Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease. Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol. We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (Avy), in the offspring. We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at Avy. This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the Avy mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than Avy, a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the Avy allele. Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

Serology has been used to indicate past infection by the human polyomaviruses BK virus (BKV) and JC virus (JCV), because the site of primary infection is not established fully. Little is known about BKV and JCV antibody stability over time. We investigated BKV and JCV seroprevalence and antibody stability over time in an Australian population-based study. Serum was collected from 458 adults participating in a longitudinal skin cancer study in Queensland in 1992, 1993 and 1996, and 117 people had a fourth sample collected in 2003. Serum samples were analysed for BKV and JCV VP1 antibodies by multiplex detection using the Luminex platform. The seroprevalence for BKV and JCV over 4.5 years was 97 and 63 %, respectively. The BKV seroprevalence was 99 % in 25-60-year-olds, and 94 % in people older than 60 years. JCV seroprevalence was around 60 % in people younger than 50 years, 68 % in people 50-70 years of age and 64 % in people older than 70 years. BKV seroprevalence was very stable over 11 years, with 96 % of people staying seropositive and 2 % remaining seronegative. JCV antibody status over time was less stable; 57 % of participants remained seropositive and 31 % seronegative. The same proportion of people (4 % each) seroconverted, seroreverted or had fluctuating JCV antibody levels. These results confirm the previously believed stability of polyomavirus antibodies, with BKV antibodies being highly stable and JCV antibodies moderately so. Thus, a single measure can be used as a reasonable indicator of long-term antibody status in epidemiological studies aiming to understand associations between polyomaviruses and disease.

This synbiotic supplementation with B. lactis and resistant starch, in the doses used, induced unique changes in fecal microflora but did not significantly alter any other fecal, serum, or epithelial variables. This trial was registered in the Australian New Zealand Clinical Trials Registry at www.anzctr.org.au as ACTRN012606000115538.

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Linked administrative population data were used to estimate the burden of childhood respiratory syncytial virus (RSV) hospitalization in an Australian cohort aged <5 years. RSV-coded hospitalizations data were extracted for all children aged <5 years born in New South Wales (NSW), Australia between 2001 and 2010. Incidence was calculated as the total number of new episodes of RSV hospitalization divided by the child-years at risk. Mean cost per episode of RSV hospitalization was estimated using public hospital cost weights. The cohort comprised of 870 314 children. The population-based incidence/1000 child-years of RSV hospitalization for children aged <5 years was 4·9 with a rate of 25·6 in children aged <3 months. The incidence of RSV hospitalization (per 1000 child-years) was 11·0 for Indigenous children, 81·5 for children with bronchopulmonary dysplasia (BPD), 10·2 for preterm children with gestational age (GA) 32-36 weeks, 27·0 for children with GA 28-31 weeks, 39·0 for children with GA <28 weeks and 6·7 for term children with low birthweight. RSV hospitalization was associated with an average annual cost of more than AUD 9 million in NSW. RSV was associated with a substantial burden of childhood hospitalization specifically in children aged <3 months and in Indigenous children and children born preterm or with BPD.

Oncogenic PIK3CA mutations contribute to colorectal tumorigenesis by activating AKT signaling to decrease apoptosis and increase tumor invasion. A synergistic association of PIK3CA mutation with KRAS mutation has been suggested to increase AKT signaling and resistance to antiepidermal growth factor receptor inhibitor therapy for advanced colorectal cancer, although studies have been conflicting. We sought to clarify this by examining PIK3CA mutation frequency in relation to other key molecular features of defined pathways of tumorigenesis. PIK3CA mutation was assessed by high resolution melt analysis in 829 colorectal cancer samples and 426 colorectal polyps. Mutations were independently correlated with clinicopathological features including patient age, sex and tumor location as well as molecular features including microsatellite instability, KRAS and BRAF mutation, MGMT methylation and the CpG Island Methylator Phenotype (CIMP). Mutation of the helical (Exon 9) and catalytic (Exon 20) domain mutation hotspots were also examined independently. Overall, PIK3CA mutation was positively correlated with KRAS mutation (p < 0.001), MGMT methylation (p 5 0.007) and CIMP (p < 0.001). Novel, exon-specific associations linked Exon 9 mutations to a subgroup of cancers characterized by KRAS mutation, MGMT methylation and CIMP-Low, whilst Exon 20 mutations were more closely linked to features of serrated pathway tumors including BRAF mutation, microsatellite instability and CIMP-High or Low. PIK3CA mutations were uncommonly, but exclusively, seen in tubulovillous adenomas (4/124, 3.2%) and 1/4 (25.0%) tubulovillous adenomas with a focus of cancer. These data provide insight into the molecular events driving traditional versus serrated pathway tumorigenesis.

