Pusat Pengajian Sains Perubatan - Tesis

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The effects of tamoxifen on TNFR2 in NMU-induced breast cancer rat model
(2025-03)
Idris, Ros Akmal Mohd
The tumor necrosis factor receptor 2 (TNFR2) has been implicated in cancerrelated inflammation and immune responses, yet its role in breast cancer remains unclear. This study aimed to explore the effect of Tamoxifen (TAM) on TNFR2 expression in an N-methyl-N-nitrosourea (NMU)-induced breast cancer rat model, as well as others associated biomarkers (ER, PR, HER2, Bax, Bcl-2). Rats were divided into three groups: healthy controls, NMU-induced positive group, and NMU-induced group treated with TAM. Immunohistochemistry (IHC) was performed to assess biomarkers expression. Results showed that TNFR2 was undetectable in both the Positive and TAM-treated groups, suggesting that TNFR2 may not play a significant role in this NMU-induced breast cancer model. ER and PR levels were found to decrease after TAM treatment, indicating TAM's influence on hormonal receptor signalling in this model. HER2 expression was almost undetectable across all groups, while Bax, a pro-apoptotic marker, showed reduced expression in the positive group meanwhile TAM group shows moderate expression. In contrast, Bcl-2, an antiapoptotic protein, displayed varied expression patterns across the groups. These findings suggest that TAM impacts hormonal receptor signalling and apoptosis regulation but does not appear to influence TNFR2 expression in this NMU-induced breast cancer rat model. This is the first study that investigating the role of TNFR2 with others associated markers in NMU-induced breast cancer rat model.
Effect of 12 hours overnight fasting on brain perfusion using TC-99M ETHYL cysteinate dimer Spect/Ct with scenium analysis in smokers
(2025-03)
Norsan, Nor Maslina Mohamad
Cigarette smoking is not only a common habit that occurs in Malaysia but also the whole world. This habit has been common among adults but nowadays teenagers are also addicted to smoking cigarettes. The destructive substances in cigarettes such as nicotine can reduce activity in limbic, posterior cingulate, prefrontal cortex and increase activity in their cuneus and precuneus. This study recruited subjects that are 18 years old and above and fulfill inclusion and exclusion criteria, smokers (n=18) from Klinik Rawatan Keluarga (KRK) and non-smokers (n=11) from volunteer poster. The brain perfusion between both groups was compared by using Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) in Hospital Universiti Sains Malaysia (HUSM) by using technetium-99m-ethyl cysteinate dimer (99mTc-ECD) as a radiotracer for both fasting and non-fasting state and Scenium software was use for quantitative brain image interpretation. Smokers were categorized into mild (n=17), moderate (n=1) and severe smoker (n=0) based on level of addiction fagerstrom questionnaire. Thus, this study objectives were to determine brain perfusion between smoker and non-smoker, to compare the difference in brain perfusion among smoker between fasting and non-fasting state and to compare the difference in brain perfusion among non-smoker between fasting and non-fasting state. The result of Mann Whitney U test for the first objective shows that there is significant difference in left and right of superior frontal gyrus (SFG) dorsolateral and orbital. Wilcoxon Signed Rank test was used for second and third objective and there is significant difference in left amygdala among smoker and no significant difference in brain perfusion area observed among non-smokers after overnight fasting (12 hours fasting).
Developing individualised therapy for colistin through application of pharmacokinetic model tailored for critically ill Malaysian patients utilizing the HPLC-FLD
(2025-02)
Zabidi, Mohd Shafie
Colistin is an antibiotic used as a last option to treat bacterial infections. Due to its toxicity, colistin is administered in the form of an inactive prodrug, colistin methanesulfonate sodium (CMS). The conversion of CMS to colistin in vivo varies greatly, leading to variations in plasma colistin concentration and pharmacokinetic parameters in critically ill patients. A novel analytical method is necessary for any pharmacokinetic studies to succeed. Colistin has a narrow therapeutic window and needs to be monitored for dose optimisation. Therefore, this study aimed to develop personalised medicine for colistin using a pharmacokinetic model for Malaysian critically ill patients. The Human Research Ethics Committee of Universiti Sains Malaysia and the Malaysian Ministry of Health Research Ethical Committee approved the study. The high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was developed and validated to measure colistin in human serum. This validated method was then used to analyse serum from critically ill patients receiving CMS. Colistin population pharmacokinetics was modelled with a nonparametric approach using Pmetrics software. The constructed pharmacokinetic model of colistin was then applied to optimise individual patient therapeutic drug doses. Linear calibration curves were obtained for colistin concentrations of 0.3 to 8 μg/mL, with good fit (r2 = 0.9993). This analytical method accurately measured the amount of colistin in serum, with no significant hydrolysis of CMS into colistin in vitro observed during the procedure. The accuracy ranged from 98% to 100%. In most patients, the trough concentration was higher than the recommended average steady-state concentration (2 μg/mL) and may be associated with nephrotoxicity. The Non-Parametric Adaptive Grid algorithm within Pmetrics software was used to develop a colistin pharmacokinetic model using meta-analysis data from 15 pharmacokinetic studies, and external validation of the final model was performed in 25 subjects (Malaysian and meta-analysis data). A two-compartment model with first-order elimination best describes colistin pharmacokinetics. Model validation was assessed by using a plot of observed versus individual predicted colistin concentration, and an R-squared of 0.974 was obtained in the validation group. The colistin pharmacokinetic model was then implemented for individual patient therapeutic drug dose optimisation. Applying a model-informed approach, focusing on personalised medicine, may help achieve precise dose individualisation.
