Saudi Cultural Missions Theses & Dissertations
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Item Restricted is there evidence in the literature supporting the use of structure-activity(SAR) relationships in cobalt complexes for the treatment of breast cancer, using MCF-7 as a cellular model?(Saudi Digital Library, 2025) almalki, abrar; canelon, isoldaBreast cancer remains a major global health burden, with limitations in current therapies driving the search for novel agents. Transition-metal complexes, particularly cobalt-based compounds, have attracted attention due to their redox-based mechanism of action in hypoxic tumours. This systematic review critically evaluated whether evidence in the literature supports the use of structure-activity relationships (SAR) in cobalt complexes for the treatment of breast cancer, with a specific focus on the MCF-7 cell line as a representative in vitro model. A comprehensive search of Scopus (2015–2025) identified 29 eligible studies, yielding 61 distinct cobalt complexes tested in MCF-7 cells. Data were systematically extracted using a PICO framework and normalised by the cisplatin factor to enhance comparability. Findings revealed that several cobalt complexes demonstrated cytotoxic potency comparable to or exceeding cisplatin. However, no consistent direct structure–activity relationship (SAR) was observed for oxidation state, aromaticity, or halogenation. Instead, these factors appear to influence activity indirectly. The analysis showed no consistent direct relationship between oxidation state, aromaticity, or halogenation and cytotoxicity in MCF-7 cells. Evidence indicates that these features contribute indirectly: Co(III) complexes may act as prodrugs activated in hypoxic conditions, while Co(II) species are more reactive but less stable. Aromatic rings and halogens can also enhance lipophilicity, DNA stacking, and membrane permeability. Cobalt SAR is influenced by multiple factors, and context-dependent rather than linear. Progressive filtering reduced the dataset to 29 studies (61 complexes), excluding non- numerical results and inconsistent reporting. Normalisation using the cisplatin factor allowed cross-study comparisons despite differences in assays and exposure times. Although this reduced statistical power, it improved reproducibility and highlighted methodological weaknesses such as poor reporting of controls and recovery times. The refined dataset provides a reliable but selective foundation for future SAR studies. Cobalt complexes exhibit significant potential as anticancer agents in breast cancer models, but it requires expanded datasets, mechanistic assays, and in vivo validation. Future studies must prioritise standardisation, broader cell models, and exploration of combination therapies to fully establish cobalt’s role in oncology.8 0Item Restricted DNA repair in bacteria: mechanisms and regulation(Saudi digital library, 2025) aldhafeeri, Rayan; busby, StephenDNA integrity is important for survival, yet constantly threatened by mutagens, antibiotics, and host defenses. In Escherichia coli, genomic stability is regulated by several repair pathways: direct reversal, base excision repair, nucleotide excision, repair mismatch correction, and homologous recombination coordinated through stress-responsive regulatory networks. Three major regulons exemplify this regulation. The Ada system links direct repair of alkylation damage to transcriptional activation, the Mar system regulates multidrug resistance and oxidative stress tolerance, and the LexA/SOS system orchestrates a global DNA damage response via RecA-mediated LexA cleavage. Together, they show a common concept: repressor-based switches that rapidly convert stress signals into adaptive gene expression. These responses go beyond repair and cause microbes evolution. SOS-induced mutagenesis, while prophage mobilization enhances antibiotic resistance and facilitates horizontal gene transfer, sending virulence factors and influencing infection outcomes. Stress control thereby affects both bacterial survival and host–pathogen dynamics. Insights from E. coli have broader significance. Core repair methods are preserved in eukaryotes, and deficiencies in human processes contribute to genomic instability and cancer. Therapies like PARP inhibitors exploit vulnerabilities in repair, which is like how microbes work. Bacterial stress responses clarify fundamental principles of genome preservation, connecting microbial adaptation with biotechnology, infectious disease biology, and cancer research.11 0Item Restricted An Exploration of the Association of ZDHHC2 and ZDHHC15 with Various Cancers: Expression Profile and Prognostic Implications(Saudi Digital Library, 2025) Alsolme, Badr; Luke, ChamberlainS-Acylation is a post-translational modification that is essential for the function of many proteins, playing a key role in inflammation, cell proliferation, and signal transduction. This process is catalysed by the ZDHHC enzyme family, which has 23 members. Several studies have suggested their involvement in cancer development. This study aimed to investigate the association of ZDHHC2 and ZDHHC15 with various cancers. A bioinformatics approach was used to evaluate oncogenic and tumour-suppressive roles, gene expression, prognostic implications, genetic