Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigating resistance mechanisms to chemotherapy and targeted therapy in a model of BRCA2-mutated breast cancer(University of the West of England, 2024-07) Almuafi, Mashael; Ordonez, LilianaIntroduction Breast cancer ranks as the most frequently occurring cancer in the UK. Although there have been promising advancements in survival rates, it remains the second leading cause of cancer-related death among women in the UK. BRCA2 mutations predispose individuals to breast cancer and affect DNA repair mechanisms. While targeted therapies such as olaparib (PARP inhibitors) and carboplatin (platinum-based chemotherapies) have shown efficacy, resistance remains a significant challenge. This study aims to investigate the mechanisms underlying resistance to carboplatin and olaparib in BRCA2-mutated breast cancer, focusing on epithelial-mesenchymal transition (EMT) as a potential pathway contributing to therapy resistance. Methods Using a previously genetically engineered mouse model with BRCA2/TP53 mutations, tumour samples were analysed using hematoxylin and eosin (H&E) for morphological characteristics and expression of key markers (E-cadherin, vimentin, Ki67) via immunohistochemistry (IHC). Tumours were categorised into untreated, olaparib-resistant and carboplatin-resistant groups. Statistical analysis was performed to compare marker expression and morphological features across these groups. Results H&E analysis revealed interestingly that carboplatin-resistant tumours showed an equal distribution of epithelial and mesenchymal features, not significantly different from untreated and Olaparib-resistant tumours. IHC analysis of EMT markers showed that carboplatin-resistant tumours maintained moderate E-cadherin levels. Vimentin expression showed no significant differences in carboplatin-resistant tumours compared to untreated and Olaparib-resistant tumours. Notably, Ki67 expression analysis revealed no significant differences in proliferation rates across all three cohorts, challenging the assumption that resistant tumours would exhibit increased proliferation. These findings suggest distinct resistance mechanisms between olaparib and carboplatin in BRCA2-mutated breast cancer. EMT appears to play a crucial role in olaparib-resistance but not in carboplatin-resistance. These findings underscore the need for tailored treatment strategies and further research into the diverse mechanisms of therapy resistance. Future studies should focus on developing EMT-targeted therapies and exploring their efficacy in combination with existing treatments to improve patient outcomes.13 0Item Restricted Exploring Iridium Complexes as Promising Alternatives for Breast Cancer Treatment(University of Birmingham, 2024-09-03) Alsaif, Norah; Canelon, IsoldaBreast cancer is one of the most common cancers in women and it poses a significant health threat to the entire world. Cisplatin, a widely known metal-based chemotherapeutic agent, is effective towards various malignant cells but its extensive side effects and drug resistance limits its application. This has led to platinum-based therapies being replaced by other transition metal-based anti-cancer drugs. This systematic review evaluates the current evidence supporting the efficacy and selectivity of iridium complexes in the treatment of breast cancer in comparison to traditional therapy. Searching through the Web of Science database completely led to 426 records. PICO format was screened and applied by focusing on specific criteria including inclusion and exclusion criteria thereby identifying ten articles for final review. The results demonstrated that different iridium compounds have lower IC50, and higher SI compared to cisplatin, indicating more effectiveness and selectivity particularly against MDA-MB-468 and MDA-MB-231 cell lines. However, it should be noted that there is a significant gap in the studies of structure- activity relationship (SAR) on these iridium compounds. Optimisation of their efficacy and safety profiles has been hindered by lack of detailed SAR data which poses a huge challenge for clinical trial development. However, before iridium-based drugs can be assessed for use in clinical trials, complete SAR data must be obtained.8 0Item Restricted The Role of an online health forum for Women with Breast Cancer Treated by Chemotherapy(Saudi Digital Library, 2023-11-03) Aljehani, Shroog; Bath, PeterBreast cancer, which affects more women than men, is among the global death-leading chronic conditions that have triggered the need for online health forums as interventions to help meet various healthcare goals. Women with breast cancer treated with chemotherapy have diverse needs, some of which can be met through these forums. Therefore, this dissertation is a systematic review that evaluates evidence from different journal publications to investigate the role of an online health forum for women with breast cancer treated by chemotherapy. The PICO framework was the preferred method for developing the study’s research question, while the Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was the selected methodology for presenting results for this systematic review. This study is important because the findings will inform the relevance and usage of online health forums, informational needs, and the perceptions and information-seeking behaviours of women with breast cancer treated by chemotherapy.10 0Item Restricted The Effect of Test-Set Training on Mammography Screen-Reading Performance(Saudi Digital Library, 2023-09-20) Qenam, Basel; Brennan, Patrick; Ekpo, ErnestAims: Screening mammography is a universally accepted early breast cancer detection tool. However, the value of screening depends on the abilities of breast screening readers to detect cancer, which can vary widely. Mammographic test sets represent an important evaluation and education tool for the readers to maintain acceptable screen-reading quality. While multiple studies investigated the capacity of test sets to improve readers’ performance, the improvements identified in those studies were measured by following the readers’ test-set results over time. This thesis aimed to validate the value of test-set training on observers’ clinical performance in screening mammography. First, it scopes the literature to examine the importance of test sets and their role in addition to clinical audits in maintaining screen-readers’ performance. Afterwards, the thesis includes three studies that explored test sets’ effects on clinical performance by utilising clinical audit data of breast screening readers. The first study explored trends over time in the annual audit results of participants in the BreastScreen Reader Assessment Strategy (BREAST) test-set program in association with their participation. The second study further investigated the change over time in BREAST participants’ clinical performance by including peers with no test-set training as a control. Last, the third