https://www.um.edu.mt/library/oar/handle/123456789/39648 2026-05-07T16:14:43Z 2026-05-07T16:14:43Z https://www.um.edu.mt/library/oar/handle/123456789/120577 2024-04-16T06:10:56Z 2018-01-01T00:00:00Z

Title: Identifying genetic factors underlying osteoporosis and fragility fractures in Malta Abstract: Osteoporosis is a complex metabolic bone disease with a strong genetic background. Family-based studies have identified significant candidate genes implicated in bone pathophysiology. A two-generation Maltese family with primary osteoporosis at the spine or hip was recruited, with the aim of identifying known or novel genes and gene variants contributing to osteoporosis pathogenesis. A total of fifteen relatives were recruited with ages ranging from 28 to 74 years. Whole genome sequencing was performed on twelve relatives and a number of filtering schemes together with in silico modelling were applied to narrow down the list of potentially causal variants. Five missense variants segregating in a dominant inheritance pattern were shortlisted, all of which had an alternative allele frequency of ≤1% in the 1000Genome project. The variants identified were ADAMTS20 Tyr1364Asn (rs138035327), BMP1 Arg727Gln (rs368615556), SELP Tyr726Cys (rs754086574), TGF-β2 Pro379Leu (rs773943154) and TRIM45 Ser339Pro (rs146244405). Replication of ADAMTS20 Tyr1364Asn and TGF-β2 Pro379Leu variants in a case-control collection of 1045 Maltese postmenopausal women was performed to determine association with bone mineral density (BMD), fracture risk and other bone-related phenotypes. Heterozygosity for the ADAMTS20 Tyr1364Asn variant was associated with an increased risk of low total serum calcium levels compared to the homozygosity for the reference allele. Although heterozygosity for the TGF-β2 Pro379Leu variant was higher in research subjects with a low BMD and fracture history, numbers were too small to infer any statistical association. In conclusion, results suggest that identified variants, alone or in combination, could be disease-causing in the family, and possibly at the population level, requiring replication across larger collections. ADAMTS20 encodes a protease enzyme that cleaves aggrecan, required for cartilage and bone formation. TGF-β2 plays a role in bone remodelling by stimulating matrix protein synthesis. The two genes indirectly interact via the TGF-β pathway. Functional follow-up of the variants is warranted to determine their effect on bone physiology, particularly BMD and calcium homeostasis. Description: M.Sc.(Melit.)

2018-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/40580 2020-05-14T05:41:43Z 2018-01-01T00:00:00Z

Title: Correlation of total and phosphorylated HSP27 with HER2-positivity in breast cancer Abstract: Human epidermal growth factor receptor-2 (HER2)-positive breast cancer is a highly aggressive subtype of breast cancer, found in around 20% of diagnosed breast cancer cases. The overexpression of the HER2 cell surface protein is associated with a poor prognosis, high recurrence and low survival rate. Over-expression of this receptor is routinely tested for in breast cancer classification and determination of eligibility for treatment with the monoclonal antibody trastuzumab (Herceptin®). Despite promising results in most patients, the presence of innate or acquired resistance to the drug is a well-documented hurdle of trastuzumab treatment. In previous studies, it has been indicated that a) an increased concentration of the heat shock protein 27 (HSP27) is associated with HER2-positive breast cancer and b) the presence of HSP27 phosphorylated at serine 78 (pHSP27ser78) in tumour cells may render them resistant to trastuzumab. Nonetheless, the involvement of HSP27 in HER2-positive breast cancer as well as its role in the resistance to trastuzumab are not yet fully understood. The aim of this study was to determine whether the expression of HSP27 and its phosphorylated portion pHSP27ser78 is indeed higher in HER2-positive breast cancer cells as opposed to HER2-negative tumours. Thus, 168 formalin-fixed paraffin embedded (FFPE) samples consisting of 89 HER2-positive cases and 79 HER2-negative controls were separately stained by immunohistochemistry with anti-HSP27and anti-pHSP27ser78 antibodies. The sections were then scored using the H-score and the difference in the scores of HER2-positive and HER2-negative samples was tested using statistical methods. It was determined that, while HER2-positive and HER2-negative tumours express similar amounts of total HSP27, the expression of pHSP27ser78 is significantly higher in HER2-positive tumours. This might contribute to the development of resistance to trastuzumab. Description: B.SC.(HONS)APPLIED BIOMED.SCI.

2018-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/40564 2020-05-14T05:39:41Z 2018-01-01T00:00:00Z

Title: Transporter polymorphism and risk of MI in the Maltese population Abstract: Serotonin (5-HT) is a mild platelet agonist and its plasma concentration is regulated by the serotonin transporter, 5-HTT, present on platelet surfaces. The 5-hydroxytryptamine transporter linked polymorphic region (5-HTTLPR) is a functional polymorphism in the promoter region of the SLC6A4 which codes for 5-HTT. It involves an imperfect size polymorphism of 43-44bp thus giving rise to a long (L) or short (S) allele. Previous studies have shown conflicting evidence between the different genotypes and the risk of myocardial infarction (MI). The aim of this study was to determine if any genotype of the 5-HTTLPR polymorphism (alone or in combination with other known risk factors) is associated with an increased risk of MI in the Maltese population. Genotyping for the 5- HTTLPR by sizing was carried out on 1064 Maltese samples from the Maltese Acute Myocardial Infarction (MAMI) study which includes both cases with a first MI, relatives of cases and controls. Odds ratios with a 95% confidence interval were calculated using SPSS. The 5-HTTLPR polymorphism alone was not associated with increased risk of MI. However, combined analysis of genotype and smoking showed a slightly increased risk of MI in smokers with the SS genotype. Description: B.SC.(HONS)APPLIED BIOMED.SCI.

2018-01-01T00:00:00Z https://www.um.edu.mt/library/oar/handle/123456789/40517 2020-05-14T05:37:45Z 2018-01-01T00:00:00Z

Title: Evaluating the use of mortuary samples to assess survival bias in myocardial infarction Abstract: Myocardial infarction (MI) is the leading cause of death in Europe and a great financial burden on society. Whilst studies on the genetics of MI are plentiful, findings are often conflicting, with the reported effect of a genetic variant ranging from protective to deleterious or no effect. Survival bias may be a reason for these inconsistent results, necessitating a study which adequately assesses its effect on studies of MI. The aim of this project is to assess survival bias by comparing the allele frequency of variants in post-mortem formalin fixed paraffin embedded (FFPE) tissue samples from individuals who died from cardiovascular-related conditions to the allele frequency in survivors of MI. The DNA isolated from the FFPE tissue samples was not of sufficient quality to successfully carry out restriction enzyme digest, regardless of the various optimisation procedures carried out. This was not due to PCR inhibitors. The major problem was that of DNA fragmentation which was observed to increase with duration of storage. Time from death to tissue processing may also be having an effect. From data collected from the Maltese Acute Myocardial Infarction (MAMI) study on the integrin subunit beta 3 T196C (ITGB3 T196C) polymorphism (known to increase susceptibility to MI), it was noted that the allele frequency of this variant did not change with increasing age group and thus this polymorphism was not significantly affected by survival bias. Survival bias could be assessed using more sensitive techniques such as real-time PCR and next generation sequencing. Description: B.SC.(HONS)APPLIED BIOMED.SCI.

2018-01-01T00:00:00Z