alterations, and protein interactions of these enzymes. IntOGen, COSMIC, UCSC Xena, cBioPortal, STRING, and BioGRID databases were used. The results showed that ZDHHC2 and ZDHHC15 were not classified as tumour drivers or suppressors. Gene expression of ZDHHC2 was significantly downregulated in several types of cancers, while ZDHHC15 was downregulated in all cancers tested, except for cholangiocarcinoma. Survival analysis showed ZDHHC2 and ZDHHC15 overexpression was associated with either better or worse prognosis depending on the cancer type. For ZDHHC2, deep deletion of the gene was seen in some cancer types and was associated with lower mRNA expression but not with changes in patient survival. Finally, BioGRID analysis revealed potential interactions of ZDHHC2 and ZDHHC15 with tumour drivers and tumour suppressors that may be relevant to their associations with cancer.6 0Item Restricted Preclinical Testing of Bispecific T Cells Attracting Monoclonal Antibodies for Immunotherapy of Colorectal cancer(Saudi Digital Library, 2025) Alrishedan, Norah; Bodmer, WalterAbstract: Immunotherapy using bispecific monoclonal antibodies (BiMAb) is a promising cancer therapy. Such BiMAbs bind simultaneously to immune effector cells and to a cancer-specific antigen on tumour cells, resulting in killing of the latter. The heterogeneity of tumour associated antigen (TAA) expression in a tumour as well as poor infiltration of the T cells into the tissue can pose challenges to the use of BiMAb in solid tumours, raising the need for mechanistic insights into the mode of BiMAb-dependent cell killing. It has been shown that IFNγ secreted by antigen specific T cells can act on bystander tumour cells resulting in contact independent cell killing; for efficient eradication of tumours a bystander effect is essential. Placental alkaline phosphatase (PLAP) is an enzyme expressed on the cell surface only in the placenta not in other normal tissues. PLAP is ectopically expressed in some tumours such as ovarian tumours, seminomas, and about 20% of colon carcinoma, making it a good target for BiMAb immunotherapy. Colorectal cancer (CRC) causes one of the highest numbers of cancer-related deaths worldwide. That emphasises the urgency to find an effective treatment to treat colon cancer. We have a collection of 116 different CRC cell lines in our lab, well characterised in terms of gene expression and mutations, providing a reliable tool to test potential therapeutic agents. The specificity of an anti-PLAP monoclonal antibody (H17E2) produced by our lab was used to develop a BiMAb that binds to T cell co-receptor CD3ε chain and to PLAP (CD3 x PLAP BiMAb (RPLP3)). iii Microarray analysis of our CRC cell lines showed that 21.5% of them express PLAP. Interestingly, immunofluorescence and FACS analysis showed that some of the lines are heterogeneous in their expression, with levels ranging from PLAP-negative to PLAP-high. We found that the CD3-PLAP BiMAb induced specific killing of PLAP-positive colorectal cancer cell lines cultured with peripheral blood mononuclear cells (PBMCs) as source of T cells, and that the killing depends on PLAP expression. Moreover, we found that the effect of CD3-PLAP BiMAb (RPLP3) treatment was extended to PLAP-negative cells, when co-cultured with PLAP-positive ones, indicated a bystander effect. The bystander effect on PLAP-negative cells is only visible after 48 hours of treatment, suggesting a different mechanism for the indirect killing. Understanding the mechanism behind the bystander killing would be key to improving antibody therapy for colorectal cancer. As well as understanding the cause of PLAP expression on CRC cell lines.4 0Item Restricted Dissecting the structural requirements for Notch/ligand interactions with mutations derived from cancer genome sequencing(The University of Manchester, 2025) Alanazi, Areej; Baron, MartinNotch is a cell surface receptor with critical roles in development and cellular differentiation, and its altered activity is frequently associated with cancer. Despite extensive sequencing efforts identifying numerous cancer-associated mutations in Notch, the functional consequences of many of these mutations remain poorly understood. Notch activation is mediated by its interaction with cell surface ligands, Delta and Serrate/Jagged, triggering proteolytic cleavage events that release the Notch intracellular domain (NICD). The NICD translocates to the nucleus to regulate transcription, and Notch can also be activated through ligand-independent mechanisms following endocytosis. This thesis exploits the high sequence conservation between human and Drosophila Notch to dissect how cancer-associated mutations alter receptor functionality, using an approach comprising in vitro and in vivo analyses. This work focuses on mutations within the ligand-binding region that are associated with cancers where Notch acts as a tumour suppressor. Through cell culture assays, I categorised Notch mutants based on their ligand-binding properties, signalling efficiencies, and ligand-independent activities. Using CRISPR/Cas9, these mutations were introduced into the Drosophila genome, enabling a comprehensive study of their phenotypic consequences. My analyses revealed diverse mutant classes, including those that completely eliminate