study investigated the patterns in test-set results for readers who have upscaled their clinical performance after the test-set encounters. Methods: Cancer Institute of New South Wales (NSW) provided de-identified audit data for readers in BreastScreen NSW between 2010 and 2018, some of whom have participated in BREAST test sets. The first study analysed multiple clinical audit metrics for 24 radiologists who participated in BREAST after dividing the annual audit history into pre-training and post-training, based on the year readers completed their first test set. The study compared two calendar years before test-set training to equivalent data from three periods after test-set completion. Next, the same analyses were conducted after splitting the sample into two subgroups based on radiologists’ annual screen-reading volumes to see if this factor could differentiate readers’ progress. In the second study, data from 22 readers without a prior history of test-set participation and 35 breast-screen readers who have completed BREAST test sets were analysed. The annual audit data for BREAST readers were also divided based on the year they had finished their first test set, and each non-BREAST reader was randomly linked to a BREAST reader so that performance could be analysed throughout the same years. Then, the audit measures were examined to find discrepancies between the performance development of the two cohorts. The third study used correlation tests and a multiple linear regression model to analyse the relationship between test-set metrics of 41 eligible BREAST participants and the positive or negative change in their cancer detection rate over time in screening practice. Participants were then divided based on whether they had or had not improved between the two periods, and the Mann-Whitney U test was used to inspect any differences in test-set metrics between the two subgroups. Results: In the first study, radiologists in total showed significant improvements (p<0.05) in their recall rate in consecutive screening rounds, in their positive predictive value (PPV), and in specificity. After dividing readers based on the number of reads, radiologists with greater reading numbers demonstrated the same changes in addition to further improvements in the detection rates of invasive breast cancer and ductal carcinoma in situ (DCIS). In comparison, the radiologists with lower reading numbers showed only one significant improvement in the detecting rate of small invasive cancer. In the second study, BREAST and non-BREAST readers showed similarities in over-time clinical performance change between two periods,each composed of two years; both recalled lower rates of women over time and improved their PPV significantly. However, BREAST readers showed additional significant increases in their overall and invasive cancer detection rates. An extended analysis of three years in each period indicated similar improvements in both groups’ recall rate and PPV. Also, BREAST readers’ detection rates for invasive cancer, DCIS, and all cancers increased significantly, while non- BREAST readers showed a reduction in sensitivity. In the third study, multiple significant correlations were found between the test-set results and the breast cancer detection rate changes. Those included a low to moderate positive correlation with lesion sensitivity (0.469), a moderate negative correlation with specificity (-0.528), and a moderate positive correlation with the number of years of reading screening mammograms (0.365). Additionally, a significant regression equation with an R2 of 0.493 (adjusted R2 = 0.466) based on readers’ test-set sensitivity (F=27.132) and specificity (F=9.78) was discovered. When the cohort was sub-grouped based on the change in cancer detection, the improved group had a significantly higher sensitivity and lesion sensitivity but a significantly lower specificity. Conclusion: While experience plays a major role in improving breast-screening readers’ performance over time, test-set participants can improve further over the same periods, mainly in cancer detection rates. The best test-set performance indicators to predict the latter improvements are sensitivity and specificity, which have an opposite relationship that emphasises the human limitation and the need for assessing tools to increase the accuracy of breast screening.18 0Item Restricted Exploring the Key Molecular drivers of lymphovascular invasion in Invasive Breast Cancer(2023-01) Alsaeed, Sami Abbas; Rakha, Emad AABSTRACT BACKGROUND: Lymphovascular invasion (LVI) plays a crucial role in breast cancer (BC) metastasis and presents as a reliable indicator of poor outcome in terms of distant metastasis and shorter survival. Therefore, accurate and reproducible assessment of LVI and an understanding of its molecular mechanisms can help guide management decision-making. However, molecular mechanisms of LVI are complex and overlap with other biological processes, such as metastasis and BC progression in general. Therefore, deciphering the molecular mechanisms of LVI and identifying its driver genes remain challenging. This study aimed to utilise several well-defined BC datasets, evaluating whether the LVI mechanisms in BC are controlled by distinct transcriptome and proteomic profiles, and to assess the roles of potential target genes using various molecular techniques. METHODS: In an attempt to discover new targets associated with LVI status, bioinformatics analysis was applied on multiple large cohorts of patients with BC, including the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1,980) and The Cancer Genome Atlas Breast Carcinoma (TCGA-BRCA; n = 854) as discovery datasets and the Breast Cancer Gene-Expression Miner (bc-GenExMiner) dataset (Affymetrix; n = 4,904) cohorts as a validation dataset. The differential mRNA expression was performed to identify key genes with respect to LVI status, which was previously defined based on morphology and immunohistochemistry (IHC) for endothelial markers. In addition, mass spectrometry of a well-defined subset of BC with well-characterised LVI status was utilised to identify target genes at the protein level. The targeted genes that were strongly associated with LVI at the transcriptomic levels (HSP90AA1, SLC9A3R1, NOP56 and HMGB3) were further investigated to confirm their prognostic value and association with LVI at the protein level utilising IHC and tissue microarrays of a large annotated early stage BC with long-term follow-up Nottingham cohort (n = 2,497). The protein expression of (HSP90AA1, SLC9A3R1 and NOP56) was correlated with clinicopathological parameters, a large panel of relevant biomarkers, and patient outcomes to identify clinically reliable LVI-associated genes. Further functional experiments followed this to explore the mechanistic insights of the most likely target gene (HMGB3) for LVI in BC to identify novel BC prognostic and predictive value towards personalised therapy in patients with early stage BC.22 0