ORCID Profile
0000-0002-7443-2653
Current Organisations
University of Aberdeen
,
University of Dundee
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Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.COPH.2009.06.003
Abstract: Chronic inflammation underlies many human diseases including cancer. The magnitude and direction of the inflammatory response is often directed by host genetic factors interacting with environmental exposures. Quite often, the environmental trigger is a microbial agent and the host's genetically determined response is crucial in setting the right tone for handling this threat. An inadequate response runs the risk of allowing the infection to become permanently established causing chronic damage, while too vigorous a response might cause collateral damage to the host's essential physiological pathways. Helicobacter pylori-induced gastric cancer is a paradigm for microbially induced and chronic inflammation-driven malignancy. In this review, we summarise current knowledge about the role of host genetic factors in the pathogenesis of this malignancy. The review illustrates the basic principles of genetic epidemiology and host-bacterial interactions and offers an ex le of how basic knowledge of the pathophysiology of a disease directed the search for the relevant host genetic factors. This contrasts with current approaches, driven by advanced technology, where genetic risk factors are being identified first with the hope that these will shed light on the pathogenesis of disease. Both approaches are necessary to make advances in reducing disease burden in society.
Publisher: American Society for Microbiology
Date: 03-2010
DOI: 10.1128/IAI.01226-09
Abstract: Colonization of the gastric mucosa by Helicobacter pylori can lead to serious clinical outcomes, including gastric cancer. Toll-like receptors (TLRs) play an important role in the host response to H. pylori through the recognition of pathogen-associated molecular patterns. TLR9, in particular, is partly responsible for initiating bacterial induced immunity by binding unmethylated CpG-DNA, which is abundant in bacteria. A well-documented single nucleotide polymorphism (SNP) within the TLR9 promoter ( TLR9 −1237T/C), is associated with a variety of inflammatory disorders, including allergic asthma, inflammatory bowel disease, and atopy. Analysis of the TLR9 promoter gene sequence has shown that carriage of the variant “C” allele at position −1237 creates a potential NF-κB binding site that would theoretically increase the transcriptional activity of the gene. In this study, we report that the TLR9 −1237 C allele was significantly associated with the development of H. pylori -induced premalignant gastric changes. Functional analysis of the SNP, supporting the data generated from the genetic association study, showed that carriage of the C allele increased TLR9 transcriptional activity driven mainly by activation of NF-κB. Collectively, these findings confirm that the TLR9 −1237T/C polymorphism is a risk factor for the development of H. pylori -induced premalignant gastric changes and provide a plausible mechanistic explanation.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2014
DOI: 10.1038/NRGASTRO.2014.143
Abstract: Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing in idualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Public Library of Science (PLoS)
Date: 07-01-2011
Publisher: Springer Japan
Date: 2016
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1365-2559.2009.03301.X
Abstract: The matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) system has a major role in tumour invasion and metastasis. Roles in pathways involved in early tumour development are also being identified for this system, and the aim of this study was to define the expression profile of the major MMPs and TIMPs in colorectal polyp cancers. The expression and cellular localization of in idual MMPs and TIMPs was determined in colorectal polyp cancers by immunohistochemistry. All the MMPs and TIMPs showed immunoreactivity in carcinomatous epithelium. MMP1 (P < 0.001), MMP2 (P = 0.003), MMP3 (P = 0.004), TIMP1 (P = 0.01) and TIMP2 (P < 0.001) showed significant increases in immunoreactivity in carcinomatous epithelium compared with adenomatous epithelium. MMP7 showed immunoreactivity in carcinomatous epithelium, but showed no immunoreactivity in either normal epithelium or adenomatous epithelium. MMP and TIMP expression was limited in normal epithelium to MMP1, MMP2 and TIMP3. This study defines the expression profile of MMPs and TIMPs in colorectal polyp cancers and shows that the increased expression of MMPs and TIMPs occurs at an early stage of colorectal neoplasia. It provides evidence to support the hypothesis that these molecules have a key involvement in the early stages of tumour development.
Publisher: Wiley
Date: 16-11-2012
DOI: 10.1111/J.1365-2982.2011.01818.X
Abstract: Nerve fibers can exert trophic/anti-trophic effects on epithelial cells. Substance P (SP) is a pro-proliferative neuropeptide, whereas sympathetic noradrenaline is anti-proliferative at high concentrations. Density of noradrenergic and sensory nerve fibers and presence of nerve repellent factors specific for noradrenergic (semaphorin 3F) and sensory nerve fibers (semaphorin 3A) were investigated in colorectal adenomas. The pedunculus was innervated by noradrenergic fibers, whereas the mucosa was sparsely innervated. The control submucosa compared with control mucosa demonstrated increased density of noradrenergic fibers. Control tissue was much better innervated than the polyp. This was accompanied by strong expression of semaphorin 3F in epithelial cells. Density of sensory SP+ nerve fibers was higher in control colon mucosa compared with polyp mucosa, and SP+ cell clusters and semaphorin 3A-positive cells appeared in the intercrypt space in polyps, but not in control tissue. This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. Up-regulation of the sympathetic repellent semaphorin 3F in the polyps possibly triggers sympathetic repulsion and polyp growth due to the loss of anti-proliferative noradrenaline and presence of SP from local SP+ cells.
Publisher: Springer Berlin Heidelberg
Date: 2011
DOI: 10.1007/978-3-642-03503-6_11
Abstract: Genetic epidemiology is an important discipline that is helping to unravel the aetiology and pathogenesis of complex human diseases. In the context of gastrointestinal malignancy, the paradigm model of host genetic influence on disease outcome is H. pylori-associated gastric adenocarcinoma. This cancer represents a classic ex le of an inflammation-induced malignancy and highlights the importance of host genetics in disease development. This chapter gives an insight into how genetic epidemiology can play an important role in the development of gastric cancer. Increasing our understanding of host genetics in cancer development may allow particularly susceptible in iduals to be targeted for screening or treatment to reduce risk of future malignant transformation.
Publisher: Springer Science and Business Media LLC
Date: 06-2013
DOI: 10.1038/BJC.2013.264
Publisher: Wiley
Date: 07-05-2008
DOI: 10.1111/J.1365-2559.2008.03038.X
Abstract: To assess cyclooxygenase-2 (COX-2) expression in sporadic colonic adenomas and to explore the association of COX-2 positivity with adenoma characteristics linked to increased risk of malignant transformation. COX-2 expression and localization were assessed in 64 colorectal adenomas and 35 paired adjacent normal colonic mucosal biopsy specimens. The number of adenoma specimens was then extended to include polyps exhibiting an increasing degree of epithelial dysplasia. Forty colonic hyperplastic polyps were also identified from the pathology diagnostic database and included in the analysis. Immunohistochemistry was performed with the Envision+ peroxidase-linked biotin-free system incorporating a signal lification step. There was a statistically significant increase in COX-2 expression in colonic polyps compared with paired adjacent normal mucosa, chi(2) = 40.1, P = 0.001. The probability of COX-2 expression increased along with increasing adenoma size and increasing degree of epithelial dysplasia. Fifty-five per cent of the hyperplastic polyp specimens expressed COX-2. This study associates COX-2 epithelial expression with a number of adenoma characteristics that convey an increased risk of malignant transformation. This is in keeping with a positive role for COX-2 in early colorectal carcinogenesis.
Publisher: Public Library of Science (PLoS)
Date: 23-02-2011
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mairi McLean.