SACM - United Kingdom
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9667
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Item Restricted Optimizing Deep Learning Architectures for Enhanced Breast Cancer Detection on Mammography Images(University of Liverpool, 2024) Albalawi, Alaa; Anosova, OlgaBreast cancer is a major health issue affecting millions of women globally, and early detection through mammography is critical for improving survival rates. However, mammography often faces challenges, such as imbalanced datasets and poor image quality, especially in dense breast tissue, which complicates accurate detection. This project explores the use of deep learning techniques, including Convolutional Neural Networks (CNNs) and Vision Transformers (ViTs), to address these challenges and enhance breast cancer detection. Five models—ResNet50V2, MobileNetV2, VGG16, ResNet from scratch, and ViT—were compared using various evaluation metrics. Two datasets, RSNA and MIAS, were used, with preprocessing applied only to the RSNA dataset. The experiments were divided into three stages: the first stage evaluated the original RSNA dataset without preprocessing, the second stage tested the balanced and preprocessed RSNA dataset with and without data augmentation, and the third stage applied similar experiments on the MIAS dataset. The results showed that preprocessing and balancing the RSNA dataset significantly improved model performance, while data augmentation further enhanced accuracy and generalization. ViT models outperformed other CNN architectures, demonstrating superior detection abilities after augmentation. ResNet from scratch also showed strong results, benefiting from its controlled architecture that adapted well to high-resolution images. This study highlights how addressing class imbalance and optimising model architectures can lead to more effective breast cancer detection using deep learning.18 0Item Restricted Evaluation of Replication Protein A (RPA) as a Prognostic and Therapeutic Target in Breast and Ovarian Cancer(University of Nottingham, 2024-02-14) Algethami, Mashael Abdulaziz; Madhusudan, SrinivasanIntroduction: Replication protein A is a heterotrimeric complex composed of three linked subunits encoded by unique genes: RPA1 (chromosome 17p13, 70 kDa), RPA2 (chromosome 1p36.11, 32 kDa), and RPA3 (chromosome 7p13.3, 14 kDa). RPA is a critical ssDNA binding protein that coats and protects exposed ssDNA from endogenous nucleases during repair. RPA is essential for DNA replication, repair, and recombination. The oligosaccharide/oligonucleotide binding fold (OB-fold) is an integral structural and functional component of RPA. RPA consists of a series of OB-folds (Domains A-F). In the RPA complex, RPA1 contains four ssDNA-binding domains (DBD): A, B, C, and F. These domains are responsible for most of the DNA binding activity of the complex. Both RPA2 and RPA3 contain a single DNA-binding domain and are involved in DNA binding. To understand the role of RPA in the pathogenesis of breast and ovarian cancer, we conducted a comprehensive transcriptomic, proteomic and preclinical study. Patients and methods: RPA1, RPA2, and RPA3 protein expression were evaluated in 4221 primary invasive breast carcinomas and 776 breast ductal carcinoma in situ (DCIS) specimens using immunohistochemistry. Transcriptomic investigations were completed using the METABRIC cohort (n=1980). RPA1, RPA2, and RPA3 protein expression were also evaluated in 331 cases of epithelial ovarian cancer (EOC). Transcriptomic investigations were completed using a publicly available online gene expression dataset of 1259 patients with ovarian cancer. Cisplatin and PARP1 inhibitor (PARPi) sensitivity were tested in RPA-deficient breast and ovarian cancer cell lines. Results: Loss of RPA1, RPA2, and RPA3 are frequent in DCIS and linked to aggressive features including high grade and ER and PR negativity. Low RPA was also associated with poor local recurrence-free survival in DCIS. In invasive breast cancer, low RPA1, low RPA2, and low RPA3 were all associated with larger tumour size, lympho-vascular invasion, higher histological grade, high stage, ER negativity, and poor breast cancer specific survival. Pre-clinically, RPA deficient breast cancer cells were more sensitive to cisplatin therapy compared to control cells. Additionally, the PARP1 inhibitor was synthetically lethal in RPA1- and RPA2-deficient cells compared to controls. Increased Olaparib sensitivity was associated with double strand breaks, cell cycle arrest, and increased apoptosis. In ovarian cancer, overexpression of RPA was associated with aggressive clinicopathological characteristics in EOC. In addition, high RPA expression was associated with a poor prognosis in platinum-sensitive ovarian tumours. Pre-clinical assessment showed that basal levels of RPA1 and RPA2 were higher in cisplatin-resistant A2780cis and PEO4 cells compared to cisplatin-sensitive A2780 and PEO1 cells. Additionally, depletion of RPA1 and RPA2 caused substantial platinum sensitization and increased PARP inhibitor sensitivity in A2780cis and PEO4 cells compared to control cells; this increased sensitivity was associated with increased accumulation of double strand breaks, S-phase cell cycle arrest, and apoptotic cells. Conclusions: We provide the first comprehensive evidence that loss of RPA is an early event in the pathogenesis of breast cancer and promotes aggressive phenotypes. Pre-clinically, cisplatin