EDUCATION
Dr Mark Bates holds a PhD in Ovarian Cancer research from Trinity College Dublin and a BSc in Biomolecular Science from Technological University Dublin (formerly Dublin Institute of Technology) as well as a number of professional certificates.
PhD Ovarian Cancer - TCD
(2012-2016)
Dr Bates’ PhD work focused on ovarian cancer and utilised a number of molecular techniques including PCR, Western Blotting, IHC, Cytotoxicity assays, siRNA and plasmid transfections, immunofluorescence and flow cytometry. Dr Bates thesis was entitled “A therapeutic roadmap for ovarian cancer using TLR4, MyD88 and MAD2 as prognostic indicators”. The aim of Dr Bates’ project was to assess the in-vitro relationship between these novel ovarian cancer biomarkers and determine whether they can be used in combination to predict patient chemoresponse and outcome.
Summary
Thesis Abstract
Ovarian cancer is 4th leading cause of cancer death in woman and the most lethal gynaecological malignancy. Most patients present with advanced disease where the 5 year survival rate is less than 40%. Standard treatment for advanced ovarian cancer includes cytoreductive surgery followed by paclitaxel/carboplatin-based chemotherapy. However, despite the use of these front-line chemotherapeutic agents, mortality rates for ovarian cancer have remained almost unchanged for the past 30 years. A major reason for this poor prognosis is the development of chemoresistance and recurrent disease. Therefore there is a dire need for prognostic biomarkers which can predict patient response to chemotherapy from the outset and prevent the development of chemoresistant recurrent disease. Currently there are no reliable prognostic markers in routine use for ovarian cancer. In this study we investigated the role of three protein biomarkers TLR4, MyD88 and MAD2 in ovarian cancer. High TLR4 and MyD88 expression and low MAD2 expression have been associated with poor survival and paclitaxel resistance in-vitro.
The aim of this project was to assess the combined utility of these three markers in predicting patient prognosis and to investigate any potential in-vitro link between these three markers and the paclitaxel resistance mechanisms in which they are involved. Interestingly in this study, siRNA knockdown of MAD2 in A2780 and SKOV-3 ovarian cancer cells resulted in a 3 fold increase in TLR4 mRNA expression demonstrating an in-vitro link between these two biomarkers. Knockdown of TLR4 in SKOV-3 was shown to recover chemosensitivity of these cells to paclitaxel. Furthermore knockdown of MAD2 was shown to render SKOV-3 chemoresistant to paclitaxel. This perhaps demonstrates a partial overlap in the paclitaxel resistance mechanisms associated with both markers. Following knockdown of MAD2, SKOV-3 cells displayed an increase in β-galactosidase activity, an enlarged cell phenotype and exhibited an upregulation of a number of senescence associated genes as confirmed by microarray analysis. Microarray analysis of SKOV-3 cells following knockdown of TLR4 identified a number of altered gene pathways which may be responsible for the increase in sensitivity of these cells to paclitaxel. Two novel signalling pathways altered following the knockdown of TLR4 were the olfactory receptor and the ErbB signalling pathways. A number of olfactory receptor genes were downregulated following knockdown of both TLR4 and MAD2. Cross comparison of arrays identified a number of other differentially expressed genes affected following knockdown of TLR4 and MAD2 which may help us to better understand the in-vitro relationship between these two biomarkers.
Combined assessment of these three markers in a TMA cohort demonstrated that these markers can be used very successfully in combination to predict patient prognosis. The three markers when used in combination identified different at risk subpopulations of patients. Patients with high TLR4, high MyD88 and low MAD2 expression exhibited the worst prognosis. These patients are unlikely to respond to paclitaxel therapy and in fact paclitaxel therapy may be harmful to these patients. Therefore these patients should instead receive alternative therapies or be directed towards clinical trials. In future patients should be triaged based on the expression of these three markers and should be given more appropriate therapies such as targeted therapies based on the molecular evidence.
PhD
Certificate
PhD
Thesis
BSc Hons Biomolecular Science - DIT
(2011-2012)
Summary
Following completion of his primary level seven degree in Bioscience Dr Bates completed a 1 year add on degree in Biomolecular Science, graduating at the top of his class with a first class honours degree. His thesis project was conducted at the coombe hospital molecular pathology lab under the supervision of Dr Cara Martin and Ms Christine White.
Course Description
A 1 year level 8 add on degree to the level 7 BSc in Biosciences. This course covered key modules including Biochemistry, Advanced Molecular Biology, Molecular Immunology, Analytical Methods in Biosciences, Research Methods & Biostatistics to provide students with an in-depth theoretical and practical knowledge on a range of topics, reflecting the integrated nature of biomolecular science, such as the importance of macromolecular structure, interactions and function in relation to normal and diseased states. In semester 2 the optional module molecular mechanisms of disease provided more comprehensive overview of disease pathology to enhance student understanding of diagnosis and treatment of human disease.
