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Naguib A.,Medical Research Council Dunn Human Nutrition Unit | Wilson C.H.,Wellcome Trust Sanger Institute | Adams D.J.,Wellcome Trust Sanger Institute | Arends M.J.,University of Cambridge
Journal of Molecular Signaling | Year: 2011

The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant. © 2011 Naguib et al; licensee BioMed Central Ltd. Source

Davidson S.M.,University College London | Yellon D.M.,University College London | Murphy M.P.,Medical Research Council Dunn Human Nutrition Unit | Duchen M.R.,University College London
Cardiovascular Research | Year: 2012

Aims: Opening of the mitochondrial permeability transition pore (mPTP) is an important step on the pathway towards cardiomyocyte death, defining the extent of injury following cardiac ischaemia and reperfusion. In isolated mitochondria, mPTP opening is triggered by calcium overload facilitated by oxidative stress. In isolated cells, however, it has been suggested that mPTP opening occurs before calcium overload and is stimulated by oxidative stress. Our objective was to establish the events that cause mPTP opening in the intact heart. Methods and results: We performed multiphoton imaging of Langendorff-perfused mouse hearts expressing an inducible, Ca 2+-sensitive reporter (circularly Permuted GFP and calmodulin (CaM), version 2), to examine the spatiotemporal relationship between [Ca 2+] c, redox state, and mPTP opening in the intact heart during hypoxia and reoxygenation at sub-myocyte resolution. We found that during reperfusion, calcium waves propagated across multiple cells at 3.3 μm/s. mPTP opening caused an abrupt loss of mitochondrial membrane potential, measured using a potentiometric dye, which was invariably preceded by a rise in [Ca 2+] c. The probability that localized [Ca 2+] c waves led to mPTP opening was greater early during reoxygenation. During reoxygenation, coordinated redox changes also occurred across large regions and preceded mPTP opening on average by 122 ± 38 s. Fewer [Ca 2+] waves led to mPTP opening in the presence of mPTP inhibitor cyclosporin A or mitochondrial-targeted scavenger of reactive oxygen species, MitoQ. Conclusion: These experiments define the spatiotemporal relationship between changes in [Ca 2+] c, redox state and mPTP opening during reoxygenation in the intact heart. Tissue oxidation coincident with localized calcium waves together conspire to cause mPTP opening and subsequent cell death. © The Author 2011. Source

Jeurnink S.M.,University Utrecht | Jeurnink S.M.,National Institute for Public Health and the Environment RIVM | Buchner F.L.,National Institute for Public Health and the Environment RIVM | Buchner F.L.,Radboud University Nijmegen | And 53 more authors.
International Journal of Cancer | Year: 2012

Diets high in vegetables and fruits have been suggested to be inversely associated with risk of gastric cancer. However, the evidence of the effect of variety of consumption is limited. We therefore investigated whether consumption of a variety of vegetables and fruit is associated with gastric and esophageal cancer in the European Prospective Investigation into Cancer and Nutrition study. Data on food consumption and follow-up on cancer incidence were available for 452,269 participants from 10 European countries. After a mean follow-up of 8.4 years, 475 cases of gastric and esophageal adenocarcinomas (180 noncardia, 185 cardia, gastric esophageal junction and esophagus, 110 not specified) and 98 esophageal squamous cell carcinomas were observed. Diet Diversity Scores were used to quantify the variety in vegetable and fruit consumption. We used multivariable Cox proportional hazard models to calculate risk ratios. Independent from quantity of consumption, variety in the consumption of vegetables and fruit combined and of fruit consumption alone were statistically significantly inversely associated with the risk of esophageal squamous cell carcinoma (continuous hazard ratio per 2 products increment 0.88; 95% CI 0.79-0.97 and 0.76; 95% CI 0.62-0.94, respectively) with the latter particularly seen in ever smokers. Variety in vegetable and/or fruit consumption was not associated with risk of gastric and esophageal adenocarcinomas. Independent from quantity of consumption, more variety in vegetable and fruit consumption combined and in fruit consumption alone may decrease the risk of esophageal squamous cell carcinoma. However, residual confounding by lifestyle factors cannot be excluded. Copyright © 2012 UICC. Source

Gay L.J.,Medical Research Council Dunn Human Nutrition Unit | Arends M.J.,University of Cambridge | Mitrou P.N.,University of Cambridge | Bowman R.,Medical Research Council Dunn Human Nutrition Unit | And 6 more authors.
Nutrition and Cancer | Year: 2011

There is conflicting evidence for the role diet and lifestyle play in the development of mismatch repair (MMR)-deficient colorectal cancers (CRC). In this study, associations between MMR deficiency, clinicopathological characteristics, and dietary and lifestyle factors in sporadic CRC were investigated. Tumor samples from 185 individuals in the EPIC-Norfolk study were analyzed for MLH1 gene promoter methylation and microsatellite instability (MSI). Dietary and lifestyle data were collected prospectively using 7-day food diaries (7dd) and questionnaires. MMR-deficient tumor cases (MLH1 promoter methylation positive, MSI-H) were more likely to be female, older at diagnosis, early Dukes' stage (A/B), and proximal in location (MSI-H P = 0.03, 0.03, 0.02, and 0.001, respectively). Tumors with positive MLH1 promoter methylation (20%) were associated with poor differentiation (P = 0.03). Low physical activity was associated with cases without MSI (P = 0.05). MMR deficiency was not significantly associated with cigarette smoking or alcohol, folate, fruit, vegetable, or meat consumption. We conclude that MMR-deficient tumors represent a distinct subset of sporadic CRC that are proximal in location, early Dukes' stage, and poorly differentiated, in cases that are female and older at diagnosis. There is no overall role for diet and lifestyle in MMR status in CRC, consistent with age-related susceptibility to MLH1 promoter methylation. Copyright © 2011, Taylor & Francis Group, LLC. Source

Naguib A.,Medical Research Council Dunn Human Nutrition Unit | Cooke J.C.,Medical Research Council Dunn Human Nutrition Unit | Happerfield L.,University of Cambridge | Kerr L.,University of Cambridge | And 6 more authors.
BMC Cancer | Year: 2011

Background: The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions.Methods: 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires.Results: Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55).Conclusion: These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage. © 2011 Naguib et al; licensee BioMed Central Ltd. Source

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