SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item Restricted Integrative Genomic Analysis of Cytogenetically Normal Acute Myeloid Leukaemia(University College London, 2025) Alhawaj, Ali Fouad; Mansour, MarcAcute Myeloid Leukaemia (AML) is a haematological malignancy characterized by increased proliferation and blocked differentiation of haematopoietic progenitors. Cytogenetically normal AML (CN-AML) accounts for approximately 50% of all AML cases, with a 5-year survival rate of approximately 50%. Approximately 40% of patients exhibit primary resistance to induction chemotherapy; however, the molecular basis remains poorly understood. Additionally, high SETBP1 expression has been implicated in AML development, although the underlying mechanism remains unclear. This thesis aimed to explore the genomic and transcriptomic profiles of primary-resistant CN-AML in adults, and SETBP1 allele-specific expression (ASE) as a potential cause of high SETBP1 expression. Through whole-exome and RNA sequencing of resistant and matched remission samples, we identified a high presence of UBTF-TD in CN-AML (12%) and a higher incidence of WT1 mutations in the resistant versus remission cohorts (29% vs. 10%, p=0.005). However, CRISPR knockout of WT1 in a 416B mouse model did not confer resistance to Cytarabine or Daunorubicin RNA sequencing indicated enrichment of senescence signatures in the resistant cohort, along with novel gene fusions of LATS2-ZMYM2 (20.9%) and LATS2-HMGB1 (14.3%) in CN-AML. Lastly, integrative genomic and transcriptomic analyses revealed GATA2 and SETBP1 ASE, including a novel non-coding SETBP1 mutation, potentially driving its high expression. Future studies are required to validate UBTF-TD lesions and refine the WT1 knockout, potentially revealing new resistance mechanisms amenable to treatment. LATS2 fusions also require validation to clarify their impact on the tumour-suppressive Hippo pathway. Finally, long-read and whole-genome sequencing may reveal additional mechanisms underlying GATA2 pathogenic expression, whereas functional assays of the novel non-coding SETBP1 variant may elucidate its role in driving AML. These findings may ultimately refine the prognosis and inform new therapeutic strategies for high-risk CN-AML.13 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 Role of somatic copy number alterations in the aetiology and prognosis of Acute Myeloid Leukaemia(Newcastle University, 2024-02) Alharbi, Abrar Abdulghani; James, AllanAcute Myeloid Leukaemia (AML) is a group of highly heterogeneous haematological malignancies that arises from the accumulation of acquired genetic lesions, including point mutations, translocations, and DNA copy number alterations (CNAs) that confer a survival advantage to the leukaemic cell. The identification and characterisation of these aberrations have not only shed light on the pathogenesis of AML but also have improved patient stratification and the selection of therapeutic strategies. Despite these advances, drug resistance and relapse remain persistent clinical challenges, which may reflect the presence of as yet undetected alterations that influence disease progression and outcome. Recent advances in high throughput platforms such as microarray‐based genotyping technologies have revealed previously unrecognised cryptic chromosomal aberrations associated with DNA copy number changes. Given the heterogeneity of AML genomes, input from these platforms can potentially supplement cytogenetic data to improve prognostication and guide treatment decisions, and perhaps lend further insight into the mechanisms underlying AML pathogenesis. In this study, we analysed SNP‐microarray data from a large cohort of over 3000 AML cases for CNAs and copy‐neutral regions of homozygosity. In addition to providing a comprehensive overview of the landscape of acquired CNAs and regions of homozygosity in AML, this large cohort enabled us to identify and validate recurrent novel focal CNAs. Among validated gene targets affected by focal CNA is MIR4447, a previously uncharacterised microRNA. To investigate the potential role of MIR4447 in AML pathogenesis, we developed both gain‐ and loss‐of‐function cell models via gene overexpression and CRISPR/cas9‐mediated gene editing, respectively. These models were interrogated using RNA sequencing to analyse the transcriptional impact of miR‐4447 modulation. Our findings suggest that miR‐4447 has a multifaceted and context‐dependant role in regulating cellular functions, impacting energy metabolism, ribosome synthesis, immune response, and possibly leukaemogenesis through alterations in nutrient transport, mitochondrial function, and cell