SACM - United Kingdom
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Item Restricted Evaluation of DNA Repair Biomarkers in Epithelial Ovarian and Breast Cancers(Saudi Digital Library, 2025-01-02) (Shoqafi, Ahmed); Madhusudan, SrinivasanDNA damage signalling and repair pathways play a crucial role in the regulation of genomic stability. Impaired DNA repair promotes genomic instability, a key route to the development of cancers. Cells have developed signalling pathways that are activated in response to DNA damage to detect and repair the damage that has occurred. Ataxia-Telangiectasia Mutated (ATM) and Ataxia-Telangiectasia and Rad3-related (ATR) kinases are activated in the presence of DNA damage and initiate a series of phosphorylation events that lead to the activation of downstream effectors. Some of these effectors include p53 and BRCA1, which regulate cell cycle, DNA repair, and apoptosis. The major DNA repair pathways are nucleotide excision repair (NER), which removes bulky DNA adducts; base excision repair (BER), which is involved in repairing small, non-helix-distorting base lesions; mismatch repair (MMR), which corrects replication errors and double-strand break repair which include homologous recombination (HR) and non-homologous end joining (NHEJ). All these pathways are regulated in a manner that is specific to the type of damage that needs to be repaired so that repair is as accurate as possible. Since conventional therapies for advanced epithelial ovarian cancer (EOC) and breast cancers have been found to be less effective, there has been a shift to search for new therapeutic approaches that aim at targeting the DNA repair pathways. The host laboratory, using whole-exome sequencing in platinum-sensitive (PEO1, A2780) and platinum-resistant (PEO4, A2780cis) ovarian cancer cell lines, identified TP73 and POLE as potential predictors of platinum resistance. In the current study, I have investigated the role of TP73 and POLE in EOC and breast cancers in detail. TP73 is a member of the TP53 family of transcription factors that are involved in DNA repair, cell growth, migration, and death. In 331 EOC samples, I observed that high protein expression of TP73 was associated with higher tumour grade, late-stage disease and shorter progression free survival (PFS). In the large publicly available clinical cohort (n=522) and the cancer genome atlas (TCGA) ovarian cohort (n=182), TP73 transcript was upregulated in tumours compared to normal tissues and associated with shorter PFS. Preclinically, I have shown that overexpression of TP73 in A2780 platinum-sensitive ovarian cancer cells enhanced cell proliferation, invasion and increased DNA repair capacity. In clinical breast cancers, analysis of TP73 expression in 1,369 invasive breast cancers and 317 DCIS cases revealed that high cytoplasmic TP73 expression is significantly associated with aggressive disease features, including high tumour grade, ER negativity, triple-negative phenotype, and poor breast cancer-specific survival, particularly in the TP53 mutant subgroup. These findings highlight the prognostic and predictive significance of TP73 in EOC and breast cancers. POLE has roles during DNA replication and repair pathways. I have investigated POLE expression in EOC and breast cancers. Immunohistochemical analysis of 331 EOC samples revealed that 75% exhibited low nuclear POLE expression, while 25% showed high expression. High POLE levels were significantly associated with higher tumour grade, poor progression free survival (PFS) and overall survival (OS). The transcriptomic levels of POLE were analysed in patients with EOC, revealing that high POLE mRNA expression was significantly associated with poor progression free survival (PFS) and overall survival (OS) (All p=<0,05). Functional studies in platinum-resistant OVCAR 4 cells demonstrated that POLE knockdown increased cisplatin sensitivity, which was associated with double-strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. The data supports the role of POLE in predicting response to platinum chemotherapy in EOC. The study of 1,480 invasive breast cancer cases revealed that exhibited low nuclear POLE expression, which was associated with aggressive tumour features, poorer breast cancer specific survival (BCSS), and reduced response to endocrine therapy in ER+ and luminal subtypes. These findings suggest that POLE may be a predictive factor in ER+ breast cancers. Taken together, the data provides evidence for the role of TP73 and POLE as potential biomarkers in EOC and breast cancers.37 0Item Restricted Hope, Despair, and Environmental Discourses in Contemporary North American Speculative Fiction(Saudi Digital Library, 2025-06-24) Alotaibi, Hind Mater; Feghalim ZalfaThis thesis examines contemporary North American speculative fiction through an environmental perspective. It explores emotions