Saudi Cultural Missions Theses & Dissertations
Permanent URI for this communityhttps://drepo.sdl.edu.sa/handle/20.500.14154/10
Browse
2 results
Search Results
Item Restricted Identification of BRD4 as a Synthetic Lethal Gene to Treat MCPH1 deficient Ovarian Cancer(Saudi Digital Library, 2023) Altowairqi, Ahlam; Bell, Sandra; Johnson, Colin; Bond, JacquelynBackground: Ovarian cancer (OC) and endometrial carcinoma (EC) are aggressive, heterogeneous gynaecological cancers. MCPH1 is a tumour suppressor in several cancers and is reported to be downregulated and mutated in OC and EC. BRD4 (Bromodomain Containing 4) plays a vital role in gene regulation and chromatin remodelling. BRD4 overexpression has been implicated in tumorigenesis and therapeutic resistance in several cancers, including OC. Targeting synthetic lethality (SL), involving mutations in two functionally related pathway genes, is a promising therapy for OC. In EC, immune-checkpoint inhibitors (ICIs) have become important treatment options, particularly for tumours with deficient mismatch repair or microsatellite instability, which are associated with higher response rates to PD- 1/PD-L1 blockade. Objectives: This study investigates whether BRD4 inhibition with siMCPH1 knockdown in OC cells is a potential SL target and explores the underlying mechanisms. The association between MCPH1 and BRD4 protein expression and clinical markers in OC and EC are also examined. Methods: Previous siRNA screen of two high-throughput screens identified BRD4 as a potential MCPH1 SL target. A colony-forming assay was used to determine the reduction in cell viability. Mechanistic studies, including flow cytometry, DAPI staining and RNA-Seq analysis, identified the pathways involved. To determine the clinical relevance of MCPH1 and BRD4 protein expression, 431 OC and 376 EC samples were investigated. Results: siMCPH1 knockdown combined with JQ1 inhibitor treatment showed a significant decrease in viability. Apoptosis was significantly increased in siMCPH1 SKOV-3 cells treated with JQ1. An increase in premature chromosome condensation was identified in SKOV-3 (10.33%) and OVCA-433 (16.96%) cell lines. RNA-Seq identified potential SL pathways, including extracellular matrix organisation, apoptosis, p53 signaling, angiogenesis, chromatin remodelling. Low MCPH1 protein expression in OC cases is correlated with reduced overall survival (OS) (p=0.003), progression-free survival (PFS) (p<0.001) and BRCA status (p=0.004). 13.22% of OC samples with low MCPH1 and high BRD4 expression, demonstrated a targeted group of SL treatment. By contrast, in EC, high MCPH1 (p=0.034) and BRD4 (p=0.044) expression were associated with reduced disease-specific survival and correlated with immune-checkpoint markers. Conclusion: This study suggests that BRD4 is a promising SL target for MCPH1- deficient OC. MCPH1 and BRD4 could serve as potential prognostic markers for OC and EC and a possible ICI therapy.11 0Item Restricted The use and evaluation of integrated diagnostics in haematological malignancy(Manchester, 2020-09-30) Altowairqi, Ahlam; Byers, RichardBackground: Haematologic malignancies are one of the most challenging diagnostic fields. Many discrepancies have been reported in diagnoses of this disease over the last few years that affect patient outcomes. Such discrepancies have promoted the introduction of guidelines and classifications to improve identification and predict an optimal therapy approach. The Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS), which was introduced in the UK as a special service for haematologic malignancies, to provide a second review, promote multiple techniques for proper diagnosis and prognosis and to choose the best treatment approach. Objectives: This study aims to identify the effectiveness of diagnosing lymphoma using SIHMDS in Manchester by comparing this service to local in MRI and other hospitals diagnoses. Also, it aims to identify the role of interpretation and diagnostic techniques in accurate lymphoma diagnosis. Methods: A total of 2,014 cases were collected from January 2019 to December 2019 from HODS system in SIHMDS. Among these, 295 cases were lymphoma cases and their details were taken from an integrated report. The primary diagnoses of these cases were taken to compare and identify discrepancies. Results: From 295 cases, the discrepancy was 10% in the total cases diagnosed, while the discrepancy rate was lower in MRI (7.4%), and higher in other hospitals by (29%). The role and need of the second review and multiple techniques were confirmed to improve the diagnoses in the special service. Also, needle core biopsy was shown to be useful in lymphoma diagnosis. Conclusion: Introducing special diagnostic service in haematologic malignancies is crucial due to the great benefits of second review and multiple advance techniques. New advances in this field will further improve the diagnosis sensitivity and further enhance patient outcomes.20 0