migration. Collectively, our findings contribute to our understanding of the genomic intricacies of AML and highlight the need for further research to investigate the downstream targets of miR‐4447, its effects in different cellular contexts, and its interaction with other regulatory molecules.7 0Item Restricted Rme-6, a Novel Regulator for EGFR Trafficking and Signaling(University of Sheffield, 2024-02-21) Alshahrani, Fahad Ayidh M; Smythe, ElizabethThe Epidermal Growth Factor Receptor (EGFR) is a key regulator for critical cellular processes including proliferation, migration, and apoptosis. Dysregulation of EGFR trafficking and signaling plays a crucial role in cancer development and contributes significantly to resistance to chemotherapy. This thesis examines the novel regulatory role of Rme-6, a Rab5 guanine nucleotide exchange factor (GEF), in modulating EGFR signaling by influencing its endocytic flux, a key determinant in the spatial and temporal dynamics of EGFR-mediated signaling pathways. Through a series of molecular and cellular experiments, I demonstrate that Rme-6 critically influences EGFR endocytic trafficking. Specifically, loss of Rme-6 results in increased accumulation of EGFR in APPL1-positive endosomes. This accumulation alters the downstream signaling fate of ERK1/2 by modulating its nuclear translocation. I have shown that Rme-6 has a positive effect on ERK1/2 signaling, while its disruption leads to aberrant ERK1/2 activity. This change in ERK1/2 signaling correlates with altered cell proliferation rates, suggesting a potential mechanism for cancer progression. Additionally, I reveal that Rme-6 may act as a scaffold for CK2 to phosphorylate ERK1/2 on its SPS motif, which is essential for its nuclear translocation and activation of transcription factors such as c-Fos. This phosphorylation impacts gene expression and subsequent cell fate decisions. This research not only advances our understanding of the molecular dynamics of EGFR signaling but also proposes Rme-6 as a potential therapeutic target in cancers characterized by dysregulated EGFR signaling pathways.16 0Item Restricted Orofacial Development Changes in Children Following Cancer Treatment: A Comprehensive Review of Literature and Analysis of Current Data in Leeds Dental Institute.(University of Leeds, 2024) Alghamdi, Talal; Drummond, BernadetteIntroduction: Childhood cancer survivors often experience various side effects after treatment, including dental and orofacial developmental conditions. According to the literature, the treatment for cancer in children can affect the development of teeth, the function of salivary glands, the development of facial structures, and the operation of the temporomandibular joint [TMJ]. Leeds Dental Institute [LDI] has accumulated a wealth of data while providing dental healthcare for cancer survivors. This extensive data has not been thoroughly explored or published. Thus, this study aims to investigate the long-term effects of cancer treatment on dental and orofacial structures from the literature and the available records in children at Leeds Dental Institute. Methods: This research is structured into two sections. The first is a comprehensive literature review of existing studies on the adverse effects of cancer treatments on oral and facial structures in children by searching six databases to establish a foundation for understanding the broader context of the issue. The second section is a retrospective data collection and analysis of paediatric patient data from the electronic records in LDI using a list of appointments attended by cancer patients in LDI. Results: Fifty-one articles were included in the comprehensive literature review following the database search and the inclusion criteria. Numerous studies concluded that chemotherapy and other anticancer treatments in children are linked to increased dental anomalies like microdontia and enamel defects, especially when treatment occurs at a young age. The findings have been summarised in tables. Of the 806 registered appointments identified, the clinical records of 85 childhood cancer survivors who met the inclusion criteria were included. The post-treatment identified conditions included microdontia, hypodontia and enamel hypoplasia. Demographics, cancer diagnosis and type of treatment, in addition to dental findings, were summarised in tables. The data were also categorised according to age at the cancer treatment time and type of treatment provided. Conclusions: The literature review and LDI patient data revealed that childhood cancer survivors commonly face serious long-term dental issues due to their treatments. These findings highlight the importance of a better