and environmental discourses portrayed in nine novels, tracing authors’ utilization of hope and despair both as themes and emotional states to envision the future interconnectedness of humanity and the environment. As it connects literature, emotions, and the environment, this study expands the scope of how contemporary environmental speculative fiction is analysed by moving beyond the focus on scientific and economic facts to also include the emotional language and expressions in such texts. It does so through analysing nine novels in which the bonds between humanity and the environment are explored, both emotionally and ecologically: Margaret Atwood's Oryx and Crake (2003), Paolo Bacigalupi's The Water Knife (2015), T. C. Boyle’s A Friend of the Earth (2000), Barbara Kingsolver’s Flight Behavior (2012), Nathaniel Rich’s Odds Against Tomorrow (2013), Kim Stanley Robinson’s New York 2140 (2017), Louise Erdrich’s Future Home of the Living God (2017), Sherri L. Smith’s Orleans (2013), and Cherie Dimaline’s The Marrow Thieves (2017). Across the three broad sections on the consequences of human behaviour on the natural world, climate change, and environmental justice, this thesis asserts the vital role of the expressions of hope and despair as tools for communicating and shaping environmental discourses in contemporary speculative fiction and as fundamental elements of the storytelling, mirroring the ambiguity and uncertainty of future environmental issues. The simultaneous presence of both hope and despair in such narratives is not only determined by human-nonhuman interconnectedness but also aligns with the underlying cultural, historical, societal, and environmental contexts that shape this connection. This alignment, I contend, allows for more broader understanding of the term “Anthropocene” in contemporary texts, one that highlights diverse experiences and voices, especially when applied to literary texts that explore human-nonhuman interactions within various community contexts. Reading contemporary speculative fiction at the intersection of ecocriticism, environmental humanities, and affective ecocriticism, I argue, not only reveals the intricate depiction of human-nonhuman connection in these novels but also the ways in which authors position readers to be part of a wide range of environmental issues.6 0Item Restricted Implementation of a Competency Framework in Saudi Undergraduate Medical Education(Saudi Digital Library, 2025-06-24) Alqarni, Mohammed; Roberts, Trudie; Farnsworth, Valerie; Goddard-Fuler, RikkiIn 2011, a competency-based medical education (CBME) framework called SaudiMEDs was developed in Saudi Arabia to serve the community with medical graduates who can competently fulfil society’s health needs. SaudiMEDs serves as a guide to designing, developing, and evaluating medical school curricula. Despite the widespread implementation of SaudiMEDs, no research has been conducted on how medical education has been shaped as a result of SaudiMEDs. This study’s primary aim is, therefore, to investigate the real-time implementation of SaudiMEDs and its impact on Saudi medical schools. Qualitative case studies with two medical schools across the country were conducted to investigate how SaudiMEDs had been implemented. Documentary analysis of the medical schools’ documents, semi-structured interviews with academic leaders, and focus groups with faculty members and students were carried out for each school. Framework analysis for documents and Reflexive thematic analysis for interviews and focus groups were used to identify patterns and concepts and to conceptualise and construct meaning from the data. Analysis revealed a complex network of mixed perceptions of SaudiMEDs which, based on identified variations in teaching strategies, ways of learning and assessment methods, are considered as a key influence shaping implementation of SaudiMEDs. The perceptions of faculty members and students provide insight into the culture of each medical school and how it mediates implementation. The study also identifies different challenges in the SaudiMEDs implementation, which could provide further explanation for the variation in each medical school context. A key finding was the challenge of translating curriculum innovation developed in and for Western, specifically North American, contexts to the distinct organisational and institutional culture of Saudi Arabia. One consequence of this was that schools in this study approached implementation as a mapping activity and focused on the short-term accreditation standard requirement rather than a longer-term evaluation. This limited the ability of SaudiMEDs to achieve its stated aims. The research helps to identify what needs to be done to enable the fruitful transformation of SaudiMEDs into robust curricula: a) a rigorous review of SaudiMEDs to contextualise community health