SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item 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 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.10 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.30 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.7 0Item Restricted Epidemiological evaluation of oral anticoagulants prescribing and clinical outcomes in atrial fibrillation patients with and without cancer: analysis of primary care data in England(University of Manchester, 2024-05-01) Ajabnoor, Alyaa Mohammedali; Kontopantelis, EvangelosAtrial fibrillation (AF) is a prevalent cardiac arrhythmia imposing a substantial global burden. Given its five-fold increase in stroke risk, prescribing oral anticoagulants (OAC) to intermediate to high-risk AF patients is crucial. However, OAC prescribing rates vary, influenced by factors beyond stroke risk, particularly evident in patients with cancer who face complex clinical conditions affecting stroke and bleeding risks. Yet, the efficacy of risk assessment tools in this population remains unexplored, complicating anticoagulation therapy initiation, often tailored to individual patients. Nevertheless, evidence regarding this matter remains limited. Using the Clinical Practice Research Datalink (CPRD), this thesis presents unique research on Nonvalvular Atrial Fibrillation (NVAF) epidemiology in England. It addresses five key questions: 1) NVAF incidence and OAC prescribing, 2) factors influencing OAC prescription, 3) MB incidence and OAC resumption in NVAF patients, 4) stroke and bleeding risk comparison in NVAF patients with and without cancer, and 5) CHA2-DS2-VASc and HAS-BLED score performance in predicting stroke and bleeding in NVAF patients with and without cancer history. Key findings reveal a temporal increase in NVAF incidence in England until 2015, subsequently plateauing. Disparities in OAC prescription correlate with comorbidities, ethnicity, and socioeconomic status, emphasizing the need for interventions to address inequities in NVAF patient care. Between 2009 and 2019 the incidence of MB in NVAF patients surged tenfold with many experiencing MB despite lacking OAC prescription at the time of bleeding. The decision to resume OAC post-MB appears contingent upon the initial anticoagulant used and does not significantly associate with recurrent MB risk. Examining NVAF patients with different cancer types revealed varying stroke and bleeding risks, with certain cancers exhibiting higher bleeding risks than stroke risks. Notably, certain cancer types, such as haematological and lung cancer, were less likely to receive OAC, highlighting disparities in care. Finally, it was found that CHA2-DS2-VASc score performed similarly in predicting ischemic stroke in NVAF patients, irrespective of cancer history. In contrast, the HAS-BLED score, while well- calibrated, lacked discrimination in predicting major bleeding events in the NVAF population overall and in specific cancer cohorts. Overall, this thesis contributes to the evidence around the pharmacoepidemiology of OACs in the NVAF population in England and highlights socioeconomic disparities in NVAF care. It addresses challenges in managing NVAF cohorts with major bleeding or specific cancers, where current risk assessment scores may inadequately predict clinical outcomes. Further research is necessary to explore health inequalities in OAC prescribing for AF patients in England and understand why certain cancers predispose individuals to bleeding or stroke events.16 0Item Restricted Iridium(III) in-cell catalysis: a new strategy for the treatment of cancer(Saudi Digital Library, 2023-12-04) Alsaif, Sitah; Coverdale, JamesPlatinum-based chemotherapy is the most effective and widely used chemotherapy agent for the treatment of many different types of cancer. Unfortunately, the development of drug resistance has become a major obstacle to successful cancer treatment. Catalytic metallodrugs with anticancer properties, when administered at low concentrations, have the potential to mitigate adverse effects, offer innovative strategies to counteract resistance, and broaden the range of anticancer therapeutic efficacy. In this study, we use a stable chiral piano-stool organometallic iridium(III) complex, [Ir(arene)(TsDPEN)] (TsDPEN, N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine), to establish its in-cell catalyst property based on the Noyori-type asymmetric transfer hydrogenation process. Reduction of specific molecule is shown when the iridium(III) catalyst is co-administered with sodium formate as a source of hydride in both the model system and A2780 human ovarian cancer cells. The catalytic process exhibits preferential targeting of A2780 ovarian cancer cells over MRC5 non-cancerous fibroblasts. Moreover, to achieve a high potency to in-cell catalyst, we determined the antiproliferative activity (IC50) for sodium formate in A2780 cells, which guided the use of the limited concentration that can be used for sodium formate as a hydride source. The catalyst transfer hydrogenation strategy has the potential to both reduce cell proliferation and induce cell death, providing an effective therapy for cancer.25 0