understanding of cancer therapy's impact on orofacial development, requiring more attention and support from healthcare professionals, particularly dentists.37 0Item Restricted Contribution of Chronic Myeloid Leukaemia Niche to Metastasis and Treatment Resistance(University of Glasgow, 2024) Albilasi, Hakem; Machesky, Laura; Kirschner, Kristina; Jorgensen, HeatherChronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder hallmarked by the Philadelphia chromosome, leading to the formation of the BCR::ABL1 fusion protein and subsequent uncontrolled cell proliferation. Although the advent of tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) has considerably improved patient outcomes, drug resistance and relapse remain a significant challenge. Leukaemia-related deaths and mortalities are often linked to these challenges which are a major cause of human financial and social costs of the disease. The bone marrow microenvironment (BMM) plays a crucial role in normal haematopoiesis and is also the main protection of leukaemic stem cells (LSCs). In CML, the BMM enhances leukemogenesis through an interaction with LSCs, and in turn, LSCs modify the BMM based on their requirements. Mesenchymal stem cells (MSCs) within the BMM are particularly significant, as they can support haematopoietic cells distinctly. The interactions between CML cells and the BMM, including MSCs and the extracellular matrix (ECM), have been shown to influence CML cell proliferation and responsiveness to IM. Moreover, cytoskeletal dynamics also play a crucial role in CML progression and drug resistance. In CML, alterations in cytoskeletal dynamics have been linked to drug resistance and disease progression. Therefore, this thesis will focus on the contribution BMM to these issues, with a particular interest in the role of MSCs and ECM on CML cells. In this thesis, direct contact with MSCs, treatment with MSC-conditioned media, and ECM component exposure were employed to investigate the role of the BMM and MSCs in the proliferation of CML cells and their interaction with the ECM and cell adhesion molecules. Furthermore, the effect of inhibiting specific cytoskeletal components on CML cell behaviour will be examined. The results of this thesis shed light on the complex interplay between CML cells and the BMM, highlighting the critical role of MSCs in modulating CML cell behaviour. While our results did not find a definitive impact of the ECM components on CML cell proliferation or IM sensitivity, the observations suggest that MSCs have the potential to influence the behaviour of CML cells but not definitively affecting their sensitivity to the TKI, IM. Furthermore, inhibiting cytoskeletal components such as the Arp2/3 complex and FAK did not significantly alter the CML cells' contact with MSCs. However, further investigation is necessary to investigate the molecular mechanisms regulating the interaction between CML cells and their microenvironment. Finally, the relationship between CML cells and MSCs, as shown by our transcriptomic analysis, reveals not just alterations in gene expression but also the promise of identifying novel therapeutic targets. The dysregulated pathways in co-cultured K562 cells and MSCs highlight the potential for therapeutic intervention strategies that could disrupt the supportive role of the BMM in CML persistence. The modulation of integrin alpha 9 (ITGA9) expression in K562 cells under co-culture conditions highlights the complexity of CML-MSC interaction and suggests an adaptive mechanism that may contribute to the survival and drug resistance of CML cells within the BMM. Therefore, targeting integrins could potentially enhance the efficacy of existing CML treatments, which in turn, might lead to more effective management of the disease and an increased rate of successful patient outcomes.13 0Item Restricted Understanding the roles of the Reprimo family of proteins in regulating cell behaviour in normal and cancer cells(University of Leeds, 2024-04-23) Arab, Mohammed Mahmoudsami A; Blair, GeorgeThe human Reprimo gene family comprises two genes, RPRM and RPRML. Lack of expression of the RPRM gene has been detected in many human cancer cell lines and tissues. In this study, an immunochemical analysis of the human RPRM was performed. This showed that RPRM could be detected as a FLAG-tagged protein in transfected 293T cells by Western blotting using either an anti-FLAG antibody or (at greatly reduced efficiency) a polyclonal antibody against RPRM. Subcellular fractionation experiments indicated that transiently-expressed RPRM is mainly present in the cytoplasmic fraction of transfected cells, however fractionation of the cytoplasm