SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item Restricted Legal implications of digital currency on traditional commercial transactions(Bangor University, 2024) Alshehri, Mohammad; Andrew, BakerThe dissertation examined the legal implications of digital currency integration into traditional commercial transactions and proposed regulatory adaptations to address the connected challenges. The dissertation adopted a secondary research methodology with a doctrinal legal research approach and analysed data from academic journals, industry documents and regulatory reports. The legal aspect of the study, including legislation and case laws, was analysed using the doctrinal legal research method. Thematic analysis of the secondary sources helped to synthesise the findings to respond to the five key research questions on the evolution of UK laws on money digitisation, regulatory challenges and integration into traditional contractual frameworks, implications for consumer protection and regulatory compliance and lastly, policy recommendations. The findings indicated that even though digital currencies are beneficial as they enhance data privacy, are cost-effective and leverage the gains of smart contracts, major challenges like regulatory uncertainty and legal ambiguities remain. The dissertation recommended policies such as establishing guidelines for adaptive regulation, strengthening AML measures, enforcing fair and transparent practices, promoting standards for data privacy and security and launching consumer education programmes. The implications of the study extend to financial institutions, regulators, policymakers and consumers, with the suggestion that digital currency integration into traditional financial systems calls for clear regulatory adaptation. Future research should assess the success of collaborative efforts among stakeholders and analyse the wider economic impacts of digital currency integration21 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 Hypercholesteremia as a regulator in Haematopoiesis and Leukaemic Stem Cells in Acute Myeloid Leukaemia(Cardiff University, 2023-06-15) Taha, Sarab; Rodrigues, NeilAccumulating evidence suggests an emerging association between perturbed haematopoiesis, development of leukaemia and cardiovascular disease in the context of a high-fat western diet. To explore this subject, I investigated the role of atherosclerosis prone low-density lipid receptor (Ldlr) in normal and leukaemic haematopoiesis and the impact of a high-fat diet (HFD) or normal chow diet (ND) in this setting. In steady-state, under normal dietary conditions, mice engineered to be deficient in the LDL receptor (Ldlr-/-) had increased numbers of haematopoietic stem cells (HSCs), which was associated with increased cell cycling and an increase in inflammatory cytokines and chemokines. In Ldlr-/- mice bone marrow differentiation, as assessed by the CFC assay, was decreased while paradoxically white blood cells were increased which mapped to CD4+ T cell and monocyte increases in the peripheral blood. To induce hypercholesteremia and atherosclerosis, Ldlr-/- mice were fed a HFD and the attendant impact on haematopoiesis was evaluated. A significant increase in HSCs and associated early progenitor compartments (HSPCs) was noted in Ldlr-/- mice fed HFD alongside an increase in committed progenitor cells of both the myeloid and lymphoid lineage. As expected, inflammatory immune cell subsets were increased together with increases in platelets and alterations in regulatory immune cells in Ldlr-/- mice fed HFD. HSCs from Ldlr-/- mice fed HFD performed poorly in functional analysis, as judged by competitive transplantation, displaying significant multi-lineage differentiation defects. Underpinning these defects, RNA-seq analysis revealed altered apoptosis, inflammation, lipid metabolism pathways, RNA biology, and AML-enriched gene pathways in HSCs from Ldlr-/- mice fed a HFD. These molecular pathways mapped not only to haematological diseases, like AML, and cardiovascular disease, but also nephrotoxicity and hepatoxicity, highlighting the widespread impact of perturbed haematopoiesis induced by HFD and atherosclerosis. Unexpectedly, we found that MLL-AF9 transformed HSPCs from Ldlr-/- mice fed a HFD developed AML later than their ND counterparts, but this was likely reflected by a delayed migration of leukaemic blast cells from BM to PB. This argument was supported by altered adhesion protein expression in human MLL-AF9 AML cell lines exposed to atherogenic lipoproteins in vitro. Decreased markers of immune recognition were also observed in human MLL-AF9 AML cell lines exposed to atherogenic lipoproteins in vitro. The data provided in this thesis provide mechanistic insights into how HFD epigenetically disrupts HSC function and haematopoiesis in the setting of atherosclerosis, and it provides a starting point to explore further relationship between HFD, atherosclerosis and how perturbed haematopoiesis can lead to AML.8 0Item Restricted Thermal shift analysis of small molecule inhibitors of YTHDC1 and YTHDF1 using Differential Scanning Fluorimetry as a target for treating acute myeloid leukaemia.