Saudi Cultural Missions Theses & Dissertations
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Item 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.16 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 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.9 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.26 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 Regulation of Human Ether À Go-Go 1 (hEAG1) Potassium Channels(University of Leicester, 2017-08) Lin, Salwa; Mitcheson, JohnHuman ether à go-go (hEAG1) channel is a voltage-gated potassium channel that is only expressed in brain tissue. This channel consists of four transmembrane α helices, in which each α subunit has six domains (S1-6), S1-4 as voltage sensors and S5 and S6 are pore-forming domains. When action potential generated and subsequently the membrane potentials (Vm) depolarized, this channel repolarizes the cell back to resting potential. To date, little is known about the physiological role of EAG1 channel. In regard to diseases, ~ 70% of cancers exhibit hEAG1 overexpression. hEAG1 channel contributes to cancer proliferation indirectly through control of cytoplasmic Ca2+ (Ca2+ i). The aberrant overexpression of this channel in cancers prompted us to study its regulation by Ca2+ and hemin. To study hEAG1 regulation, currents from hEAG1-expressing Xenopus oocytes were measured by two-electrode voltage clamp (TEVC) technique. The results showed that hEAG1 currents substantially inhibited in response to increased Ca2+ i with maximal inhibition of 93.2± 2.9 %. In addition, the gating properties of hEAG1 currents in I and T was changed, in which the activation was clearly slowed without exhibition of rectification. Whereas the activity of hEAG1 channel with a deletion of PAS-cap domain in I and T substantially potentiated with 9± 1.4–fold compared to the control currents. Surprisingly, we found that upon application of extracellular hemin (5 µM) into hEAG1-expressing oocytes, the channel current significantly reduced with percentage of maximal inhibition of 24.8±5.2%. The gating of hEAG1-expressing oocytes upon persistent application of extracellular hemin interestingly resembles the gating of hEAG1 inhibited by an increase in Ca2+ i. Injection of hemin (1 µM) into hEAG1-expressing oocytes, however, showed no current inhibition. This study provides the first evidence that hemin inhibits hEAG1 channel from the extracellular side.9 0Item Restricted Inside Cancer Pathology: Human Polyomavirus and Bovine Meat and Milk Factors(Saudi Digital Library, 2023-11-21) Mobaraki, Ghalib Ibrahim; Hausen, Axel zur; Speel, Ernst-Jan; Winnepenninckx, VéroniqueEven though cancer incidence is increasing rapidly around the world, the cause and cure of many malignant neoplasms remain largely unknown. Studies suggest that 20% of cancers worldwide may be due to high-risk infectious agents. There has been a long-standing link between the development of cancer and viral infections. Up to 15% of all human malignancies have been linked to viruses. In the last two decades, new molecular technologies such as Next Generation Sequencing have enabled us to come across new members of human polyomaviruses (HPyVs), however few have been found to be connected to cancerous diseases in humans; mainly Merkel cell carcinoma (MCC) which is caused by MCPyV in 80% of cases. Researching further into HPyVs and their involvement in tumorigenesis needs more exploration. Other infectious agent such as BMMFs have been recently found in colon, pancreases, lung and in our study of RCC cohort. The primary objective of this thesis was to screen and test for novel HPyVs and BMMFs in various cancer tissues to gain a better understanding of the role and possible involvement of these infectious agents in human tumorigenesis. Our goal was to detect HPyVs at single-cell levels within the histomorphological context using FFPE tissues and a variety of sensitive and specific molecular techniques for BMMFs DNA detection. Chapter 1 provides a general introduction of how DNA and RNA tumor viruses and BMMFs contribute to carcinogenesis, either directly or indirectly. Moreover, this chapter focused more on