signalling or retain partial functionality. For example, I identified mutants that discriminated between different Notch ligands, removed ligand-dependent signalling while retaining ligand-independent activity, and one mutant that retained ligand-dependent activation but removed ligand-independent activity. I also found that different cell-based assays could distinguish between levels of ligand associations required for cell adhesion and cell signalling. In vivo genetic interaction studies further refined our understanding of mutant classifications, revealing Notch mutant-specific interactions with a panel of genetic modifiers and uncovering phenotypes that deviated significantly from null-like behaviour. Additionally, I demonstrated that several mutations compromised cis-inhibitory interactions, with heterogeneous impacts on this regulatory mechanism across different developmental contexts. These findings provide valuable insights into the regulatory dynamics of Notch signalling, paving the way for advancing our understanding of the pathway’s role in development and disease.23 0Item Restricted Nurses’ Experiences of Breaking Bad News in Oncology Settings With Adolescents and Young People(Trinity College Dublin, 2024-08-22) Alyami, Malak; Murphy, MaryanneABSTRACT Background: Oncology nurses communicate with adolescents and young adults (AYAs) at the end of life to break bad news, communicate important information, or gain insight into the patient’s condition, anxiety, fear, or pain. However, oncology nurses face many barriers to communicating with AYAs to break bad news at the end of life, so identifying these barriers is an essential step in overcoming them. What barriers do oncology nurses face when communicating with AYAs to break bad news at the end of life? Aim: To conduct a systematic review examining barriers oncology nurses face when communicating with AYAs to break bad news at the end of life. Methods: A systematic review question was developed, a search strategy was defined, and inclusion and exclusion criteria were applied to the search results. Afterwards, a quality assessment of the included studies was conducted, and data extraction was conducted according to JBI standards and protocol. The meta-aggregative approach was applied, and the extracted data were grouped into prominent themes. Results: The search and selection strategy resulted in 2,080 studies to which the inclusion and exclusion criteria were applied. After filtering the studies, 20 remained. Four met the high-quality assessment criteria and were included in the thematic analysis and meta-aggregative process. The analysis and synthesis process resulted in the emergence of five main themes related to the barriers faced by oncology nurses in breaking bad news to AYAs at the end of life: 1) communication skills and experiences of oncology nurses, 2) individual barriers, 3) professional barriers, 4) institutional barriers, and 5) societal barriers to breaking bad news. Conclusions: Oncology nurses face many barriers related to their lack of competence and effective communication skills. These barriers may be professional or related to the lack of protocols for breaking bad news and communicating with AYA oncology patients. They may also be due to institutional barriers resulting from inadequate resources, time, and nurses. In addition, the relationships between nurses and multidisciplinary teams, the overlap of tasks, and the lack of clarity of roles in the process of breaking bad news constitute barriers to the success of the communication process, in addition to the linguistic and cultural diversity between nurses, patients, and their families, which constitute major challenges in the communication process.24 0Item Restricted The role of isoform switching and neoantigen formation in the response to radiation(University of Oxford, 2023) Abdulghani, Majd Yousef; Humphrey, Timothy CarterThis thesis investigates the role of isoform switching in response to ionising radiation (IR) and the modulation of this process by SRSF1, a proto-oncogenic splicing factor. Utilising deep RNA-sequencing of B-cell lines from ten healthy individuals, the study reveals extensive IR-induced isoform switching across the transcriptome, leading to potentially shorter transcripts that influence DNA damage response, apoptosis, and cell cycle arrest. Intriguingly, nearly half of the genes exhibiting isoform-level changes showed no differential expression at the gene level, highlighting the importance of isoform-specific analysis in understanding cellular responses to IR. The RNA-binding protein SRSF1 is identified as a mediator of IR-induced isoform switching. Loss of SRSF1 expression, which is a common response to IR across various cell types, enhances radiosensitivity in cell lines and in cancer patients. Moreover, the thesis explores the combined effect of SRSF1 knockdown and IR on triple-negative breast cancer cells, revealing an altered antigenic landscape with 86 putative neoantigens, and therefore offering insights into novel targeted immunotherapies. The findings propose SRSF1 as a prognostic marker for radiotherapy efficacy in the short-term, and present a foundation for future therapeutic approaches targeting SRSF1 in cancer treatment.16 0Item Restricted Pyrimidine Triones as Potential