Saudi Cultural Missions Theses & Dissertations
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Item Restricted Engineering Amphiphilic Platinum(IV) Prodrugs for Treating Drug Resistant Ovarian Cancer(Kent State University, 2022-12) Alqarni, Suha; Zheng, YaorongThe platinum(IV) prodrug approach is a promising method to develop a replacement for classic platinum-based chemotherapy. The mitochondria-damaging Pt(IV) prodrugs have proven effective against drug-resistant ovarian cancer cells and cancer stem cells, which represent long-standing issues in classic platinum chemotherapy. In this work, we present a comprehensive study on engineering novel amphiphilic Pt(IV) prodrugs as mitochondria-damaging agents. The key findings in this study include: 1). Hydrophobicity of the head group of such prodrugs dictates their cell entry and cytotoxicity; 2). Amphiphilic Pt(IV) prodrugs exhibits superior therapeutic effects compared to cisplatin and overcomes drug resistance in ovarian cancer; 3). Amphiphilic Pt(IV) prodrugs trigger mitochondrial damage.10 0Item Restricted Ambulatory Oncology Chair Utilisation in Australia: Apilot Study(Queensland university of technology, 2020-10-23) Alquzi, Fatimah; Chan, RaymondBackground Cancer is one of the principal diseases which afflicts Australians, with statistics suggesting that half of all Australians will be diagnosed with some form of cancer by the age of 85. In recent years, the largest increase in demand for enhanced cancer care services has occurred amongst out-patients, rather than in- patients. In order to deliver quality ambulatory oncology care services, it is essential that service providers fully appreciate both the relevant demand issues and the associated supply challenges. Once knowledge in both these areas has been secured, appropriate strategies can be devised through which the implementation of fair, effective, and needs-based services can be ensured. Objectives This study investigates chair utilization in an oncology ambulatory therapy unit in Brisbane, Australia. Specifically, the study examines the relationship between oncology chair utilization and various treatment factors, including the type of cancer, the day of the service, whether the OOS is related to a clinical trial, whether the OOS is SACT or non-SACT, and how the relationship between the trial and the department. Design and methodology In order to achieve the research objectives, this study adopts a retrospective analysis of an administrative dataset (CHARM® Pharmacist at the Princess Alexandra Hospital) related to chair utilization in an ambulatory oncology unit. The relevant data is cleaned by a Metro South Health employee, who has unrestricted access and widespread familiarity with CHARM, ieMR, and Electronic Scheduling Management System (ESM) records. This data cleaning was performed using Microsoft Excel®, wherein different approaches were employed to ensure that the analysed data reflects actual chair utilization in the hospital setting. iii Results The data analysis revealed a number of principal results, to wit: weekdays had a higher incidence of Occasions of Services (OOS) than the weekend, Systemic Anti-Cancer Therapy (SACT) recorded higher levels of OOS than Non-Systemic Cancer Therapy (Non-SACT), and gastrointestinal cancer, lung carcinoma, lymphoma, and breast cancer were the main types of cancer treated in the unit. Since this is the first study to quantify chair utilization in a day oncology setting, the results of this study can be used to inform the future design of a larger multicentre study to enable a comparison to be made between service growth and demand. These findings also have applicability in workforce planning since they can forecast the extent to which capacity should be expanded in order to guarantee effective and responsive cancer care services in ambulatory oncology settings. Based on these findings, it is recommended that future longitudinal studies should be conducted to identify and predict trends in ambulatory oncology cancer care demand. Moreover, the paper recommends a nationwide programme of exploration of ambulatory oncology services in order to arrive at more generalizable conclusions regarding chair utilization in ambulatory oncology care centres.19 0Item Restricted Remodeling the Lung Tumor Microenvironment with Locally Administered Nano-Immunochemotherapies for Osteosarcoma Lung Metastases(Saudi Digital Library, 2021-12) Sunbul, Fatemah; Da Rocha, SandroOsteosarcoma (OS) is the most common type of primary bone cancer in all ages1 and metastasizes exclusively to the lungs2. The majority of patients present with micrometastases at the time OS is first diagnosed. When lung metastasis (OSLM) develops, and gross lesions are detected, the curability of disease and the overall survival rate diminish drastically (<20%)2,3. OSLM is thus the leading cause of death in those patients1,4. The current standard of care with chemotherapy has failed to improve patients' therapeutic outcomes with OSLM2,3. The interplay between tumor cells and immune infiltrates in the tumor microenvironment (TME) is a critical determinant of metastasis growth. Systemically administered gemcitabine (GMT) chemotherapy is currently being used in the clinic to treat patients with OSLM, alone or in combination with other chemotherapies, but the response rates are very low. Early studies leading to current trials with GMT administered via pulmonary route have shown promise in decreasing tumor burden – but unfortunately not eradicating the tumor. New therapeutic strategies are needed to tackle this unmet need in clinical oncology. We propose the combination of orally inhaled GMT chemotherapy with colony-stimulating factor-1 receptor inhibitors (CSF-1Ris), macrophage immunotherapy, for the treatment of OSLM also via the pulmonary route. The benefits of CSF-1Ris have been recently shown in manipulating TME away from tolerance (but not for OSLM yet) and is now in the clinic 5. Immunotherapies for tumorassociated macrophages (TAMs) are particularly important in OSLM as immune checkpoint inhibitors (ICIs) have yielded very low response rates in such "cold tumors". Moreover, TAMs are the most abundant infiltrates in OSLM tumors. Our particular interest is PLX-3397 (PLX, or Pexidertinib), which has been recently approved by the FDA. As with systemic chemotherapy, potential limitations of CSF-1Ris are the poor biodistribution to the lungs upon systemic administration and the high off-target toxicity (mainly hepatotoxicity)6. Thus, there is an opportunity to develop novel combination immunochemotherapy and local lung delivery strategies to improve the therapeutic potential and decrease off-target toxicity of currently available therapeutics. In this work, we develop a reproducible, robust in vivo model of OSLM that enables screening of various therapeutics via local administration to the lungs and their influence on tumor growth in vivo and ex vivo. We also investigated the effect of gender as a variable in this model, given that tumor growth and treatment outcomes have been shown to be impacted by gender in the clinic. We evaluated the tolerability and efficacy of the local lung delivery of PLX TAM immunotherapy alone and in combination with GMT chemotherapy, and their effect in remodeling the TME to prevent the development of micrometastases to large lesions. We studied the impact of those therapies at the TME level using a combination of flow cytometry, immunofluorescence, and H&E staining, to assess levels of expression of upregulated Fas/FasL in both OS cells and infiltrating lymphocytes, and also the abundance of classically vs. alternatively activated TAMs with the CSF-1Ri treatment. We correlate those results with tumor burden and survival. As lung tissue retention and clearance limit this combination therapy's potential, we started our investigations of the effect of nanoformulation as a potential strategy to enhance drug efficacy by improving the lung pharmacokinetic profile of the treatments. We started with a translatable, lipid-based platform for the development of GMT nanoformulations that can be in the future delivered in nebulizer form; initial studies in the lung retention of GMT and optimization of the lipid formulation are presented. Our studies are clinically significant as they have the potential to introduce new translatable approaches to treat OSLM. They are scientifically significant and innovative, as for the first time, we are elucidating the tolerability and effect of TAM immunotherapy locally delivered to the lungs in combination with chemotherapy in the TME of an immunocompetent OSLM model.23 0