Saudi Cultural Missions Theses & Dissertations
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Item Restricted Breast Cancer Treatment Disparities in Patients with Severe Mental Illness: A Systematic Review and Meta-Analysis(Queensland University of Technology, 2024) Alotiby, Meshary; Protani, Melinda; Kisely, Steve; Siskind, DanBackground Disparities in breast cancer treatment for people with pre-existing severe mental illness (SMI) have not been well studied compared to disparities in cancer screening and stage at diagnosis. Aims To conduct a systematic review of the available evidence and investigate whether female breast cancer patients with pre-existing SMI had equitable access to guideline recommended breast cancer treatment compare to those without SMI. Methods We conducted systematic review and meta-analysis of observational studies that were retrieved from PubMed, EMBASE, CINAHL and PsycINFO databases from 22 February 2021 to 26 March 2021. Female breast cancer patients with SMI were included in the analyses. SMI was defined as Schizophrenia, Bipolar disorder, and major depression. Guideline recommended treatment was defined as surgery, chemotherapy, radiotherapy and adjuvant endocrine therapy. Pooled odds ratios, and other estimates, such as hazard ratios and risk ratios were presented. Risk of bias was assessed using Newcasle-Ottawa scale. DerSimonian-Laird random effects models were used. Results 3,325 citations were identified; 10 studies were included, and 4 studies were meta-analysed. Pooled analyses suggested that people with SMI were less likely to receive guideline recommended breast cancer treatment than those without SMI (OR: 0.83; 95% CI: 0.77 to 0.90). Breast cancer patients with schizophrenia had a reduced likelihood for receiving adjuvant radiotherapy (Crude RR: 0.81, 95% CI: 0.77 to 0.85), while those with major depression and bipolar I disorder had lower likelihood of receiving adjuvant chemotherapy (Crude RR: 0.71, 95% CI: 0.60 to 0.84). Conclusions This review identified disparities in breast cancer care for individuals with pre-existing SMI, which contributed to poorer prognosis and excess mortality. Improving collaboration between psycho-oncology teams is advised to address patients’ needs for treatment. Future research is necessary for identifying disparities in primary and systemic treatments and investigating the reasons for treatment inequity.6 0Item Restricted Functional characterization of gonococcal toxin-antitoxin systems(University of Nottingham, 2024-03) Bagabs, Salwa; Oldfield, Neil; Turner, David; Stocks, MichaelNeisseria gonorrhoeae is the causative agent of the sexually transmitted infection, gonorrhoea. Gonorrhoea is a global health problem and one of the most common sexually transmitted infections in the world. Antibiotic resistance in N. gonorrhoeae is a growing problem, and in order to overcome this, it is necessary to develop preventative vaccines or novel treatments. Bacteria have evolved toxin-antitoxin (TA) systems to protect themselves from stressful conditions. TA systems have been linked to various functions including persister cell formation, biofilm formation, phage resistance and stabilisation of genetic elements. Previous work using the Toxin-Antitoxin DataBase (TADB) revealed the presence of three chromosomally-encoded type II TA systems (HicAB, MazEF, VapBC/FitAB) in N. gonorrhoeae strain FA1090. These were hypothesised to play an important role in the lifestyle of this human-restricted pathogen. In addition, exploitation of one or more of gonococcus TA systems could lead to novel treatment interventions. In this study, further bioinformatics analysis using PubMLST.org examined the prevalence and conservation of the TA systems across isolates. The FitAB, MazEF (and to a lesser extent the HicAB) TA systems were very highly prevalent and conserved across over 5000 N. gonorrhoeae isolates examined. To provide experimental confirmation that the predicted TA systems could influence bacterial growth, DNA fragments corresponding to fitA, fitB and both genes were amplified from N. gonorrhoeae FA1090, ligated into an arabinose-inducible expression plasmid and transformed into E. coli. Qualitative and quantitative growth assays utilizing these strains, along with previously engineered strains harbouring hicAB and mazEF constructs, revealed a lack of FitB or MazF-mediated toxicity in E. coli. In contrast, a HicA-mediated growth arrest effect, which could be abolished by co-expression of HicB, was detected, thus providing confirmation that the N. gonorrhoeae FA1090 genes, NGO1627/1628, encode a functional HicAB TA system. Subsequently, the HicA residues His24, His29, or His40, respectively, were changed to alanine residues by site-directed mutagenesis. Quantitative growth analysis confirmed that the His24 and His29 residues, but not His40 of gonococcal HicA are required for toxicity. Mutagenesis of the three TA systems was undertaken where both toxin and antitoxin genes were deleted and replaced by a kanamycin cassette in N. gonorrhoeae FA1090. Furthermore, complemented derivatives of FA1090ΔhicAB that expressed IPTG-inducible HicA, HicB or HicAB, respectively, were also generated. The growth characteristics of the complemented strains (FA1090ΔhicAB:hicA, FA1090ΔhicAB:hicB and FA1090ΔhicAB:hicAB) were examined in comparison to the wild-type and mutant strain. The results confirmed that all strains grew as the wild-type, either with induction with IPTG or not, with the exception of FA1090ΔhicAB:hicA induced with IPTG which exhibited growth arrest as judged by OD measurements. Another study finding was confirmation of hicAB gene expression in wild-type FA1090 during in vitro growth by extraction of total RNA and reverse transcription polymerase chain reaction (RT-PCR) analysis to detect specific mRNA transcripts. The use of specific hicA and hicB primers confirmed expression of both genes, and the combination of a hicA forward and hicB reverse primer provided evidence that both genes are co-transcribed. A final finding came when the total RNA preps were examined using