAm hydrogels) was measured using Rheology and Nanoindentation. The three stiffnesses fabricated and used were soft 305.9±16.9 Pa, which is similar to normal brain tissue, medium 10.5±0.4 kPa, comparable to glioblastoma stiffness and rigid 34.9±5.1kPa which is stiffer than glioblastoma tumours. The nanoindentation measurements were for soft 321.72±59.83 Pa, medium 8.01±0.37kPa and rigid 39.19±2.58kPa, illustrating that the stiffnesses are unfirmed across the surface and reproducible. EMT markers like N-CAD, VIMENTIN and TGF-β showed increased protein levels in the medium and rigid hydrogels compared to soft hydrogels. This response was further by increased protein expression of the EMT transcription factor SNAI1(SNAIL), which showed a significant increase in levels of SNAI1(SNAIL) (p≤0.05) on the medium and rigid hydrogels. II CSC markers showed increased protein levels highlighted by the significant increase in the protein levels of NESTIN (P≤0.001), CD133 (P≤0.0001), POU5F1(OCT-4) (P≤0.05), and EGFR (P≤0.05), respectively on the rigid hydrogels compared to soft hydrogels. Medium hydrogels showed significant increases in the protein levels of CD133 (P≤0.0001) and POU5F1(OCT-4) (P≤0.05), respectively. The findings of this research suggest that mechanical stiffness promoted EMT and cancer stemness in glioblastoma cells, underlining the influence of microenvironment stiffness in promoting invasion capabilities in glioblastoma cells.7 0Item Restricted Subcellular Location-Dependent Regulation of Interferon-Induced Transmembrane Protein 1 in Glioblastoma(The University of Edinburgh, 2024) Mubarak, Rawan; Ball, KathrynGlioblastoma multiforme (GBM) is one of the most aggressive and lethal brain cancers, known for its highly invasive nature and resistance to conventional therapies. Central to this resistance is the presence of glioblastoma stem cells (GSCs), which contribute to tumour recurrence and heterogeneity. This thesis investigates the roles of interferon-induced transmembrane proteins (IFITMs), specifically IFITM1 and IFITM3, within GSCs and their potential as therapeutic targets. The study provides a detailed analysis of IFITM1’s expression, subcellular localisation, and interaction with other proteins in response to interferon stimulation, employing advanced molecular techniques such as co-immunoprecipitation, immunofluorescence microscopy, and proteomic analysis. Key findings include the discovery that IFITM3 plays a critical role in regulating IFITM1’s expression and localisation, with significant implications for IFITM1’s function in cancer cell biology. This thesis also contributes to validating a novel interaction between IFITM1 and Lysosomal-associated membrane protein 1, suggesting a potential role for IFITM1 in autophagy, which could be pivotal in GBM’s resistance to treatment. These insights not only advance the understanding of IFITM proteins in GSCs but also highlight their potential as targets for therapeutic intervention in GBM. This work lays the foundation for future studies aimed at manipulating IFITM proteins to develop novel strategies for overcoming GBM treatment resistance.46 0Item Restricted The Feasibility of Diffusion Tensor Imaging in Magnetic Resonance- guided Linear Accelerator for a Glioblastoma(Saudi Digital Library, 2023-12-14) Alfraih, Ghalia; Eccles, Cynthia; Aznar, MarianneBackground and aim: Glioblastoma (GBM) is the most malignant primary brain malignancy in adults, and radiotherapy (RT) can be one of the most crucial treatment options. However, RT has the potential to damage white matter (WM), resulting in cognitive and functional deficits. Although the introduction of the magnetic resonance-guided linear accelerator (MR-linac) promises high-precision RT coupled with real-time imaging, there is still a significant need for advanced imaging sequences to ensure the protection of WM tracts. Diffusion tensor imaging (DTI) provides insights into the microscopic characteristics of tissue cellularity and anisotropy, offering clear visualization of WM tracts. While DTI is promising, the integration of DTI within the MR-linac system for GBM treatment remains unexplored. This study aims to investigate the feasibility of DTI in MR- linac for GBM. Methods: This longitudinal prospective case study examined a GBM patient treated with radiotherapy via conventional linac. DTI images were acquired by the MR-linac imaging component at two predetermined timepoints after 8Gy and 20Gy radiation delivery. Using the 3D Slicer open-source platform, a directionally encoded colour map, fractional anisotropy (FA) scalar measurement, and tractography were generated to compare WM tracts in direct relation to the tumour with WM tracts on the unaffected contralateral side, along with their changes across second imaging sessions. Additionally, mean diffusivity (MD) scalar measurements were processed to evaluate tumour response between imaging sessions. Results: Analysis of DT images yielded an overall low image quality. However, these images can illuminate WM pathways. The unaffected contralateral hemispheres consistently exhibit normal WM tracts, whereas the affected side revealed anatomical alterations due to the tumour. Directionally encoded colour maps post-8Gy and 20Gy revealed a significant asymmetry between the cerebral hemispheres, with enhanced visibility post- 20Gy. Fractional anisotropy (FA) map images indicated compromised WM structural integrity near the tumour, with decreased FA values, notably after 20Gy of delivery. The mean diffusivity (MD) map images show no significant changes between the two time points, and the MD value for the tumour indicated a similar response. Conclusion: The incorporation of DTI into the MR-linac system could be demonstrated as feasible approach for GBM patients and other cerebral malignancies. This integration might be useful in obtaining more precise and targeted radiotherapy, with the potential to enhance treatment outcomes and reduce complications associated with RT.17 0