01. PhD Thesis
Permanent URI for this collection
Browse
Browsing 01. PhD Thesis by Title
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Open Access THE AXL INHIBITOR TP-0903 AND ARTESUNATE SYNERGISE TO INDUCE REACTIVE OXYGEN SPECIES, DNA DAMAGE AND APOPTOSIS IN TRIPLE NEGATIVE BREAST CANCER CELLS(Nazarbayev University School of Medicine, 2024-01) Terragno, MirkoTriple Negative Breast Cancer (TNBC) is an aggressive, often rapidly growing form of breast cancer. TNBC usually displays a basal molecular phenotype that associates with epithelial mesenchymal transition (EMT), a cellular program that confers chemoresistance and metastasis. Approximately 56% of TNBC cases show a basal-like gene expression profile and roughly 46% of TNBC patients have distant metastasis. In general, the absence of molecular targets in TNBC is the main obstacle for the development of an effective therapy. For example, TNBC does not respond to endocrine and anti-human epidermal receptor (HER2) treatments as it does not express estrogen and progesterone receptors (ESR/PgR) and human epidermal receptor 2 (HER2). In addition, though initially TNBC is more responsive to cytotoxic drugs compared to other subtypes, TNBC presents a higher relapse rate. Therefore, new anti-TNBC treatment strategies are urgently needed. Drug combination therapy for TNBC could rely on protocols whereby EMT reversal sensitizes TNBC to anti-cancer compounds that are effective against epithelial tumors. Recently, the anti-malaria compound Artesunate (ART) has been shown to exert cytotoxicity in breast cancer by generating reactive oxygen species (ROS) and DNA double strand breaks (DSBs). However, the effect was more pronounced in tumors of epithelial than mesenchymal origin. In this project, the hypothesis was to verify whether EMT inhibition could sensitize TNBC cell lines to ART cytotoxicity. To address this, two aims were pursued. Aim 1 verified whether receptor tyrosine kinase (RTK) AXL inhibitors TP-0903/R428 and AXL/ZEB1 knockdown sensitised TNBC cell lines to ART-generated ROS, DNA damage and apoptosis. Aim 2 was to test whether TP-0903 and AXL/ZEB1 knockout in TNBC cell lines suppressed expression of superoxide dismutase 1/2 (SOD1/2), glutathione peroxidase 8 (GPX8) and catalase (CAT)...Item Open Access TARGETED DELIVERY OF CYTOKINES, GROWTH FACTORS AND PRE-DIFFERENTIATED CELLS FOR MI TREATMENT(Nazarbayev University School of Medicine, 2023-12) Raziyeva, KamilaFollowing myocardial infarction (MI), cardiac tissue undergoes irreversible cellular alterations, with cardiomyocytes being replaced by fibrotic tissue. To combat this our lab synthesized a novel chitosan-based cryogel containing heparin and poly-vinyl alcohol, showcasing distinct porosity and interconnected pore design. A novel cryogel system was previously established as efficacious for tissue regeneration and sustained drug delivery and has been optimized for the repair of cardiac tissue post-MI in a murine model. The treatment regime involved the systematic loading and sequential injection of the cryogel with specific cytokines, growth factors, and pre-differentiated cells. Initially, the cryogel loaded with interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) was injected intramyocardially immediately post-MI, targeting the acute inflammatory response. On day 4 post- MI, a second injection was administered, this time utilizing cryogel loaded with vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), aiming at promoting tissue regeneration and neo-angiogenesis. Subsequently, on day 6 post-MI, the group received cells previously differentiated from mouse mesenchymal stem cells: cardiomyocyte-like cells, smooth muscle cells, and endothelial cells. These cells, in synergy with cytokines and growth factors, aim to repopulate the lost cellular populations, thereby enhancing myocardial repair. Our results highlighted significant myocardial repair in cohorts treated with the combination of cryogel loaded with IL-10,TGF-β and VEGF,FGF-2 and pre-differentiated cells (Cryo/GFs/Cells). Echocardiographic assessments revealed amplified ejection fraction, fractional shortening, and reduced fibrotic regions, as confirmed by Masson Trichrome staining. Further analyses confirmed the immunomodulatory and regenerative capacity of the treatment. Our novel chitosan-based cryogel, enriched with anti-inflammatory and proangiogenic factors, serves as a promising platform for the controlled release of therapeutics, significantly helping tissue repair and regeneration post-MI. In addition, the separate administration of pre-differentiated cells acts in synergy with the Cryo/GFs, further enhancing the regenerative process. The combination of cellular therapy with the Cryo/GFs treatment provides a comprehensive approach for myocardial recovery, using the unique benefits of both techniques to maximize the efficacy of the therapy.Item Embargo THERAPEUTIC POTENTIAL OF CYTOKINE-PRECONDITIONED HUMAN UMBILICAL CORD BLOOD DERIVED MESENCHYMAL STEM CELLS IN THE EXPERIMENTAL MODEL OF RHEUMATOID ARTHRITIS(Nazarbayev University School of Medicine, 2024) Sarsenova, MadinaRheumatoid arthritis (RA) is a persistent autoimmune condition primarily marked by the generation of autoantibodies. RA causes the gradual deterioration of joints due to the breakdown of cartilage and bone tissues, resulting in to a debilitating illness for the patient. Approximately 30% of instances result in people becoming incapacitated within the initial 10 years if the condition is unmanageable. The pathophysiology of RA is linked to the imbalance of both innate and adaptive immune responses. Currently, therapeutic practice is using traditional therapies such as steroid medications, antirheumatic medicines, and biological agents. These treatments have shown to be effective and provide a longer time of remission. Nevertheless, prolonged use of these medications leads to adverse reactions, and some individuals with RA may develop resistance to these therapies. Recent research has uncovered that mesenchymal stem cells (MSCs) have strong capabilities to regulate and suppress immune system activity. These cells possess significant potential for differentiation into several cell types, such as adipocytes, chondrocytes, and osteoblasts, among others. MSCs possess distinctive immunomodulatory features, in addition of their progenitor traits. The MSCs can adopt either a pro-inflammatory or anti-inflammatory phenotype, depending on the surrounding environment. Given this fact, we propose that the cell preconditioning technique with pro-inflammatory cytokines can be utilized to enhance the therapeutic effectiveness of MSCs in treating RA. This study aims to assess the immunomodulatory and immunosuppressive characteristics of MSCs in a laboratory setting. Furthermore, the impact of administering cytokine-preconditioned MSCs systemically will be evaluated in mice with collagen antibody induced arthritis. The study findings indicate that MSCs could be considered as a viable alternative for treating RA.