Pusat Pengajian Sains Perubatan - Tesis

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Role of genetic variations of abc (abcb1, abcc1 and abcg2) on triple negative breast cancer susceptibility risk
(2024-09)
Ing, Yeoh Hao
Triple-negative breast cancer (TNBC) is known for its aggressive behaviour and is associated with poor prognosis. ABC transporter genes were widely studied for their association with multiple drug resistance in cancer patients and other diseases. However, the evidence on ABC transporter gene polymorphisms and TNBC susceptibility remains limited and inconclusive. The main objective of this study was to investigate the association of ABC transporter genes ABCB1, ABCC1, and ABCG2 polymorphisms with TNBC susceptibility in the Malaysian population. This case-control study was conducted at Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan. A volume of three mL of peripheral blood samples were collected from 79 TNBC patients and 100 healthy controls, followed by genomic DNA extraction from the blood. Next, the genotyping was performed by employing polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) using enzymes such as TaaI, BseMI, RsaI, EcoO1091, MboI and PspF1 as well as amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) methods. The genotypes were examined by observing the band sizes of digested fragments and PCR products on 3% agarose gel through electrophoresis. The allele, genotype and haplotype of polymorphisms were evaluated, and the independent χ2 test was carried out to elucidate their association with TNBC susceptibility and other clinicopathological variables while the logistic regression was performed to measure the strength of association. The allele and genotype analysis showed that the T allele and TT genotype carrier of ABCB1 1236 C>T were associated with the increased risk of TNBC susceptibility (p = 0.026 and 0.035, respectively) with OR of 1.628 (95% CI: 1.060-2.501) and 3.034 (95% CI: 1.171-7.866) respectively. Besides, ABCG2 421 C>A was also associated with the advanced staging of the tumour (p = 0.004) and the OR for the A allele and AA genotype carrier was 3.464 (95% CI: 1.687-7.111) and 11.625 (95% CI: 2.187-61.804) respectively. Likewise, a significant association was also observed in the AA genotype carrier of ABCG2 421 C>A with rarer histologic subtypes of metaplastic and medullary carcinoma (p = 0.016), with an OR of 6.171 (95% CI: 1.467-25.961). Meanwhile, the haplotype analysis demonstrated a significant association between the ABCB1 1236C/3435T/2677G carrier and TNBC susceptibility (p = 0.011), showing the protective effect with reduced OR of 0.120 (95% CI: 0.015-0.952). Besides, the haplotype carrier of ABCG2 34G/421A was associated with an increased risk of advanced staging (p = 0.030, OR: 2.333, 95% CI: 1.005-5.417) and rarer histologic type of metaplastic and medullary carcinoma (p = 0.009, OR: 2.599, 95% CI: 1.027-6.576). In conclusion, the present study suggests that ABCB1 and ABCG2 polymorphisms were associated with TNBC susceptibility, advanced staging, and rarer histologic types of carcinomas. This study supports the hypothesis that selected variants in ABC transporter genes contribute to TNBC susceptibility risk and could be considered candidate biomarkers and prognostic factors in TNBC management.
Tindak balas antikanser-imun terhadap sel kanser payudara mda-mb-231 dan penilaian teratogenik daun pereskia bleo.
(2024-08)
Dalfi, Taif Kareem Khalf
Conventional treatment for breast cancer, especially radiation and chemotherapy, have significant adverse effects on patients. Thus, an increased global focus on finding nontoxic and cytoselective treatments has emerged, which includes the study on herbs. Various herbs showed excellent bioactivities; however, there are herbs that can be toxic and teratogenic at certain dosage. The current study was conducted to assess the anti-cancer properties of P. bleo leaves in terms of their ability to induce apoptosis and to determine its anti-cancer-immune response by stimulating Natural Killer (NK) cells’ cytotoxicity against MDA-MB-231 breast cancer cells, as well as to evaluate its toxicity and teratogenicity in the animal model. Hexane, ethyl acetate and methanolic extracts of P. bleo leaves were tested for their cytotoxicity against normal cells MCF-10A and MDA-MB-231 cell lines by MTT assay. Methanolic extract showed the best activities and was used for subsequent experiments. Annexin V/PI assay and flow cytometric analysis were used to measure the induction of apoptosis, cell cycle arrest, and apoptotic protein expression by methanolic extract of P. bleo leaves (MEPB). Enzyme-linked immunosorbent assay (ELISA) was utilised to measure the level of interferon-gamma (IFN-γ), interleukins (IL)-8, IL-10, IL-12, IL-18, perforin, and granzyme B in healthy blood donors to determine the best concentration of MEPB leaves for activating NK cells. Flow cytometry and trypan Blue were used to measure NK cell counts and purity for subsequent experiments. Flow cytometric analysis