needs and b) support for CBME implementation through the enactment of the legislation, training, and establishment of appropriate information technology infrastructure to provide authentic experiences for learners.22 0Item Restricted Development of a novel and affordable vaccine against hepatitis A virus(Saudi Digital Library, 2024) Aljanabi, Walla; Groppelli, ElisabettaThis project aimed to develop an inventive and affordable vaccine against hepatitis A virus (HAV) by producing HAV virus-like particles (VLPs) in plant systems. The main objective was to generate the expression plasmids for the structural protein P1 and the non-structural protein 3C, with the addition of an HA-tag, and to validate their expression through several laboratory experiments. The workflow begins with primer designing specific to the P1 and 3C regions of the HAV genome, followed by PCR amplification and the creation of the expression constructs pCMVTnT-P1 and pCDNA3.1-HA-3C. Verification of these plasmid constructs was confirmed via restriction enzyme digestion and ligation. Primary protein expression was carried out in vitro using Rabbit Reticulocyte Lysates (RRL). At around 27 kDa bands were observed in both the HA-3C and control lanes, referring to unexpected bands and non-specific rather than successful protein expression, as shown and confirmed by Western blotting. These findings suggest that while the TnT RRL system did not generate enough amounts of the desired proteins, in mammalian cells the constructs were successful and detectable. The observations of this study integrate with past research on applying heterologous systems for viral protein expression and support the possibility of converting to plant-based expression systems to produce VLPs. This technique has implications of significance for generating affordable and expandable HAV vaccines, specifically for low-income areas where hepatitis A has a high incidence rate. Further studies will focus on enhancing expression protocols and evaluating and analysing the immunogenicity of plant-produced VLPs to progress toward clinical practice.12 0Item Restricted CT Texture Characterisation of Perirenal Fat in Patients with Upper Urinary Tract Cancers(Saudi Digital Library, 2025-05) Al Mopti, Abdulrahman; Chunhui, LiThis thesis investigates the diagnostic and prognostic potential of perirenal fat (PRF) radiomics in upper urinary tract cancers through three interconnected studies. Using computational techniques to extract quantitative features from CT images, the research establishes PRF as a valuable biomarker for tumour behaviour assessment. The first study, examining clear cell renal cell carcinoma in 474 patients, demonstrates that models integrating tumour features, PRF radiomics, and clinical variables achieve high accuracy for tumour grade (AUC 0.780) and stage prediction (AUC 0.829). Analysis reveals that PRF regions at 4-10mm radial distances from tumours contain the most predictive information. The second study on upper tract urothelial carcinoma (UTUC) reveals excellent performance of combined models in predicting tumour grade (AUC 0.961) and stage (AUC 0.852). PRF-only models also show substantial discriminative capability, confirming that PRF contains distinct textural patterns associated with tumour aggressiveness. The final study establishes the prognostic value of PRF radiomics in UTUC through survival analysis, with the combined radiomics-clinical model achieving a C-index of 0.784. Key radiomics features emerge as strong prognostic indicators, particularly when integrated with clinical variables like stage and hydronephrosis. Methodologically, the research develops a semi-automated approach for PRF analysis and implements a standardised radiomics workflow. The findings contribute novel insights by establishing PRF as an independent source of diagnostic information, developing standardised methodology for analysis, identifying specific radiomic signatures of aggressive disease, and creating predictive models that outperform conventional assessment. This work demonstrates that non-invasive analysis of PRF can enhance risk stratification and treatment planning in upper urinary tract cancers.20 0Item Restricted ISLAMIC CIVILISATION AND SAUDI NATIONAL IDENTITY AT ITHRA MUSEUM: CULTURAL HERITAGE AND EXPERIENCES OF DIGITISATION(Saudi Digital Library, 2025) Almalki, Rabab; Hatchwell, SophieThis thesis investigates audience experiences of digitisation at Ithra Museum, Saudi Arabia. It demonstrates the impact of digitisation on the preservation of Saudi cultural Heritage and the production of collective memory through the exhibitions at Ithra. Overall, it reveals Islamic civilisation to be a central aspect of the view of Saudi national identity produced at this museum. Its originality lies in its exploration of the relationship that Ithra constructs between Islamic civilisation