Investigating bioink hydrogels for 3D bioprinting to reconstitute glioblastoma microenvironment
(2025-02)
Wei, Leong Shye
Glioblastoma, the most aggressive glioma subtype, presents significant challenges due to drug resistance, resulting in frequent recurrence and progression. Traditional two-dimensional (2D) cell cultures often fail to replicate accurately the complex tumor microenvironment and cellular interactions found in vivo, thereby limiting their ability to predict drug response reliably. Addressing this issue, three-dimensional (3D) bioprinting emerges as a modern approach for constructing glioblastoma models, vital for preclinical drug testing. This project aims to fabricate a glioblastoma microenvironment using 3D bioprinting and hydrogels. Various hydrogel compositions; alginate (ALG), a combination of alginate and chitosan (ALG-CHI), and a blend of alginate, chitosan, and hyaluronic acid (ALG-CHI-HA) — were formulated. The physical properties and cell-matrix interactions of these bioink groups (ALG, ALG-CHI, and ALG-CHI-HA) were assessed. Notably, hydrogels composed of 4% ALG, 4%:0.25% ALG-CHI, and 4%:0.25%:0.25% ALG-CHI-HA, when pre-crosslinked with CaCl₂ at the concentration of 0.102 M, they exhibited the most consistent and stable bioprinting results, highlighting the importance of evaluating different bioink compositions and crosslinking parameters to achieve the desired printing outcomes. Furthermore, the study investigated the impact of bioprinting parameters, such as speed and pressure on the quality of the printed constructs. Optimal bioprinting conditions were identified with a printing speed of 8 mm/s and printing pressure of 10 kPa, ensuring precise deposition of bioink materials and maintenance of structural integrity. Porosity assessments demonstrated varying trends over time. ALG hydrogels maintained stable porosity (n.s) after one week of DMEM incubation, whereas ALG-CHI (p<0.05) and ALG-CHI-HA (p<0.001) showed significant decreases in porosity from day 0 to day 7. Swelling ratios remained relatively stable for all bioink groups throughout the 21-day incubation period, ranging between 10.84-14.58. Cell viability assessments revealed distinct trends: ALG demonstrated an initial increase from day 1 to 14, followed by a decrease at day 21 (p<0.001). Conversely, ALG-CHI showed increased in cell viability at day 21 (p<0.05), and ALG-CHI-HA exhibited delayed but significant increased viability between days 7 and 21 (p<0.01). ALG-CHI and ALG-CHI-HA formulations sustained viability over time, suggesting potential for supporting long-term cell growth and proliferation. SEM and histological (H&E) analyses provided valuable visual confirmation into the cellular morphology and organisation within the bioprinted constructs. In conclusion, the bioprinted hydrogels from all groups demonstrated persistent stability and structural integrity throughout. Among the different formulations, ALG-CHI supported higher viability of glioblastoma cells with formation of tumour microenvironment. ALG-CHI-HA also showed similar trend and performance. Hence, ALG-CHI and ALG-CHI-HA are suitable to be used for long-term 3D cell cultures.
Psychological and mechanical profiles of incarcerated male murderers in Malaysia
(2015)
Murder is an unlawful act with the intention of killing a person. The increasingly violent murder incidents, incomplete characterisation of murder in Malaysia, inadequate Malaysian criminological studies on murder and murderers, and impacts and consequences of murder were pivotal in the desire to conduct this study on Malaysian male murderers. The present study is the pioneer national study that is conducted on murder by focusing on a sample of incarcerated Malaysian male murderers within Peninsular Malaysia. The main aim of the present study was to investigate their psychological and mechanical profiles. Nine specific objectives were formulated. The study commenced with a series of 11 year trend analyses to establish the trends and patterns of murder and murder victimology in Malaysia. Prior to the main study, a validation study was carried out to validate three psychometric instruments for the quantitative phase and the results were found acceptable and satisfactory. Following these, the main study employed explanatory mixed method research design using quantitative and qualitative approaches. In the quantitative phase, an observational cross-sectional design using a guided self administered questionnaire was applied for data collection. The sampling frame consisted of 71 Malaysian male murderers from 11 prisons who were selected using purposive sampling method with predetermined selection criteria. The questionnaire consisted of socio-demographic variables, mechanical variables of murder, and four Malay validated psychometric instruments: Zuckerman-Kuhlman Personality Questionnaire-40-Cross-Culture, Self-control scale, Aggression Questionnaire and “How I Think” Questionnaire. The present study also compares murderers and a control group (n = 300). Quantitative data were analysed using descriptive and inferential statistics. The descriptive findings successfully identified prevalent psychological and mechanical traits of male murderers. The regression analyses indicated that several personality traits have significant relationships and are predictive of other psychological variables. The correlation analyses highlighted several significant associations among the psychological variables. Findings revealed some significant mean and median differences of psychological variables score with the types of mechanical aspects committed by the murderers. The findings also indicated that there are several significant psychological traits differences between murderers and control group. In the qualitative phase, nine male murderers voluntarily participated in semi-structured interviews. Data were analysed using thematic analysis. Six main themes: violence and criminal history, substance abuse history, murder victimisation, murder victim concealment, psychological profiles, and preventive factors; were explored and several new themes emerged. The results were discussed in relation to murder, theories that underpin the present research, contexts of criminology and victimology.

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