The majority of “serrated pathway” colorectal cancers have mutation of the BRAF oncogene and display the CpG island methylator phenotype (CIMP). Half these cancers have microsatellite instability (MSI) and an excellent prognosis. In the absence of MSI (microsatellite stable, MSS), BRAF mutation has been associated with a particularly poor prognosis. “Traditional pathway” cancers are BRAF wild type. Mutation of p53 is common and this correlates with advanced stage. We therefore hypothesized that p53 mutation would be common in MSS/BRAF mutant colorectal cancer. One thousand and eighty‐one colorectal cancers were screened for BRAF mutation to identify two BRAF mutant study groups (MSI: n = 77; MSS: n = 69) and a BRAF wild type control group (n = 101). These were screened for p53 mutation by high resolution melt analysis and classified for CIMP and MGMT methylation by quantitative methylation specific PCR. Molecular data were compared to patient age, gender, tumor location and stage. p53 was mutated significantly more frequently in MSS/BRAF mutant (28/69, 40.6%) compared to MSI/BRAF mutant cancers (13/77, 16.9%), but this mutation rate did not differ from MSS/BRAF wild type cancers (47/101, 46.5%)(p < 0.0001). CIMP was less common in MSS/BRAF mutant (26/47, 55.3%) compared to MSI/BRAF mutant cancers (41/54, 75.9%), but was more common than in MSS/BRAF wild type cancers (3/85, 3.5%) (p < 0.0001). MSS/BRAF mutant cancers were more commonly proximal (38/54, 70.3%), but were similar to MSS/BRAF wild type cancers in terms of patient age, gender distribution and stage at presentation. MSS/BRAF mutant cancers share molecular and clinical features of both the serrated and traditional pathways of colorectal tumorigenesis.

Objective: To assess the reproducibility of a 135-item self-administered semiquantitative FFQ. Design: Control subjects who had previously completed an FFQ relating to usual dietary intake in a nationwide case-control study of cancer between November 2003 and April 2004 were randomly selected, re-contacted, and invited to complete the same FFQ a second time approximately one year later (between January and April 2005). Agreement between the two FFQ was compared using weighted kappa statistics and intraclass correlation coefficients (ICC) for food groups and nutrients. Summary questions, included in the FFQ, were used to assess overall intakes of vegetables, fruits and meat. Setting: General community in Australia. Subjects: One hundred men and women aged 22-79 years, randomly selected from the previous control population. Results: The weighted k and ICC measures of agreement for food groups were moderate to substantial for seventeen of the eighteen food groups. For nutrients, weighted k ranged from 0?44 for starch to 0?83 for alcohol while ICC ranged from 0?51 to 0?91 for the same nutrients. Estimates of meat, fruit and vegetable intake using summary questions were similar for both survey periods, but were significantly lower than estimates from summed individual food items. Conclusions: The FFQ produced reproducible results and is reasonable in assessing the usual intake of various foods and nutrients among an Australian adult population.Keywords Reproducibility Food-frequency questionnaire Short summary questions DietNutrition has been established as a major determinant of chronic diseases including type 2 diabetes (1) , CVD (2,3) and certain cancers (4) , with strong positive and negative effects on health throughout the lifetime. These effects may be a direct consequence of the nutrients in foods or indirectly related to energy balance, as it is widely known that habitual intake of energy in excess of expenditure results in weight gain and obesity is a risk factor for many chronic diseases. For example, the recent report from the World Cancer Research Fund and American Institute for Cancer Research concluded that red and processed meats increase risk of colorectal cancer, while high intake of certain fruits and non-starchy vegetables probably reduces risk of cancers of the ovary, pharynx and larynx, oesophagus and stomach (4) . Cohort studies have also shown that low intake of animal fat, moderate consumption of alcohol, particularly red wine, and high intakes of oily fish, fruits and vegetables are associated with reduced CHD risk (3) . Overall, it has been estimated that nutrition and associated factors (physical activity and obesity) may account for 30-40 % of all cancers (4) . In contrast to many other risk factors for disease, diet is potentially modifiable. It is therefore important that dietary intake be quantified through accurate and precise methods in order to determine the specific role dietary factors play in chronic disease promotion or prevention. In large-scale epidemiological studies...