an Agilent Bioanalyser. Notably, a doublet 16S rRNA peak was apparent in total RNA prepared from FA1090ΔhicAB:hicA strain induced with IPTG, but not the uninduced strain, suggesting interaction (or cleavage) of 16S rRNA by HicA, and potentially giving an insight into the mechanism by which gonococcal HicA influences bacterial growth and viability.18 0Item Restricted Repurposing Approved-Chemotherapeutics for Head and Neck Squamous Cell Carcinoma(Saudi Digital Library, 2022) Alkurdi, Khlood; Tappuni, Anwar; Muy, Teck- TehThe advancement in head and neck squamous cell carcinoma (HNSCC) therapy necessitates the acquisition of a superior understanding of cancer molecular biology and the capability to use this knowledge to adapt the therapy to achieve best patient outcome. HNSCC is heterogeneous in its basis, mechanism, and behaviour, and its biomarkers are considered greatly important in identifying the tumorigenesis mechanism that is involved in therapy resistance to increase patient survival. Resistance to chemotherapy is a major cause of treatment failure in HNSCC patients; the long-term assessment of a patient’s compliance with chemotherapy is key to overcoming treatment resistance and controlling cancer. FOXM1 is a known oncogene and plays an important role in conferring chemoresistance. The objective of the current study was to investigate candidate approved-chemotherapeutic drugs to inhibit FOXM1 in HNSCC cells in the aim to counteract chemoresistance. Methods: Dose-response assay was performed to investigate the potency of 16 candidate drugs using crystal violet cell viability assay in 11 human cell lines consisting of normal oral keratinocytes, oral fibroblasts, normal skin keratinocytes, premalignant oral buccal mucosa and 7 HNSCC cell lines. The most potent drugs with least toxicity towards normal control cells were selected to investigate their effect on FOXM1 gene expression using reverse transcription quantitative PCR. Results: Vincristine, lanatoside A and topotecan were found to be the most potent drugs with least toxicity across the 11 cell lines. Lanatoside A was the only effective drug for a paclitaxel resistant cell line (CaLH2-PTX). All three drugs significantly suppressed FOXM1 gene expression levels in all 7 HNSCC cell lines. Conclusion: This study identified 3 existing candidate approved chemotherapeutic drugs demonstrating potent anti-proliferation effects against a panel of HNSCC cell lines and with low toxicity towards normal cells. Further investigations are needed to understand their mechanisms and their effects on FOXM1 in HNSCC cells.7 0Item Restricted Ultrasound Nano-Scale Phase Change Contrast Agent for Hepatocellular Carcinoma Radiosensitization(Saudi Digital Library, 2023-08-05) Falatah, Hebah; Eisenbrey, John; Wheatley, MargaretThe purpose of this study was to develop and characterize nano-scale phase change droplets less than 200 nm from commercially available ultrasound contrast agents and demonstrate their ability to enhance hepatocellular carcinoma (HCC) radiosensitization, which is critically needed to enhance the poor outcomes (two years survival < 50%) of current HCC radiotherapy treatments. Primary liver cancer is the third cause of cancer death worldwide with 906,000 new cases and 830,000 deaths annually. Of these, 75-85% of patients present with hepatocellular carcinoma (HCC), while the remaining 15-25% are intrahepatic cholangiocarcinoma and other types. Due to the late clinical presentation of the disease and treatment limitations of chemotherapy and immunotherapies, HCC has a poor prognosis. Localized radiotherapy in the early and mid-stages of HCC has shown some success in treatment response 25-50%. In such therapy, the hepatic artery supplying blood to the cancer is injected with radioisotope yttrium-90 (Y90), a beta particle emitter that provides localized radiation therapy. Another therapeutic option is external beam radiation (XRT) with MRI or CT guidance. XRT has been used cautiously in HCC treatment due to the radiosensitivity of liver tissue and technological limitations. Fractionated approaches are used to overcome the toxicity to the liver or radiation-induced liver diseases caused by high doses of radiation. The result of these limitations is that the overall five years survival for HCC patients in the United States is 20%, and the two years survival is less than 50%.Therefore, developing more effective HCC treatments is essential to improve patient outcomes. In recent years, researchers have been exploring a variety of radiosensitizers as a means of overcoming radiotherapy resistance. One promising radiotherapy enhancement mechanism is ultrasound-mediated microbubble destruction, which has been shown to sensitize solid tumors to radiotherapy through endothelial cell disruption in tumors. Ultrasound microbubbles have a diameter between 1 to 8 (micrometers) μm and consist of a high molecular weight gas encapsulated by a lipid, protein, or polymer shell. However, the relatively large size of the bubbles prevents them from passing into extravascular spaces, and as a result researchers have developed phase-change contrast agents (PCCAs). PCCAs contain a low boiling point such as -37oC liquid in place of the usual gas and can transition from the liquid to the gaseous state under external stimuli. This technology has been widely used in ultrasound medical imaging, vascular occlusion, and cavitation activity enhancement. The small diameters < 400 nm of these PCCAs allow them to diffuse and accumulate in solid tumors via the enhanced permeability and retention effect before the phase transition. Using ultrasound as an acoustic stimulus can provide local vaporization as well as cavitation of the resultant microbubble, thereby generating local force in tumor tissues. The development and characterization of sub-micrometer (< 200 nm diameter) phase change droplets from commercial ultrasound contrast agents, including their ability to decrease tumor vascularity and enhance cell apoptosis are described in addition to their ability to enhance HCC tumor radiosensitization.18 0