into cytosol and membranes revealed a predominant association of the 18kDa RPRM form with intracellular membranes. Analysis of several human cell lines for the endogenous RPRM forms also revealed a membrane location of the 18kDa RPRM form. Localisation of RPRM by immunocytochemistry also revealed it to be associated with membranous structures, that co-localised with the Golgi/endoplasmic reticulum. Immunohistochemical studies on normal and cancerous human tissues (including breast, pancreas and colon) provided further evidence for a membrane location of RPRM. Studies were performed on the reduction of the endogenous RPRM forms by RNA interference and the impact of RPRM reduction on the cell cycle. These studies revealed small, although significant effects of RPRM on the G1 to S and the of G2 to M phase transition. Over-expression of RPRM by transient transfection of MCF7 breast cancer cells or 293T kidney cells resulted in a block to the G2 to M phase. In summary, RPRM exists in a number of forms related by differential posttranslational modification, probably principally N-glycosylation. It has a major location with intracellular membranes and influences the cell cycle in different ways, dependent on the level of RPRM expression. However the link between RPRM membrane association and the cell cycle remains to be elucidated.45 0Item Restricted Assessment of Healthy Tissue Metabolism to Predict Outcomes in Oncologic [18F]FDG PET/CT(King's College London, 2024-03-01) Malaih, Afnan A.; Fischer, Barbara Malene; Barrington, Sally F.Background: The use of 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) in positron emission tomography/computed tomography (PET/CT) imaging is not specific to oncologic applications but reflects various pathologic processes with high metabolic activity. Thus, evaluating healthy tissue metabolism (HTM) based on [18F]FDG in cancer patients receiving cytotoxic anti-cancer treatment may provide prognostic information which could potentially assist in identifying patients at high risk of developing treatment-related adverse events (AEs) and those who may have poor outcome. However, unlike cancer imaging HTM assessment with [18F]FDG is lacking standardization in the research setting. Purpose: The main aim of this thesis was to review the applications of [18F]FDG PET/CT in the assessment of anti-cancer treatment-related AEs and to assess methods used in the literature to measure HTM. Further, to evaluate the repeatability and interobserver variation of HTM in lung cancer patients. Finally, HTM based on [18F]FDG uptake was assessed as an imaging biomarker to predicts AEs and outcomes in Hodgkin lymphoma (HL) patients. Methods: A comprehensive literature search was conducted in PubMed, Embase and Web of Science databases for published data on [18F]FDG uptake in different HT for assessment of AEs in cancer patients. Different common and modified methods of assessment were applied to measure [18F]FDG uptake in liver, spleen and other HT. Retrospective test-retest repeatability and interobserver analyses of HTM were also performed on 22 patients with non-small cell lung cancer who underwent [18F]FDG PET/CT of the thorax 2 days apart without intervening treatment (from a prospective study) to measure the maximum, mean and peak standardised uptake values (SUVmax, SUVmean and SUVpeak). Moreover, [18F]FDG uptake in 200 patients with advanced HL from the RATHL trial was retrospectively measured in bone marrow (BM), mediastinal blood pool (MBP), liver and spleen at baseline (PET0) and after 2 cycles of chemotherapy (PET2). Results: Out of the reviewed studies, (n = 80, 94%) reported an association between [18F]FDG uptake in HT and treatment-related AEs. Quantitative assessment using SUVmean was mainly applied in those studies to assess changes in HTM at multiple timepoint. Further evaluation of the liver, spleen and other HT showed that using SUVmean reduces bias across different methods. Further, applying fixed volume of interest (VOI) was comparable to more sophisticated approaches. In comparison to other PET metrics, SUVmean also showed better repeatability as expressed with the within-subject coefficient of variation (wCV) of 20% and high interobserver agreement of ≤10% in HT in the thorax; however, left ventricle uptake was highly variable in a test-retest analysis. In HL, HT uptake changed significantly during treatment. BM uptake at PET0 was associated with baseline haematological parameters, higher risk of neutropenia at cycles 1-2 and failure of early response. Non-responding patients with high BM uptake at PET2 had inferior progression-free survival (PFS). Conclusion: Most of the studies reviewed from the