Activators of p53 Mutants(University of California, Irvine, 2024) Fallatah, Maryam; Kaiser, Peter; Buisson, Rémi; Qiao, Feng; G. Fleischman, Angelap53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small-molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.12 0Item Restricted Digital Oral Health Biomarkers - A Public Health Use A Rapid Systematic Review(King’s College London, 2024-05) Alhassan, Aseel Khaled; Zaric, SvetislavAim: To Review currently available digital devices for early detection of oral diseases (dental caries, periodontal diseases, and oral cancer) and evaluate their potential dental public health applications Methods: A literature search across seven databases, grey literature, and a hand search was performed (February 2024- April 2024) to investigate the recent developments in digital tools for early detection of dental caries, periodontal disease, and oral cancer by non-dental care professionals. The search utilized keywords such as biomarkers, digital, diagnosis, saliva, caries, periodontal diseases, and oral cancer. Results: The synthesis of findings revealed five studies on dental caries, seven on periodontal diseases, and five on oral cancer. Home-based kits in development showed promising initial results and acceptable clinical utility in detecting various oral diseases. Among these, the most notable tests included a wearable fluorescent mouthguard for dental caries, a light-induced fluorescence device for periodontal diseases, and a paper-based fluorescent sensor for oral cancer. The wearable mouthguard demonstrated high sensitivity and accuracy in diagnosing early caries, making it suitable for public use in areas with limited access to dental care. The light-induced fluorescence device connects to a mobile app and provides a practical tool for continuous plaque detection and monitoring, promoting better oral hygiene. The paper-based fluorescent sensor offers rapid screening for oral squamous cell carcinoma, showing high sensitivity and specificity for home use. Despite the absence of rigorous clinical trials, the overall quality of evidence was cautiously appraised as primarily high, with seven articles rated high, four rated moderate to high, and four rated moderate. Conclusion: While biomarkers represent a significant advancement in diagnosing and preventing oral diseases, and the findings highlight the potential of digital diagnostic tools to enhance the early detection and management of oral diseases, further studies are required to facilitate their implementation for general public use.31 0Item Restricted Delineating the signalling interplay between mTORC1 and MET in Tuberous Sclerosis Complex(Cardiff University, 2023-11-30) Alzahrani, Mohammad; Tee, AndrewTuberous Sclerosis Complex (TSC) is a genetic disease caused by mutations in the TSC1 and TSC2 genes. As a result of these mutations, there is dysregulation in the TSC complex which in turn leads to downstream hyperactivation of mTOR (mechanistic target of rapamycin), a serine/threonine protein kinase. The involvement of the MET proto-oncogene, receptor tyrosine kinase (MET) in TSC pathogenesis has been explored in this project, as MET could play an important role in cell proliferation, motility, migration, and invasion. MET could be a potential therapeutic target in TSC. Ref-1 is a redox regulator involved in DNA repair and inhibition of apoptosis. This study aimed to provide confirmatory data of the link between MET and mTOR signalling, as well as providing evidence of whether MET and Ref-1 are functionally important in TSC and associated cell models of cancer. Preliminary data indicated a potential link between MET and mTOR. Dual inhibition of MET and mTOR signalling on TSC2-deficient AML cells (621-101) and Tsc2−/− mouse embryonic fibroblast (MEF) cells demonstrate greater anti-proliferative effects compared to single agent treatments. Combined blockade of MET and mTOR pathways reduced cell growth more potently than individual MET or mTOR inhibitors alone. mTOR activity was found to potently enhance hepatocyte growth factor (HGF) and autocrine signalling in TSC2-deficient model cells of TSC, which was blocked with rapamycin treatment. Data indicates that co- targeting aberrant MET, Ref-1 and mTORC1 signalling has potential as a therapeutic strategy in cancers dependent on these oncogenic pathways. Blockade of dysregulated MET and Ref-1 signalling pathways demonstrated greater anti- tumour effects compared to inhibition of mTORC1 alone in AML and MEF cells lacking functional TSC2. Combining MET and Ref-1 inhibitors with mTOR-targeted agents may provide additional therapeutic benefits for TSC. The combination of MET inhibitor, Crizotinib, and mTOR inhibitor, rapamycin, on AML, MDA-MB-231 and ST8814 cells demonstrates synergistic anti-tumour effects in preclinical cancer models. Early phase clinical trials show this drug combination is tolerable with encouraging efficacy signals in certain malignancies, yet their outcomes were not conclusive. In conclusion, this thesis demonstrates the potential of targeting MET, mTORC1, and Ref-1 signalling as an anti-cancer strategy. Further optimization of MET/mTORC1 inhibitor combination therapies inhibiting these pathways is needed to translate the findings into improved clinical outcomes for cancer patients.9 0