and olaparib were selectively toxic to RPA-deficient breast cancer cells. Moreover, RPA expression is a crucial predictor of platinum response in EOC. Thus, a combined approach of RPA inhibition and PARP inhibition may offer a more effective treatment paradigm for ovarian cancer.23 0Item Restricted Assessing the Effectiveness of Educational Interventions on Breast Cancer Knowledge, Practice Uptake and Beliefs Among Adult Saudi Women: A Systematic Review(Saudi Digital Library, 2023-11-29) Sahli, Maryam; Hopkins, RuthBackground: Several systematic evaluations have examined the importance of educational interventions in promoting breast cancer screening (BCS) and reducing the incidence of breast cancer (BC). However, studies have yet to evaluate these educational interventions comprehensively among Saudi women. Aim: This review sought to systematically assess the efficacy of various educational interventions in enhancing women’s knowledge, breast self-examination (BSE) practices, and beliefs of breast cancer Screening (BCS) in different regions of the Kingdom of Saudi Arabia. Objectives: The research aimed to determine whether health education intervention programmes can increase the level of knowledge, BSE practice, and beliefs of BCS among women in Saudi Arabia and to identify the effective characteristics of these interventions in terms of the intervention’s duration, provider, strategies, theoretical framework and components (knowledge of BC, BSE uptake and health beliefs about BCS), and whether a one-component or multi-component approach is appropriate. Method: The study followed the Prospero protocol and utilised the Systematic Review guidelines and PICOSS inclusion and exclusion criteria. A comprehensive literature search used seven electronic databases: Scopus, Medline, CINHAL, EMBASA, Web of Science, ProQuest, and PsycInfo. In addition, a Google Scholar search and citation chaining from the included studies were conducted in June of 2023. Search terms were employed with AND and OR Boolean operators. Study type, intervention settings, country, region, intervention type and elements, sample size, age group, intervention duration, main finding, intervention effectiveness, data collection, delivery method, intervention sustainability, theoretical perspective (if applicable), and study limitations were described. Additionally, the Effective Public Health Practice Project (EPHPP) was used to evaluate the data quality of the included studies. The intervention strategies and study characteristics were analysed using a qualitative synthesis narrative of the included studies’ data. Results: Eleven interventional investigations were reviewed in their entirety. Multiple intervention strategies based on theory and language were primarily implemented among adult Saudi women in university and workplace contexts. The defining characteristics of the educational interventions included the provider, duration and mode of delivery. Conclusion: Most studies on the efficacy of educational interventions revealed favourable outcomes regarding Saudi women’s knowledge, BSE practice and beliefs of BCS. Thus, potential educational interventions could increase BSE practice, knowledge and ideas among Saudi women. Recommendations: The educational intervention studies included in this review had numerous limitations, including heterogeneous research designs, intervention strategies and outcome measures. Consequently, future research and policies implementing educational interventions for BC among Saudi women should consider these implications.15 0Item Restricted Understanding the Role of NIPBL loss on Drug Sensitivity in 3D Cancer Cell Line Cultures(Saudi Digital Library, 2023-10-23) Alotaibi, Aliyah; Peck, BarrieBreast cancer (BC) remains the most widespread cancer globally and stands as the fifth leading cause of mortality. Despite available therapeutic and preventive strategies for many BC subtypes, Triple-negative BC poses distinct challenges because of its high genomic instability and lack of conventional therapeutic biomarkers. This report offers a comprehensive overview of Triple-negative BC, emphasizing its unique attributes and genomic alterations. It further explores the present biomarkers aiding targeted therapies in Triple-negative BC, with a specific focus on the prospective role of NIPBL as a promising biomarker. The report subsequently presents the project’s scope, details its aims, objectives, methodologies, and materials used. More specifically, we find that loss of NIPBL in 3D cultures impacts vinka alkaloid sensitivity. Next, we investigated the expression of genes that encode known drug transporters and show that these are impacted by NIPBL loss and Vinorelbine treatment. In summary, we posit that NIPBL loss in cancer could represent as a negative prognostic biomarker for response to vinka alkaloids. 