literature reported an association between HTM and treatment-related AEs among different cancer types and treatment modalities. SUVmean was mainly used in those studies to correlate changes in HTM with treatment-related AEs which was shown to be more stable than SUVmax and SUVpeak. [18F]FDG uptake in uninvolved BM has a prognostic value in HL.20 0Item Restricted The impact of a cancer diagnosis and its subsequent treatment on the HRQOL of children in Saudi Arabia in light of international practices for newly diagnosed cases A quantitative systematic review(Saudi Digital Library, 2023-12-13) Alhussain, Fayzah; Langmack, GillThe global impact of cancer on health-related quality of life (HRQOL) is significant, especially for children undergoing oncological treatment. While research on HRQOL among child cancer survivors is abundant, there is a lack of representation among those actively undergoing treatment. Furthermore, Saudi Arabian data remains less explored. Objective This systematic review aims to bridge this research gap by quantitatively evaluating the HRQOL of children in Saudi Arabia during their active cancer treatment phase. The study also juxtaposes these findings with global practices, emphasising demographic, medical and parental predictors of HRQOL. Methods A comprehensive search was conducted across prominent databases including MEDLINE, CENTRAL, EMBASE, PsycINFO, and CINAHL. The search explored studies conducted in Saudi Arabia investigating HRQOL during oncological treatment for children and adolescents, alongside studies from other countries exploring newly diagnosed cases. The JBI-Critical Appraisal Checklists were used to assess the quality of each study. The outcomes were synthesised using narrative methods. Results A systematic review of nine studies was conducted, encompassing 859 paediatric cancer patients. It was observed that all children undergoing cancer treatment experienced a decline in HRQOL. In Saudi Arabia, the psychosocial domain was particularly impacted, more so than the physical domain. The newly diagnosed phase was identified as having the most compromised HRQOL compared to the other stages of the illness. Longitudinal studies showed improvement over time. Several predictors influenced HRQOL including clinical, demographic and parental factors. Conclusion Paediatric cancer patients face profound physical, emotional and psychosocial challenges. Tailored interventions and paediatric palliative care integration are urgently needed to enhance HRQOL. This study underscores the need for more in- depth clinical research in Saudi Arabia, focusing on diverse aspects of HRQOL to optimise treatment outcomes for children with cancer.42 0Item Restricted What are the barriers to the early integration of paediatric palliative care? A systematised review(Saudi Digital Library, 2023-12-03) Aljardahi, Rakan; Mcfeely, ClareBackground: Children with serious illnesses, such as cancers or congenital anomalies, require special care that alleviates the disease burden. Paediatric palliative care (PPC) is comprehensive, interdisciplinary care for patients and their families that begins once a life-threatening disease has been diagnosed. PPC’s early integration with curative treatments has been proven to relieve suffering and enhance both patients’ and families’ quality of life. Nonetheless, few paediatric patients access and receive these services. Aim: To identify and synthesise the barriers to PPC’s early integration. Methods: This systematised review is based on PRISMA guidelines. The Medline, Embase, PsychInfo and CINAHL databases were searched using controlled and non-controlled keywords and a variety of research strategies. This search was limited to peer-reviewed studies published in English between 2018 and 2023. Based on the inclusion criteria, Covidence software was used to screen, extract and assess the retrieved studies, which were evaluated using the CASP and MMAT checklists. Findings were synthesised using narrative synthesis with inductive thematic analysis. Results: Eight studies of medium to high quality met the inclusion criteria. Three main themes were identified: limited resources, the lack of a standardised referral process and fears associated with palliative care. Conclusion: Reflecting the insufficient attention the speciality receives, several modifiable barriers impede paediatric patients from accessing the early benefits of palliative care services. PPC requires financial support, community awareness and a clear referral process. Policymakers play an important role in supporting PPC, and researchers must work to explore policymakers’ perspectives on these barriers and find facilitators.32 0