describing the polyomaviruses in general, then giving a brief background of each known HPyV as well as BMMFs. Furthermore, the outline and the purpose of this thesis are discussed. Chapter 2 reviews the current evidence to evaluate a possible role of HPyV6 and 7 in the etiopathogenesis of neoplastic human diseases. The frequent prevalence of HPyV6 and 7 DNA in non-neoplastic and neoplastic tissues along with their high seropositivity in the normal population indicate that both viruses have long-term latency in humans. Interestingly, HPyV6 prevalence was higher in skin malignancies than that of HPyV7. In contrast, HPyV7 was more frequently detected in non-cutaneous malignancies such as cholangiocarcinoma and renal cell carcinoma . Notably, previous studies revealed that the seropositivity of HPyV6 was found to be higher than HpyV7 and increased with age. In conclusion, HpyV6 and 7 remain important putative candidates that may contribute to the etiopathogenesis of human diseases, especially skin cancer. Chapter 3, we assess the relation of BKPyV-positive urine cytology specimens (UCS) to the detection of UCC in a large UCS database and the following evaluation of BKPyV in the UCC of the urinary bladder. In addition, we aimed to evaluate the relation of BKPyV to intravesicular BCG or mitomycin treatment of UCC patients. Our results shown that PCR detected BKPyV- DNA in urine samples of patients with either in situ or invasive UCC of the urinary bladder, while BKPyV-IHC and PCR were negative at the FFPE level of primary UCCs and metastases. However, the BKPyV detected in urine was not linked to previously resected urothelial cell carcinomas, excluding this virus as a possible cause of conventional type UCC in our cohort. BKPyV-reactivation has been observed not only in immunocompromised individuals, but also among those with urothelial cell carcinoma and no prior history of transplantation, malignancy or chronic diseases. The intravesical treatment could be associated with the reactivation of the latent BKPyV. Moreover, Cystitis may be behind the reactivation of the latent BKPyV in immunocompetent patients. Therefore, evaluating for BKPyV presence in post-UCC patients might be pertinent for assessing the risk of BKPyV-nephropathy and further studies are necessary to understand this complex relationship. Recently, we studied the association between the BKPyV infection and urothelial cell carcinoma in patients with urine cytology positive for Decoy cells. However, in our patient cohort, both primary and recurrent UCC tissues tested negative for BKPyV by PCR and immunohistochemistry (IHC) as outlines in chapter 3. Chapter 4 evaluates the presence of JCPyV, HPyV6, HPyV7, and MCPyV in the UCC samples and in the voided urine in the patients, diagnosed with UCC and with Decoy cells in urine cytology. JCPyV-DNA was detected in the urine and urothelial cell and MCPyV was detected in urothelial cell carcinoma. However, both HPyV6 and 7 were not detected in all UCCs and urine specimens. Since there is inadequate evidence of a role for JCPyV in carcinogenicity in UCC, these findings support the hypothesis that JCPyV infection could play a role in urothelial carcinoma tumorigenesis. Going forward, it is important to define whether or not both JCPyV and MCPyV are involved in UCC tumorigenesis. The Chinese research group recently detected HPyV6 DNA in 27% of the bile fluid from cholangiocarcinoma (CCA) patients, prompting us to look further into this possible link. In Chapter 5, we aimed to investigate the prevalence of HPyVs in CCA tissues to elucidate possible clinicopathological correlations between HPyVs and CCA. Interestingly, HPyV7 (69%) was highly prevalent in the CCA cohort, the next most frequent was MCPyV (24%) followed by HPyV6 (14%). An important finding of this study was that HPyV7, HPyV6, and MCPyV are hepatotropic viruses and able to infect non-neoplastic human hepatocytes, bile duct epithelium, and CCA tumor cells. However, it's still not known if they contribute to or cause CCA. The frequent finding of HPyVs in adjacent peritumoral hepatocytes could suggest a robust indirect role for these viruses in inducing CCA transformation through chronic inflammation as outlines in chapter 1. Chapter 6, to investigate possible clinicopathological correlations between HPyVs and RCC, we screened for the prevalence of HPyVs in in various formalin-fixed and paraffin-embedded (FFPE) RCC tissues by human polyomavirus consensus and virus specific PCR in RCC tissues including adjacent non-neoplastic kidney tissues. PCR positive cases were further tested by FISH, RISH and IHC. Of note, 80% (44/55) of RCC and its non-tumoral tissues tested positive for one or more of the HPyVs (i.e., MCPyV, HPyV6, HPyV7, BKV, JCV and WUyV) in the same specimen. 