Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Pathogen burden and cortisol profiles over the day.

Hypothalamic-pituitary-adrenocortical (HPA) regulation in adults is influenced by early psychosocial adversity, but the role of infectious disease history is poorly understood. We studied the association between cumulative pathogen burden and cortisol profile over the day in a sample of 317 healthy men and women aged 51-72 years. Cumulative pathogen burden was defined as positive serostatus for Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1). Salivary cortisol was sampled repeatedly over the day. The cortisol slope was defined as the decrease across the day and evening. Age, gender, grade of employment, body mass index, smoking status, self-rated health, cardiovascular medication, depressed mood and time of waking were included as covariates. The pathogen burden averaged 1.76 (s.d.=0.92). The cortisol slope was inversely associated with pathogen burden after controlling for covariates. When individual pathogens were studied, only CMV was associated with flatter cortisol rhythms in isolation. We conclude that pathogen burden is independently associated with flatter cortisol slopes over the day, and may contribute to disturbed neuroendocrine regulation.

Socioeconomic status, pathogen burden and cardiovascular disease risk.

OBJECTIVE: Socioeconomic status (SES) is inversely associated with coronary heart disease (CHD) risk. Cumulative pathogen burden may also predict future CHD. The hypothesis was tested that lower SES is associated with a greater pathogen burden, and that pathogen burden accounts in part for SES differences in cardiovascular risk factors. METHODS: This was a cross-sectional observational study involving the clinical examination of 451 men and women aged 51-72 without CHD, recruited from the Whitehall II epidemiological cohort. SES was defined by grade of employment, and pathogen burden by summing positive serostatus for Chlamydia pneumoniae, cytomegalovirus and herpes simplex virus 1. Cardiovascular risk factors were also assessed. RESULTS: Pathogen burden averaged 1.94 (SD) 0.93 in the lower grade group, compared with 1.64 (0.97) and 1.64 (0.93) in the intermediate and higher grade groups (p = 0.011). Pathogen burden was associated with a higher body mass index, waist/hip ratio, blood pressure and incidence of diabetes. There were SES differences in waist/hip ratio, high-density lipoprotein-cholesterol, fasting glucose, glycated haemoglobin, lung function, smoking and diabetes. The SES gradient in these cardiovascular risk factors was unchanged when pathogen burden was taken into account statistically. CONCLUSIONS: Although serological signs of infection with common pathogens are more frequent in lower SES groups, their distribution across the social gradient does not match the linear increases in CHD risk present across higher, intermediate and lower SES groups. Additionally, pathogen burden does not appear to mediate SES differences in cardiovascular risk profiles.

Protective effect of human heat shock protein 60 suggested by its association with decreased seropositivity to pathogens.

The presence of heat shock protein 60 (Hsp60) in human plasma has been linked with cardiovascular disease (CVD). In this study, the examination of the relationship between Hsp60 in plasma and seropositivity for three microbial agents, which are thought to be risk factors for CVD, surprisingly revealed a negative association between Hsp60 and seropositivity, suggesting a protective effect of this circulating stress protein.

Phylogeographic relationships of Ixodes uriae (Acari: Ixodidae) and their significance to transequatorial dispersal of Borrelia garinii.

The seabird tick Ixodes uriae (Acari: Ixodidae) has a bi- and circumpolar distribution and is commonly infected with Lyme disease Borrelia. Identical Borrelia flagellin gene sequences have been detected in I. uriae from both the Northern and Southern Hemispheres, suggesting a transequatorial transport of Borrelia. Parsimony analysis of the internal transcribed spacer 2 (ITS2) and a part of 16S rDNA of I. uriae from the Northern and Southern Hemispheres indicated that northern and southern I. uriae might be reproductively separated. We hypothesize that Borrelia is probably not dispersed from one hemisphere to the other by ticks attached to seabirds.

Canary finches (Serinus canaria) as an avian infection model for Lyme borreliosis.

To investigate if passerine birds can be used as an avian model for Lyme borreliosis, the Borrelia burgdorferi sensu stricto strain Sh2-82 was inoculated subcutaneously on Canary finches (Serinus canaria). Spirochaetes could be detected in the blood by direct microscopy and an immunofluorescence assay (IFA) up to 2 weeks after the inoculation. DNA amplification (PCR) revealed B. burgdorferi DNA in the serum for up to 3 weeks, in the faeces up to 4 weeks, and from several internal organs at autopsy 3 months after the inoculation. Of particular interest was the finding of B. burgdorferi DNA in the liver of all birds at the end of the experiment, indicating a persistent infection. Four weeks after the primary infection, all infected birds showed an increase in anti Borrelia IgG antibodies and after 6 weeks all birds had seroconverted. Except for a brief episode of diarrhoea, none of the birds showed any signs of disease. This study shows that passerine birds experience short-term spirochaetemia after infection with B. burgdorferi, but show few clinical symptoms. This suggests that, although these birds can act as reservoirs of B. burgdorferi s.s., they may be of less importance as long lasting amplifiers for this pathogen.

Transhemispheric exchange of Lyme disease spirochetes by seabirds.

Lyme disease is a zoonosis transmitted by ticks and caused by the spirochete Borrelia burgdorferi sensu lato. Epidemiological and ecological investigations to date have focused on the terrestrial forms of Lyme disease. Here we show a significant role for seabirds in a global transmission cycle by demonstrating the presence of Lyme disease Borrelia spirochetes in Ixodes uriae ticks from several seabird colonies in both the Southern and Northern Hemispheres. Borrelia DNA was isolated from I. uriae ticks and from cultured spirochetes. Sequence analysis of a conserved region of the flagellin (fla) gene revealed that the DNA obtained was from B. garinii regardless of the geographical origin of the sample. Identical fla gene fragments in ticks obtained from different hemispheres indicate a transhemispheric exchange of Lyme disease spirochetes. A marine ecological niche and a marine epidemiological route for Lyme disease borreliae are proposed.