Prospective analysis of circulating metabolites and breast cancer in EPIC

Background: Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. Methods: A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites (n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. Results: Among women not using hormones at baseline (n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70-0.90), asparagine (OR = 0.83 (0.74-0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76-0.90)), aa C36:3 (OR = 0.84 (0.77-0.93)), ae C34:2 (OR = 0.85 (0.78-0.94)), ae C36:2 (OR = 0.85 (0.78-0.88)), and ae C38:2 (OR = 0.84 (0.76-0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11-1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06-1.24)) and PC ae C36:3 (OR = 0.88 (0.82-0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. Conclusions: These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis.

BACKGROUND: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. METHODS: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). RESULTS: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. CONCLUSIONS: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention

Effects of Hydrographic Variability on the Spatial, Seasonal and Diel Diving Patterns of Southern Elephant Seals in the Eastern Weddell Sea

Weddell Sea hydrography and circulation is driven by influx of Circumpolar Deep Water (CDW) from the Antarctic Circumpolar Current (ACC) at its eastern margin. Entrainment and upwelling of this high-nutrient, oxygen-depleted water mass within the Weddell Gyre also supports the mesopelagic ecosystem within the gyre and the rich benthic community along the Antarctic shelf. We used Conductivity-Temperature-Depth Satellite Relay Data Loggers (CTD-SRDLs) to examine the importance of hydrographic variability, ice cover and season on the movements and diving behavior of southern elephant seals in the eastern Weddell Sea region during their overwinter feeding trips from Bouvetøya. We developed a model describing diving depth as a function of local time of day to account for diel variation in diving behavior. Seals feeding in pelagic ice-free waters during the summer months displayed clear diel variation, with daytime dives reaching 500-1500 m and night-time targeting of the subsurface temperature and salinity maxima characteristic of CDW around 150–300 meters. This pattern was especially clear in the Weddell Cold and Warm Regimes within the gyre, occurred in the ACC, but was absent at the Dronning Maud Land shelf region where seals fed benthically. Diel variation was almost absent in pelagic feeding areas covered by winter sea ice, where seals targeted deep layers around 500–700 meters. Thus, elephant seals appear to switch between feeding strategies when moving between oceanic regimes or in response to seasonal environmental conditions. While they are on the shelf, they exploit the locally-rich benthic ecosystem, while diel patterns in pelagic waters in summer are probably a response to strong vertical migration patterns within the copepod-based pelagic food web. Behavioral flexibility that permits such switching between different feeding strategies may have important consequences regarding the potential for southern elephant seals to adapt to variability or systematic changes in their environment resulting from climate change

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Bedmap2: improved ice bed, surface and thickness datasets for Antarctica

We present Bedmap2, a new suite of gridded products describing surface elevation, ice-thickness and the seafloor and subglacial bed elevation of the Antarctic south of 60° S. We derived these products using data from a variety of sources, including many substantial surveys completed since the original Bedmap compilation (Bedmap1) in 2001. In particular, the Bedmap2 ice thickness grid is made from 25 million measurements, over two orders of magnitude more than were used in Bedmap1. In most parts of Antarctica the subglacial landscape is visible in much greater detail than was previously available and the improved data-coverage has in many areas revealed the full scale of mountain ranges, valleys, basins and troughs, only fragments of which were previously indicated in local surveys. The derived statistics for Bedmap2 show that the volume of ice contained in the Antarctic ice sheet (27 million km3) and its potential contribution to sea-level rise (58 m) are similar to those of Bedmap1, but the mean thickness of the ice sheet is 4.6% greater, the mean depth of the bed beneath the grounded ice sheet is 72 m lower and the area of ice sheet grounded on bed below sea level is increased by 10%. The Bedmap2 compilation highlights several areas beneath the ice sheet where the bed elevation is substantially lower than the deepest bed indicated by Bedmap1. These products, along with grids of data coverage and uncertainty, provide new opportunities for detailed modelling of the past and future evolution of the Antarctic ice sheets

Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Background Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. Methods In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. Results Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset. Conclusions Greater haem iron intake may be modestly associated with lung cancer risk.Peer reviewe

Surface mass balance and stable oxygen isotope ratios from shallow firn cores on Fimbulisen, East Antarctica

The mass balance of Antarctica is one of the crucial factors for determining sea-level change in a warming climate. The marginal zones of the continent, namely the ice shelves, are most sensitive to climate change. During the 2009/10 austral summer an extensive glaciological field campaign was carried out on Fimbulisen, an ice shelf in East Antarctica, to investigate its recent surface mass balance. Shallow (10–18 m) firn cores were drilled and accumulation rates and stable-isotope ratios determined. For firn-core dating, two different methods were compared: (1) seasonal variations of stable oxygen isotope ratios (δ18O), and (2) dielectric profiling, including using the volcanic eruptions of Pinatubo, Philippines (1991), and El Chichόn, Mexico (1982), as time markers. The mean annual accumulation for the period 1992–2009 ranges from 298 to 349 mmw.e. a–1. The interannual variability at the drilling sites is >30%. Accumulation rates show a weak decreasing trend during the past 20–30 years, which is statistically significant only for one of the cores. Stable-isotope ratios were compared to the snowfall temperature of Neumayer station. Neither the temperatures nor the δ18O values show any trend for the investigated time period