27 (61%) specimens were positive for only one of HPyV, 13 (29.5%) specimens were positive for 2 HPyVs, 3 (6.8%) specimens were positive for 3 HPyVs, and only one (2.27%) RCC specimen was positive for 4 HPyVs on the same specimen. However, 11 (20%) RCC specimens were negative for all PCR approaches. Interestingly, MCPyV was seen in 22/55 (40%) of RCC tissues, HPyV7 was observed in 13/55 (23.6%) of RCC, and HPyV6 in 7 (12.7%) of RCC tissues. However, 9/55 RCC specimens share positivity for both MCPyV and HPyV7, while 2/55 RCC specimens have positivity for both HPyV6 and HPyV7. 0/55 was seen among MCPy and HPyV6 or for these 3 viruses on the same time. Our findings strongly suggest that MCPyV, HPyV7, HPyV6, BKV, JCV and WUPyV could potentially infect both RCC and surrounding tumor tissues. While all six HPyVs have shown a tendency to target the kidneys, we observed that MCPyV and HPyV7 were more commonly present in neoplastic and non-neoplastic cells within our subset of RCC samples compared to HPyV6, BKV, JCV and WUPyV. This study is the first to not only map these HPyVs in various distances of RCC tissues but also report the presence of MCPyV and HpyV6 on a single cell level. We utilized various molecular techniques to examine the presence and bioactivity of these viruses from DNA to protein levels. The frequent identification of HPyVs, particularly MCPyV and HPyV7 in kidney tissues may also indicate a possible involvement in other kidney diseases. Our results may suggest an indirect link between these HPyVs and carcinogenesis through inflammation, further investigation is needed to fully understand their role in the development of RCC. There have been contradictory results from epidemiological studies on diet and kidney cancer, including renal cell carcinoma (RCC). Interestingly, the geographic distribution of RCC incidence also reveals a significant degree of epidemiological agreement with the geographic distribution of colon and breast cancer incidences, suggesting a link with diet. In the recent discovery of bovine meat and milk factors (BMMFs), a novel class of infectious agents is distinguished between bacterial plasmids and single-stranded circular DNA viruses in terms of their ancestral origins. Recently, it has been shown that exogenous BMMF DNA derived from milk or meat is able to replicate in human embryonic kidney (HEK) cells and found in other cancer such as colon, pancrease and lung. Chapter 7, we aimed to test the most common subtypes of RCC, i.e., CCRCC, and PRCC for the possible presence of BMMFs in formalin- fixed and paraffin-embedded (FFPE) RCC tissues. Indeed, we were able to reliably detect BMMFs-DNA in the RCC FFPE tissues. It is highly interesting that BMMF-DNA is more frequently found in non-tumoral tissues compared to RCC in both collection groups. These findings are potentially in line with the proposed model for BMMF-induced indirect colon carcinogenesis, which includes the presence of BMMFs in adjacent non-tumoral tissues. Due to the frequent finding of BMMF2-DNA in the non-tumoral FFPE kidney tissues of the retrospective RCC collection, we also tried to amplify other parts of this specific BMMF2 genotype. By using seven different BMMF2-specific primer pairs covering the rest of the BMMF2 genome, we were able to amplify all parts of the respected BMMF genome in the tested cases. This approach confirmed the results of the BMMF2 broad-range PCR and indirectly possibly suggests that the whole BMMF2 genome is present in these tissues.12 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.21 0