Thesis - The performance of the p16INK4A /Ki67 biomarker test for predicting risk of cervical pre-cancer in a population of women with persistent low grade cytology
Thesis Abstract
This study falls under project 5a of CERVIVA which is investigating HPV DNA, mRNA testing and p16INK4A in the triage of women with low grade abnormalities (LSIL and ASCSUS). Up to 28% of women with persistent low grade cytological abnormalities are potentially harbouring high grade cervical disease. HPV DNA testing is thought to play an important role in triaging women with low grade disease into those at high risk of developing high grade disease and those at little or no risk. However HPV DNA while more sensitive than cytology for detecting high grade disease, it has a low specificity and results in a considerable number of false positive results. p16INK4A is overexpressed in CIN and cervical cancer due to action of the HPV E7 oncoprotein which interferes with normal cell cycle control mechanisms. p16INK4A therefore acts as a surrogate marker of HPV infection, using p16INK4A in triage may therefore allow the identification of women with a productive HPV infection at high risk of developing high grade dysplasia and cervical cancer. In this study cervical smear samples from a cohort of women presenting at colposcopy with low grade abnormalities (n=210) were assessed for co-expression of p16INK4A and Ki67 using the CINtec PLUS test (MTM laboratories). Overall p16INK4A/Ki67 co-expression was detected in 37% of the cases examined, of these 55% were positive for high risk HPV DNA, and 70% of those cases with dual expression of both markers had CIN2 on histological examination. Overall the sensitivity and specificity of the CINtec PLUS for the detection of CIN2+ was 70.3 % (CI 0.66520-0.7543) and 77.4% (CI 0.7456-0.8023) respectively, it also had a PPV of 57% and a NPV of 85%. In comparison HPV DNA testing using the HC2 was 93% sensitive (CI 0.916-0.946) and 48.5% specific (CI 0.453-0.520) and HPV mRNA testing using the HPV proofer was 66% sensitive (CI 0.615-0.718) and 69.4% specific (CI 0.666-0.723) for detection of CIN2 in the same study cohort. Based on our findings, the data suggests that using combined HPVDNA and / p16INK4A/Ki67 for triage of low grade abnormalities may be the most effective approach to managing women with low grade disease in colposcopy.
Exam Results
BSC LVL8
Certificate
Project
Thesis
BSc Ord Bioscience - DIT
(2008-2011)
Summary
Dr Bates completed his primary degree in Bioscience with the Dublin Institute of Technology based at the Kevin St campus between 2008-2011. His 3rd year thesis project entitled "In vitro effects of low dose nano zinc oxide exposure on the expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in A375 melanoma cells" was conducted at the NanoLab within the FOCAS institute under the supervision of Dr Alan Casey and Dr Orla. Dr Bates was awarded the Lab Tech Supplies for best student project.
Course Description
This course aimed to produce graduates with the skills needed for employment as technicians/technologists or scientific personnel in the fields of biotechnology and biosciences. The first year of the course provided a solid foundation in biology, chemistry and physics. Year 2 focused on the core subject areas of biochemistry, cell and molecular biology and microbiology. The final year built on these core subjects, together with biotechnology and the specialised bio-industry-focused modules of food science and technology and biomedical science.
Thesis - In vitro effects of low dose nano zinc oxide exposure on the expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in A375 melanoma cells
Thesis Abstract
Bax and Bcl-2 are pro-apoptotic and anti-apoptotic factors respectively which regulate the formation of a pore in the mitochondrial membrane and subsequent formation of the apoptosome. This is a multi-protein complex that activates effector enzymes called caspases which subsequently carry out programmed cell death; apoptosis. In this project the level of expression of these two proteins in A375 cells (a melanoma cell line) was determined following exposure to low doses of zinc oxide nanoparticles (ZnO nanoparticles) (0, 1,5,10 and 15mg/l) over various different time points (1, 5, 10 and 15 hours). Following exposure, the level of protein expression was determined using immunocytochemistry and western blotting methods to consolidate the data. In this study exposure to low doses of zinc oxide were shown to cause increase in both Bcl-2 and Bax expression. Immunocytochemistry showed a 5-15% increase in bcl-2 and 15-25% increase in Bax expression and an increase in apoptosis was also noted with dose and time. Western blots only revealed an increase Bax expression. However it is clear from these findings that ZnO nanoparticles have a cytotoxic effect on cells
Exam Results
BSC LVL7
Certificate
Project Thesis
St Brendan's Secondary School (2002-2008)
Dr Bates attended St Brendan's Christian brothers secondary school in woodbrook, bray from 2002-2008 and took English, Irish, Maths, Accounting, Chemistry French and History for his leaving certificate all at the higher level and achieving a B2, D1, C3, B2, C2, D3 and B3 respectively.