428 0Item Restricted Exploring the role of αB-crystallin in resistance to anti-angiogenic therapies(Saudi Digital Library, 2023-01-31) Alsharif, Marwa Abdullah; Ottewell, PenelopeAnti-VEGF therapies have not improved the overall survival in breast cancer and many patients show no response to these treatments. The causes of this innate resistance need to be investigated so that they can be targeted in order improve the efficacy of these treatments. Additionally, identification of biomarkers can be utilised to select patients who are more likely to respond to treatments. αB-crystallin is a small heat shock protein encoded by the CRYAB gene and known to function as a chaperone protein. Its function is to protect misfolded proteins from degradation and apoptosis under stress conditions. αB-crystallin is thought to protect VEGF from degradation and support its stability. αB-crystallin is significantly upregulated in tumour vasculature during angiogenesis and after anti-VEGF treatment. Protecting VEGF from degradation and increasing its stability may stimulate tumour growth and contribute to resistance to anti-VEGF therapies. Therefore, this project tests the hypothesis that αB-crystallin contributes to the resistance to anti-VEGF therapies in breast cancer. To test this hypothesis, I made transgenic triple negative, MDA-MB-231, breast cancer cells that produce different levels of αB-crystallin (MDA-MB-231/CRYAB) and control cells that do not produce αB-crystallin (MDA-MB-231/WT). These cells were compared with triple negative breast cancer cells that naturally produce high amounts of αB-crystallin (MDA-MB- 468) and MDA-MB-468 cells in which levels of αB-crystallin have been reduced by siRNA. In vitro, VEGF production from breast cancer cells expressing different levels of αB-crystallin were measured by ELISA after heat shock (42°C/24h), or hypoxia (0.1% O2/24h) and sensitivity to doxorubicin induced apoptosis was measured by flow cytometry. In vivo: MDA-MB-231/WT and MDA-MB-231/CRYAB cells were administered by intra-ductal injection into BALB/c nude mice 7-days prior to PBS (control), 4 mg/kg/week doxorubicin, 7.5 mg/kg/3X per week bevacizumab or a combination of both. Tumour growth was measured using callipers, tumour/microenvironmental VEGF analysed by ELISA and tumour microvascular density (MVD) was assessed following CD31 and CD34 immunohistochemistry. The data showed that under heat shock and hypoxia, overexpression of CRYAB in MDA-MB-231 cells reduced VEGF expression compared to wild-type cells, whereas the knockdown of CRYAB in MDA-MB-468 resulted in more VEGF compared to wild-types cells. In vivo: MDA-MB-231/WT tumours grew more rapidly and produced more VEGF compared with MDA-MB-231/CRYAB tumours. Bevacizumab alone reduced tumour growth in MDA-MB-231/WT cells but not in MDA-MB-231/CRYAB cells. However, resistance to Bevacizumab was overcome by the addition of doxorubicin with the combination of doxorubicin and bevacizumab synergistically reducing tumour volume and VEGF levels of MDA-MB-231/CRYAB tumours but not MDA-MB-231/WT tumours. Furthermore, vascular marker expression was very low in MDA-MB-231/CRYAB tumours compared to MDA-MB-231/WT tumours. The in vitro and in vivo results suggest that αB-crystallin negatively regulates VEGF and breast cancer growth and angiogenesis. Overall, αB-crystallin may act as a tumour suppressor protein in our system by inactivating VEGF production. This needs further investigation to reveal its role in oncogenic-related pathways.15 0Item Restricted A role for IGFBP-2 in DNA repair in breast cancer cells(Saudi, 2023-06-22) Mohammedali, Alaa Abdulaziz; Perks, ClaireInsulin-like growth factor binding protein-2 (IGFBP-2) mediates chemoresistance in prostate and breast cancer cells, as we have previously shown. Also, we and others have demonstrated that IGFBP-2 upregulates DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in double-stranded break repair (DSBR) in prostate and oesophageal cancer cells, respectively and that IGFBP-2 might interact with the DNA damage response in breast cancer. Hence, this study aimed to determine the role of IGFBP-2 in the DNA-damage response induced by etoposide in breast cancer cells. Cells (MCF-7; high levels of IGFBP-2 and MDA-MB-231; low levels of IGFBP-2) were treated with etoposide in the absence (IGFBP-2 siRNA for MCF-7) or presence (exogenous IGFBP-2; in MDA-MB-231) of IGFBP-2. To determine if the effects of IGFBP-2 were IGF-dependent or independent, the effects of IGF-I in MCF-7 cells and Arginyl-glycyl-aspartic acid (RGD) in MDA-MB-231 cells on the DNA damage response were investigated. Western blotting of whole cell lysates was performed to monitor changes in protein abundance of DNA damage/repair markers, γH2AX and P-DNA-PKcs, respectively. With MCF-7 cells, silencing IGFBP-2 alone had no effect on the levels of P-DNA-PKcs compared to the non-silencing siRNA control, but γH2AX levels increased significantly. Etoposide alone caused an increase in γH2AX that was enhanced by silencing IGFBP-2, whereas etoposide-induced P-DNA-PKcs levels were reduced when IGFBP-2 was silenced. With or without IGFBP-2, IGF-I significantly reduced the DNA damage response and repair in MCF-7 cells. Accordingly, IGFBP-2 was acting in an IGF-independent manner. Immunoprecipitation was used to determine how IGFBP-2 interacts with DNA repair molecules. It was observed that IGFBP-2 is associated with Ku80, one of the key molecules in non-homologous end joining (NHEJ). In MDA-MB-231 cells, the exogenous addition of IGFBP-2 alone had no effect on γH2AX or P-DNA-PKcs levels. The addition of RGD and IGFBP-2 alone and in combination enhanced DNA repair and reduced DNA damage in the presence of etoposide. This suggested that IGFBP-2 and RGD were acting in a similar integrin-mediated manner. In summary, these studies revealed that IGFBP-2 reduced DNA damage by increasing the DNA repair mechanism to protect breast cancer cells. Understanding how IGFBP-2 is involved in the DNA damage response may facilitate more effective targeting and treatment regimens in breast cancer.34 0