Dietary,lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC‐Norfolk study

The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276‐1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)‐Norfolk study, with the aim of relating these to high‐quality seven‐day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC⁺) and promoter 1A methylation (PM⁺) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC⁺ or PM⁺ (p = 0.04). APC⁺ CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC^? CRCs (p = 0.05 and 0.03). APC⁺ CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM⁺ CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC⁺ or PM⁺ CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC‐to‐AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette‐smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC‐to‐AT mutations (OR 1.68, 95% CI 1.03–2.75). In conclusion, APC⁺ and PM⁺ CRCs may be influenced by diet and GC‐to‐AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N‐nitroso compounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Swine dust induces cytokine secretion from human epithelial cells and alveolar macrophages

Exposure to swine dust causes airway inflammation with increased levels of proinflammatory cytokines, and inflammatory cells in nasal and bronchoalveolar lavage fluid (BALF) in healthy subjects. Earlier studies have suggested that lipopolysaccharides (LPS) might be an important proinflammatory factor in swine dust. Since respiratory epithelial cells and alveolar macrophages are target cells for the inhaled dust, we therefore compared the release of proinflammatory cytokines from normal human bronchial epithelial cells (NHBE), an epithelial cell line (A549) and from human alveolar macrophages obtained from BALF from healthy subjects in vitro after incubation with dust collected in swine houses or LPS. Swine dust or LPS was added to the wells with A549 cells or macrophages and incubated for 8 h at concentrations of 12.5, 25, 50 and 100 μg/ml. NHBE cells were incubated with swine dust at a concentration of 25, 50 or 100 μg/ml or with LPS at a concentration of 50 or 100 μg/ml and incubated for 24 h. The supernatants were collected, centrifuged, and IL-6, IL-1β and tumour necrosis factor-alpha (TNF-α) production was measured using an ELISA method and expressed per 10⁶ cells. Swine dust and LPS caused a dose-dependant increase of IL-6 production in NHBE cells, swine dust being more potent than LPS. In A549 cells, only swine dust, but not LPS caused an increase of IL-6 production. Neither swine dust nor LPS induced IL-1β or TNF-α release from A549 cells. Both swine dust and LPS caused a dose-dependent increase of IL-1β, IL-6 and TNF-α in alveolar macrophages. Swine dust which contained 2.2 (0.2) ng endotoxin/100 μg swine dust (0.02‰) was almost as potent as LPS in inducing cytokine release from alveolar macrophages in vitro. We conclude that both epithelial cells and alveolar macrophages have the capability to contribute to the release of proinflammatory cytokines following exposure to swine dust. Some agent(s) other than LPS in the dust contribute to the marked airway inflammatory reaction.     

Familial cases of Behcet''s disease

Seven families with Behcet's disease are presented. HLA-B5 tissue type was shown in the three families in whom lymphocyte microcytotoxicity tests were carried out. Genetic factors appear to be important in the pathogenesis of Behcet's disease.