and ELISA were used to determine the ability of MEPB to enhance NK cell cytotoxicity against MDA-MB-231 cells. The toxicity and teratogenicity of MEPB leaves were evaluated by observing the oestrous cycle, body weight, general behaviour and clinical signs, histopathological analyses, absolute body weights of dam’s visceral organs, and pregnancy outcomes, including the numbers of corpora lutea and implantation sites, pre- and post-implantation death (%), gravid uterine weight, number of live and dead foetuses, foetal body weight, sex ratio, and gross examination of the foetuses. The study used 40 female rats and was divided into 10 rat-control groups (distilled water) and 30 rat-MEPB groups (250, 500, and 1000 mg/kg/day). The MTT assay showed moderate cytotoxicity of MEPB leaves towards MDA-MB-231 breast cancer cells with an IC50 value of 64.57μg/mL. The flow cytometry data indicated that MEPB can arrest the cell cycle at the G0/G1 phase and stimulate apoptosis in MDA-MB-231 cells, increasing the Bax, p53, and caspase-3 while decreasing Bcl-2 expression. The results indicated that MEPB leaves could upregulate IFN-γ, IL-12, IL-18, perforin, and granzyme B levels and downregulate IL-8 and IL-10 levels in healthy blood. Breast cancer patients were found to have fewer NK cells than healthy donors, and approximately 87.09% of NK cells were effectively isolated. MEPB enhanced NK cells to kill MDA-MB-231 cells via apoptosis by upregulating perforin, granzyme B, and IFN-γ in healthy and breast cancer patient donors. The study also showed that the rat groups treated with various doses of MEPB leaves did not affect toxicity parameters, pregnancy outcomes, and foetotoxicity parameters. Our findings concluded that MEPB leaves induced apoptosis in MDA-MB-231 cells, with a significant capacity to regulate cytokines and increase NK cell cytotoxicity towards cancer cells without any evidence of toxicity and teratogenicity in rat-MEPB groups.
Three-dimensional morphometric analysis of mandibular foramina: a cone beam computed tomography study comparing Mahajir and Pukhtoon ethnics in Pakistan.
(2024-08)
Alam, Beenish Fatima
A thorough understanding of the anthropometric landmarks on the mandible and their clinical application is necessary, before performing any surgical procedure to reduce the risk of inferior alveolar nerve injury. Cone bean computed tomography (CBCT) is a widely recognised diagnostic tool that generates high-quality, accurate images and assists in identifying the precise location of anatomical components. It has been utilised as instruments for facilitating preoperative planning of surgical procedures. This study aimed to identify the foramen located on the surface of mandible, and to determine their number, shape, classification, dimensions, position, and their distance to various anatomical landmarks. Another objective is to determine the association of mandibular foramen location with mandibular body and ramus height and length between sexes, between right and left sides, and between Mahajir and Pukhtoon ethnic groups of Pakistan. Four hundred CBCT from Mahajir and Pukhtoon Pakistani populations were collected from Khans Dental Institute, Karachi from 2016 to 2021. CBCT imaging was carried out using the New Tom VGi machine (NewTom Co., Ltd., Shawnee, Italy). Image processing and morphometric analysis of the mandibular foramina was conducted using MIMICS software (Materialise, Belgium). Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 28.0 (IBM SPSS Statistics, Armonk, NY, USA). The results of this investigation showed that midline lingual foramen was the most common form. Pukhtoon ethnicity had larger lingual foramen dimensions overall, while males exhibited larger measurements in terms of size. The Pukhtoon ethnic group exhibited a greater distance from landmarks to lingual foramen. The most prevalent shape of mental foramen was round. In terms of size and distance to landmarks, Pukhtoon showed longer measurements from mental foramen. The most typical horizontal location was next to the second premolar, and the most frequently observed vertical position was apical to the tooth's root apex. The round shape was the common for accessory mental foramen while irregular and oval shapes were more prevalent on both sides of accessory mandibular foramen. Additionally, oval shapes were observed to be more prevalent on the right and left side of mandibular foramen. Similarly, the mandibular foramen and accessory mandibular foramen dimensions and distance to landmarks were observed to be greater in Pukhtoon ethnicity. A weak but positive correlation was detected between mandibular foramen with ramus width, height, and length of the mandibular body. This study provided valuable insight and clinical reference values regarding dimensions and distances to anatomical landmarks of all foramina of the mandible for the Mahajir and Pukhtoon ethnicity in Pakistan as well as according to different sexes and sides, which potentially be useful during pre-surgical evaluation of the mandible.