and Saudi national identity in the digital age, considering the Museum’s international standpoint. It makes two contributions to museum studies: first, it investigates how the cultural context of a Saudi museum relates to the wider context of global Islamic culture; second, it asks how technology is being used in the context of Saudi museum practise. The thesis uses a mixed-methods approach based on the analysis of primary quantitative and qualitative data collected by means of a questionnaire with both closed- and open-ended questions, a second, closed-ended questionnaire and a structured interview. The first and second chapters of the thesis investigate audience experiences of digitisation at Ithra and how these affect their perspective on national identity. The third and fourth chapters explore the impact of digitisation at Ithra museum on Saudi collective memory by evaluating Ithra members’ approach to heritage preservation. The fifth and sixth chapters further consider the audience experience of digitisation and how this affects their views on the conservation of Saudi Arabian cultural heritage and the authenticity of museum objects.5 0Item Restricted The influence of hydraulic calcium silicate cements (HCSC) composition on the cell behaviour of human dental pulp stem cells (hDPSC)(Saudi Digital Library, 2025-06) AlGhamdi, Saleh; (Longridge, Nicholas), (Hamill, Kevin), (Yamamoto, Kazuhiro), (Jarad, Fadi), (Moawad, Emad)Introduction: There is growing interest in new endodontic materials used during vital pulp treatment (VPT), particularly hydraulic calcium silicate cements (HCSCs) including Biodentine™, TheraCal LC®, and TotalFill® formulations. Human dental pulp stem cells (hDPSCs) play a crucial role in reparative and regenerative pulp therapy through their capacity to differentiate into odontoblast-like cells and form reparative dentine. During VPT procedures, materials are designed to replace dentine and interact directly with viable pulp tissue. Understanding these material-tissue interactions is vital for predicting pulpal responses and optimising treatment outcomes. Aim: To investigate the influence of different hydraulic calcium silicate cements on the behaviour of human dental pulp stem cells. Methods: The study investigated the cellular response of hDPSCs to different HCSCs. The materials evaluated included Biodentine™, TheraCal LC®, TotalFill® BC RRM™ Fast Set Putty and TotalFill® BC RRM™ Putty. A multi-method approach was employed to assess cellular responses through metabolic activity, cell numbers and morphological analyses. Metabolic activity was assessed using the Resazurin assay under two experimental conditions: filtered extraction media and hanging insert methods. Cell numbers were quantified using the CyQUANT® assay, whilst morphological assessment was conducted using inverted microscopy. All analyses were performed at 24 and 48-hour time points. Additionally, scanning electron microscopy (SEM) was employed to evaluate cellular attachment to material surfaces. Results: Biodentine™ demonstrated consistently superior performance across all evaluation parameters. Its ability to maintain high metabolic activity, support normal cell morphology and facilitate cellular attachment suggested it created an optimal microenvironment for hDPSC survival and function. This superior performance was particularly evident in both the extraction media and hanging insert experiments, where Biodentine™ exhibited the highest metabolic activity at both 24 and 48-hour time points. TotalFill® BC RRM™ Fast Set Putty emerged as a promising alternative, showing comparable performance to Biodentine™, particularly after 48 hours of exposure. The material demonstrated good biocompatibility, supporting normal cell morphology and cellular attachment, with metabolic activity levels approaching those of Biodentine™ after 48 hours. Conversely, TheraCal LC® consistently showed inferior biological performance across all assessment methods. The material exhibited significantly lower metabolic activity, altered cell morphology and notably poor cellular attachment. These findings raised concerns about its suitability for direct pulp capping procedures, particularly in cases where maintaining optimal stem cell function is crucial for successful pulp repair. The CyQUANT® assay revealed similar patterns, with Biodentine™ and the control group showing the highest cell numbers at 24 hours. SEM analysis confirmed robust cellular attachment on Biodentine™ and both TotalFill® formulations, whilst TheraCal LC® exhibited poor cellular attachment. Conclusion/ Clinical application: Within the limitations of this in vitro study, Biodentine™ and TotalFill® BC RRM™ Fast Set Putty demonstrated superior biological performance, creating more favourable conditions for hDPSC survival and function compared with TheraCal LC®. The consistency of results