https://www.um.edu.mt/library/oar/handle/123456789/16100 Tue, 07 Apr 2026 06:26:45 GMT 2026-04-07T06:26:45Z https://www.um.edu.mt/library/oar/handle/123456789/139139 Title: 5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential Authors: Fenech, Kimberly; Micallef, Isaac; Baron, Byron Abstract: Background: Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. In many cases, the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil (5-FU). The epithelial-to-mesenchymal transition (EMT) and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers. This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC.; Materials and Methods: HCT-116, Caco-2, and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU. The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays. This was followed by a Western blot which analyzed the protein expressions of the epithelial marker E-cadherin, mesenchymal marker vimentin, and the EMT transcription factor (EMT-TF), the snail family transcriptional repressor 1 (Snail) in the parental and desensitized cells. Western blotting was also conducted to study the protein expressions of the protein methyltransferases (PMTs), Euchromatic histone lysine methyltransferase 2 (EHMT2/G9A), protein arginine methyltransferase (PRMT5), and SET domain containing 7/9 (SETD7/9) along with the global lysine and arginine methylation profiles.; Results: The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU. The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells. This was reflected in the observed reduction in E-cadherin, vimentin, and Snail in the desensitized cell lines. Additionally, the protein expressions of EHMT2/G9A, PRMT5, and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment.; Conclusion: This study showed that continuous, dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be less aggressive than parental cells. Mon, 01 Jan 2024 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/139139 2024-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/138157 Title: Therapeutic targeting potential of the protein lysine and arginine methyltransferases to reverse cancer chemoresistance Authors: Micallef, Isaac; Fenech, Kimberly; Baron, Byron Abstract: Cancer treatments have continued to improve tremendously over the past decade, but therapy resistance is still a common, major factor encountered by patients diagnosed with cancer. Chemoresistance arises due to various circumstances and among these causes, increasing evidence has shown that enzymes referred to as protein methyltransferases (PMTs) play a significant role in the development of chemoresistance in various cancers. These enzymes are responsible for the methylation of different amino acids, particularly lysine and arginine, via protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs), respectively. Various PMTs have been identified to be dysregulated in the development of cancer and chemoresistance. Nonetheless, the functional role of these PMTs in the development of chemoresistance is poorly characterised. This advocates the need for innovative approaches and technologies suitable for better characterisation of these PMTs and their potential clinical inhibitors. In the case of a handful of PMTs, inhibitory small molecules which can function as anticancer drugs have been developed and have also entered clinical trials. Considering all this, PMTs have become a promising and valuable target in cancer chemoresistance related research. This review will give a small introduction on the different PKMTs and PRMTs families which are dysregulated in different cancers and the known proteins targeted by the respective enzymes. The focus will then shift towards PMTs known to be involved in chemoresistance development and the inhibitors developed against these, together with their mode of action. Lastly, the current obstacles and future perspectives of PMT inhibitors in cancer chemoresistance will be discussed. Mon, 01 Jan 2024 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/138157 2024-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/99241 Title: Role of the post-translational modifications of HSP60 in disease Authors: Baron, Byron Abstract: Heat Shock Protein 60 (HSP60) is primarily a chaperone protein responsible for refolding proteins in the mitochondria. Nevertheless it has numerous other pro- and anti-apoptotis and signalling functions which it achieves through a variety of post-translational modifications (PTMs). Increasing evidence indicates that in disease states from cancer to systemic inflammation, such modifications become dysregulated, and as a result HSP60 cannot perform its functions. Understanding the biological role of these PTMs in healthy and disease states, the context in which they are generated and removed, as well as the mechanisms by which they can be targetted and modulated extraneously will help to provide better therapeutic solutions to deal with a wide range of conditions driven by stress-related processes. Tue, 01 Jan 2019 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/99241 2019-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/99240 Title: Role of regulatory t-cells in oral tolerance and immunotherapy Authors: Farrugia, Mark; Baron, Byron Abstract: Food allergies encompass a range of disorders ranging from being an inconvenience to even causing fatalities, mainly due to anaphylaxis. A large number of individuals are affected and this presents great health and economic implications. However as yet, apart from dietary avoidance, effective treatment strategies are practically non-existent. The immune environment related to allergen-tolerance is highly complex and the role of regulatory T-cells in allergenspecific tolerance, their interaction with other cells in inflamed tissues, and their role in antibody regulation have been demonstrated in several studies. Regulatory T-cells are able to control acquired immunity and achieve oral tolerance to food allergens. Immunotherapy for food allergies focuses on desensitisation by increasing the allergen reactivity threshold. So far, the only long-term curative treatment used effectively is allergen-specific immunotherapy which involves the administration of increasing doses of the causative allergen, such that a state of allergen-specific immune tolerance is induced over the course of the treatment. This review covers various forms of allergen-specific immunotherapy, focusing on the role of regulatory T-cells in such therapies, and includes a number of small studies providing ideas for future work in the area. Fri, 01 Jan 2016 00:00:00 GMT https://www.um.edu.mt/library/oar/handle/123456789/99240 2016-01-01T00:00:00Z