Role of paederia foetida twigs extract on heart and biochemical profile in streptozotocin-induced type-2 diabetic and high-fat diet rats
(2024-10)
Javaid, Amrah
Diabetes mellitus (DM) is a concerning non-communicable disease worldwide that has great socio-economic impact especially in Malaysia where the prevalence beats global figure. Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by hyperglycaemia leading to overproduction of oxidative stress that causes multiple complications. Oxidative stress is associated with its pathogenesis and hyperglycemia may cause cardiovascular complications. Paederia foetida (Rubiaceae) is an edible plant found in Asian countries, traditionally used to treat various diseases, including diabetes as it has anti-inflammatory, antioxidant, and antidiabetic properties. However, the role of Paederia foetida twigs in diabetic cardiomyopathy has not been reported yet. This study was conducted to determine the antioxidant, anti-inflammatory, and antiapoptotic effects of Paederia foetida twigs in high-fat diet streptozotocin-induced type-2 diabetes mellitus in Sprague Dawley rats. Forty-eight (48) male Sprague Dawley rats were acclimatized for a week. Out of 48 rats, 8 rats were assigned to normal control, while 40 rats were induced with obesity using a high-fat diet for 4 weeks. Out of 40 obese rats, 32 were induced with Type 2 diabetes Mellitus (T2DM) rats using 40mg/kg streptozotocin (intraperitoneally). The thirty-two (32) diabetic rats were further sub-divided into 4 groups; diabetic control, and three groups treated with 300mg/kg metformin, 50mg/kg, and 100mg/kg Paederia foetida respectively. Paederia foetida and metformin were orally administered to the rats for 28 days. Body weight, fasting blood glucose, and food intake were taken every week. The rats were sacrificed after four weeks of treatment using 200 mg/kg of sodium pentobarbital. The blood samples were collected by cardiac puncture and serum was prepared and analyzed for lipid profile and blood glucose levels. The heart was surgically removed, and the homogenate was prepared in an ice-chilled 10% potassium chloride solution. Three antioxidant enzymes (Superoxide dismutase (SOD), Glutathione peroxidase (GPx) and Catalase (CAT) and two oxidative stress markers (Malondialdehyde ( MDA ) & protein carbonyl ( PCO ) were measured along with proapoptotic (BAX and caspase-8) and antiapoptotic (Bcl-2) markers. Hematoxylin & Eosin and Masson’s Trichrome staining were done to visualize the histomorphological changes in the heart tissues of diabetic rats. Daily single oral administration of 50mg/kg Paederia foetida twigs on diabetic rats for 28 days revealed this dosage as the most effective in lowering blood glucose (27.2%), which is comparable to 300mg/kg metformin (23.1%). The antioxidant activity of the extract is demonstrated by its ability to inhibit lipid peroxidation and enhance levels of SOD, GPx, and CAT. In diabetic rats, the heart exhibit typical signs of diabetic cardiomyopathy, including cardiomyocyte hypertrophy, fibrosis, and perivascular fibrosis. Supplementation of Paederia foetida or metformin helps to safeguard against the histopathological and biochemical alterations associated with diabetic cardiomyopathy. In a nutshell, this study suggests that Paederia foetida managed to produce positive data on diabetic cardiomyopathy in rats through its antihyperglycaemic and antioxidative properties.
Isolation and molecular identification of dengue and chikungunya viruses from field-collected aedes mosquitoes in Kota Bharu areas, Kelantan
(2024-08)
Jusoh, Tuan Nur Akmalina Mat
Dengue and chikungunya infections have been a major public health threat in Malaysia with a significant number of deaths reported every year. Both diseases are transmitted mainly by Ae. aegypti and Ae. albopictus and cause a wide range of clinical manifestations from mild fever to severe fatal cases. This study aimed to investigate the circulating CHIKV and DENV serotypes from field-collected adult Aedes mosquitoes in the Kota Bharu area. A total of 114 mosquito pools (610) comprising 30 pools (69 male and 40 female mosquitoes) of Ae. aegypti and 84 pools (208 male and 293 female) of Ae. albopictus were collected at DENV outbreak localities in Kota Bharu from January to August 2019 using a sweep net and sticky ovitrap. Virus isolation was carried out in C6/36 cells and the presence of DENV was confirmed using dengue non-structural (NS1) antigen and DENV multiplex reverse transcriptase polymerase chain reaction (RT-PCR) assay. On the other hand, a one-step RT-PCR assay was performed to detect CHIKV. Badang locality showed the highest population of Ae. albopictus while no collection from the Panchor locality. Most of Ae. aegypti was recorded at Kampung Demit Sungai. For DENV multiplex RT-PCR assay, the optimum condition of annealing temperature was 60ºC, 0.1 µM (DENV 1 and DENV 2) and 0.2 µM (DENV 3 and DENV 4) for primer concentration. Of 91, four mosquito pools were positive for dengue NS1 antigen by ELISA comprising two pools (2.2%) of male Ae. albopictus (Pulau Melaka and Kubang Siput locality) and two pools (2.2%) of Ae. aegypti (Kampung Demit Sungai). DENV 1 was detected in one pool (0.9%) of female Ae. albopictus among 114 tested Aedes pools. Two pools (1.7%) from male Ae. aegypti and Ae. albopictus were positive with double serotypes, DENV 1 and DENV 2 (Pulau Melaka). Most of the positive mosquito pools by dengue NS1 antigen were negative by RT-PCR except one pool of male Ae. albopictus from Pulau Melaka. However, no mosquito pool was positive for CHIKV in the study. The findings revealed that DENV 1 and DENV 2 were the current circulating virus in the study area. In addition, Ae. albopictus was the predominant species in the Kota Bharu area. The presence of DENV and the main vectors of DENV in Kota Bharu are pertinent indicators of the need to improve vector controls to reduce arbovirus infections among people in the localities.

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