across multiple assessment methods provided robust evidence for material-dependent effects on pulp cell behaviour, with important implications for material selection in VPT procedures. These findings have important clinical implications for material selection in VPT procedures. The superior biological performance of Biodentine™ and TotalFill® BC RRM™ Fast Set Putty suggests these materials may be more favourable choices for maintaining pulp cell viability and function. The consistent underperformance of TheraCal LC® indicates that careful consideration should be given to its use in direct pulp capping and pulpotomy procedures, particularly in cases where optimal stem cell function is crucial for successful pulp repair.21 0Item Restricted Effect of Degradation on Long-term Stability of 3D-printed Dental Crowns(Saudi Digital Library, 2025-07-04) Tayeb, Hunaida Khaled; Silikas, Nick3D printing technology in digital dentistry has led to innovative approaches for fabricating indirect dental restorations. However, a comprehensive assessment of the properties and long-term performance of these materials is essential. Therefore, this thesis aimed to evaluate the durability of mechanical, optical and surface properties of novel 3D-printed ceramic-filled resin composite materials indicated for definitive crown restorations. The first experimental chapter assessed the mechanical properties (flexural strength, flexural modulus, Martens hardness, indentation modulus and Vickers hardness) of three 3D-printed resin composites (Permanent Crown Resin, VarseoSmile Crown Plus, and Crowntec) and three milled resin composite blocks (BRILLIANT Crios, SHOFU Block HC and Grandio Blocs). The findings revealed that the 3D-printed definitive resin composites showed clinically acceptable mechanical properties, however, the milled resin composites showed significantly superior mechanical properties. The second experimental chapter explored the impact of immersion in food-simulating solvents on flexural strength, flexural modulus, Martens hardness, and indentation modulus of the same three 3D-printed resin composites and milled Grandio Blocs. Results indicated that exposure to solvents adversely affected the mechanical properties of all materials. Nevertheless, all tested materials showed acceptable mechanical properties after ageing. The third experimental chapter investigated the influence of artificial toothbrushing on surface roughness and gloss of the 3D-printed resin composites and the milled Grandio Blocs. Following 20,000 brushing cycles, both 3D-printed and milled resin composites exhibited increased surface roughness and reduced gloss, with 3D-printed materials exhibited comparatively lower wear resistance. Despite these changes, all tested materials maintained clinically acceptable gloss and roughness levels. The last experimental chapter examined the effects of immersion in various beverages on the colour stability (ΔE00), translucency, gloss and Martens hardness of the 3D-printed resin composites and milled Grandio Blocs. The results highlighted that both material type and beverage had a significant influence on the investigated properties, though ΔE00 of all materials remained within the clinically acceptable threshold of colour change across all beverages and measurement points.8 0Item Restricted Investigation of mechanisms and predictive markers of immune checkpoint inhibitor-induced immune-related adverse events.(Saudi Digital Library, 2025-01-30) Aboheimed, Nourah; Dan, Carr; Dean, Naisbittbstract: Introduction: Immune-related adverse events (irAEs) are significant limitations to the use of immune checkpoint inhibitors (ICIs). Over half of the patients on these medications experience irAEs, which vary in severity and affected organ. The identification of susceptible patients through biological biomarkers and genetic variations, along with an understanding of the immune mechanisms underlying these reactions, is a crucial goal in this field. Method: Our study utilized various methods to detect serum biomarkers, including ELISA, immunohistochemistry, and transcriptomic RNA analyses. We employed in vitro assays to elucidate the modulating effects of HMGB1 on T-cell and Treg suppression functions that affect the immune response. Additionally, TaqMan assays and genome-wide association studies (GWAS) were used to identify single nucleotide polymorphisms (SNPs) of interest. Results: HMGB1 was significantly elevated in the serum of patients with ICI-induced irAEs, particularly in those with gastrointestinal (GI) irAEs. Colon biopsies from these patients showed marked decreases in nuclear staining, indicating cellular death and HMGB1 translocation. Different HMGB1 isoforms varied in their effects on CTLA4 expression on CD3+ T cells, with dsHMGB1 notably reducing it. The effect of dsHMGB1 on CTLA4 expression in Treg populations showed