(University of Nottingham, 2023-09-22) Jarallah, Somayah; Winkler, SebastiaanAcute myeloid leukaemia (AML) is an aggressive haematological malignancy. It is the leading cause of annual leukaemia-related deaths worldwide. Despite current therapeutic approaches, fewer than 30% of AML patients survive more than five years after diagnosis. Recent research has highlighted the significance of RNA modifications, particularly N6-methyladenosine (m6A), in AML pathogenesis. m6A is one of the most abundant and conserved internal co-transcriptional modifications found in eukaryotic messenger RNA (mRNA). This study focused on understanding the role of YTH domain proteins, specifically YTHDC1 and YTHDF1. These proteins recognise and interact with m6A-modified RNA, influencing mRNA fate and cellular processes. The study aimed to identify small-molecule inhibitors targeting human YTHDF1 to promote the development of novel therapeutic agents for AML. It used a series of 17 analogues derived from two previously described compounds. Differential scanning fluorimetry analysis was used to evaluate the thermal stability of these compounds with YTHDC1 and YTHDF1. The study found no significant impact of most compounds on YTHDC1 or YTHDF1, except for one compound.32 0Item Restricted Exploring the Role of Prostaglandin G/H Synthase Signalling in Chemoresistance in Acute Myeloid Leukaemia(University of Liverpool, 2024-03-05) Alshammari, Abdullah Mohammad D; Woolley, John; MacEwan, DaveAntioxidant signalling is demonstrated to be important for leukemic stem cell (LSC) and haematopoietic stem cell (HSC) function. HSCs, which are found in the bone marrow, are found to be more quiescent under hypoxic conditions. Reduced cell division creates problems for these cells, with the majority of cells using this process to address oxidative damaged DNA and proteins. In this situation, HSCs must approach oxidative damage management in other ways. Prostaglandins improve mechanisms to protect from oxidative stresses through causing reductions in reactive oxygen species (ROS). Prostaglandin G/H synthases (PTGS1/2) play the main role in catalysing synthesis of prostaglandins. Research has demonstrated that PGE2, produced through PTGS1/2 activity, assists HSCs in surviving, proliferating and homing within their niche. Similarly, the data provided in this study points to a protective function of PTGS1/2 signal pathways for acute myeloid leukaemia. PTGS genes were investigated for their association with outcomes in AML, in an approach combining biochemistry, bioinformatics, molecular biology and cellular biology. Analysis of bioinformatics databases aimed to assess how PTGS1/2 was expressed in AML and the effects of this expression on outcomes including overall survival. An efficacy assessment was made for PTGS1 inhibitors (SC560, Tenidap) for AML cell lines. Flow cytometry was used to evaluate the cell cycle and apoptosis. Lentiviral PTGS1/2 over-expression was used for U937 and HL-60 in order to assess how these genes act in cell survival, proliferative activity and resistance to drugs. Finally, PTGS1/2 was analysed in terms of promotion of immunosuppression in acute myeloid leukaemia. Investigation of freely accessible bioinformatics databases demonstrated increased PTGS1 expression in the HSC, which reduced in cells committed to a lineage for myeloid progenitor cells. This was not found for PTGS2. There is a notable association between increased expression of PTGS1 and lower overall survival in data on AML (TCGA, Verhaak), with none seen for PTGS2. Findings in vitro show that inhibiting PTGS1 (SC560, Tenidap) leads to decreased growth of cells, arrests the cell cycle and elevates apoptosis. Overexpressed PTGS1 leads to higher WNT signalling for AML cell lines, as well as raising PGE2 secretions and reversing PTGS1 inhibitor impacts. Other effects of increased PTGS1 expression include resistance to cytarabine, as linked with lower generation of ROS. It is notable that overexpression of PTGS1 and PTGS2 lead to significant differences in transcriptome alterations in AML, which could explain the varied patient outcomes with PTGS1/2 overexpression.18 0Item Restricted Exploring Mechanisms of Sensitivity and Resistance to Novel Therapeutic Targets in Aggressive Blood Malignancies.(University of Leicester, 2024-02-13) Alzahrani, Wael Ibrahim H; Macip, SalvadorChemotherapy is commonly used to induce cell death in diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukaemia (AML), but not all patients respond well, and toxicities may be great; there remains a need for effective precision cancer medicines. Dihydroorotate dehydrogenase (DHODH) is a mitochondrial matrix enzyme involved in de novo pyrimidine synthesis, playing a crucial role in DNA and RNA synthesis. CRISPR studies have shown that DHODH is an essential gene in haematologic cells. BAY 2402234 is a highly specific DHODH inhibitor. My studies revealed that BAY 2402234 induced caspase-dependent apoptosis, uridine exogenous addition rescued cells from pyrimidine starvation and showed potential for synergy with BH3 mimetics in some DLBCL and AML cell lines. DHODHi are toxic and ineffective for cancer patients in clinical trials, so acquired resistance to BAY 2402234 was investigated in the OCI-LY19 DLBCL cell line, which is highly sensitive to DHODHi (IC50 of 5pM). In a derived cell line with 200,000-fold resistance, I identified a novel DHODH missense mutation (A58T), which was predicted to prevent the binding of BAY 2402234 but not to interfere with DHODH’s function. RNA-Seq experiments exhibited significant gene expression changes occurring in hallmark pathways with a specific emphasis on MYC OXPHOS and glycolytic targets. Additionally, elevated expression of PI3KCD was observed. Copanlisib a pan-PI3Ki synergised with BAY 2202234 in resistant OCI-LY19 cells, prompting its evaluation as a potential sensitiser. Collectively these findings provide insights for developing effective DHODHi combination therapies that might mitigate toxicities seen with DHODHi in vivo. I also investigated various approaches, such as a BCL-2 inhibitor, or other BH3 mimetics in combination with 14-3-3σ stabilisers FC-A and WR-1065, or MDM2 antagonist and inhibiting the B-cell receptor pathway using Tirabrutinib, CAL-101. DLBCL and AML cell lines showed diverse responses based on subtype and genetics, underlining the need for personalised treatments.36 0