intra-variability between donors and influenced the suppression function of Tregs on CD8+ and CD4+ T cells, which relates back to CTLA4 expression on these cells. Unfortunately, SNPs in the main receptor of dsHMGB1 (TLR4/MD2) were not significantly associated with the phenotype. However, female patients and those with a history of allergic reactions were significantly more likely to develop irAEs. ARG1 – a marker for MDSC and M2, was found to be significantly expresses in patients experiencing irAE. In our GWAS 14 snps exceeded our suggestive threshol d, these SNPs were mapped to regions of genes related to autoimmune disease and cancer. Discussion: Our findings highlight HMGB1's significant role in mediating immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors. Elevated HMGB1 levels, particularly noted in gastrointestinal irAEs, suggest its potential as a biomarker for irAE risk. Additionally, the influence of HMGB1 on CTLA4 expression in T cells and Tregs underscores 6 its impact on immune modulation. Despite the lack of significant associations with TLR4/MD2 SNPs, the identification of other genetic variants related to autoimmune conditions hints at a complex genetic underpinning that warrants further investigation to enhance irAE management strategies.17 0Item Restricted Optimization of Close Space Sublimation and Post Deposition Routes for Antimony Chalcogenide Solar Cells(Saudi Digital Library, 2025-06) Sindi, Daniya; Major, JonThis thesis explores the influence of close space sublimation (CSS) growth conditions on antimony selenide solar cells as well as the possible benefits of post-growth processing approaches including an assessment of protective layer annealing. Single and two-step growth approaches involving the use of seed layers to modify film coverage and grain structure were investigated as a way of improving the solar cell performance. Both isolated layers and complete device structures were fabricated to allow investigation of the interrelation of preferred ribbon orientation with device efficiency. It was identified that, whilst the use of a seed layer was an important step to achieve good film coverage and grain morphology, the ribbon orientation appeared to have minimal influence on performance. The developed CSS growth approaches were then expanded to produce antimony sulfoselenide films and devices for a single phase source material. It was demonstrated that the approach was feasible, allowing the formation of material with a notably higher bandgap than for the base selenide. This indicated that material did not completely degrade during sublimation with the resulting devices achieve >4% efficiency and with a notably higher open circuit voltage than selenide counterparts. There were however significant issues with the formation of large oxide phase regions within the absorber. These served to reduce the device performance with the cause being attributed to sulphur loss and reaction with oxygen, the growth ambient during deposition. Post growth annealing approaches to improve antimony selenide solar cell efficiency were systematically investigated. Air, selenium, and nitrogen environments were initially compared across a broad temperature range. The results highlighted the degree of sensitivity of the material to post growth annealing with bot air annealing and selenization causing minimal changes to film morphology but drastic performance loss. Nitrogen annealing appeared more favourable with some minor open circuit voltage increases, both again the overall trend was a decrease in cell performance. To overcome these limitations the nitrogen ambient annealing approach was expanded to a protective layer annealing approach. A series of capping layers CdS, ZnO and P2O5 were deposited on the back surface prior to the annealing process to protect the antimony selenide layers and then etched off prior to device completion. The CdS capping layer was found to protect the surface from oxidation but frustratingly still resulted in performance decreases. There was however one “outlier” device series which showed a marked improvement for all device parameters. This result was not reproducible despite many attempts but seemed to indicate the potential of the approach so other materials were investigated. ZnO was considered but it was quickly determined it was unsuited as a capping layer. P2O5 however was tested and despite the limited number of samples being able to be prepared, it was found to notably improve device performance even with short time and low temperature anneals. Secondary ion mass spectrometry analysis showed significant quantities of phosphorus had been incorporated in the film during annealing. This finding demonstrates there is high potential from the protective layer annealing approach and indicates additional work in this area could leave to improved device efficiencies.7 0