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  • 1
    Abstract: BACKGROUND: Circulating oxysterols have been proposed as biological markers of disease risk. However, within-person reproducibility of circulating oxysterols over time is not well established. METHODS: We evaluated the one-year reproducibility of 11 oxysterols and lanosterol among 30 postmenopausal women with repeat blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) - Heidelberg, Germany cohort. Liquid chromatography-mass spectrometry (LC/MS) was performed to quantify serum concentrations of 22R-hydroxycholesterol, 2beta-hydroxycholesterol, 24S-hydroxycholesterol, 27-hydroxycholesterol, 22S-hydroxycholeterol, 24,2beta-epoxycholesterol, 5alpha,6beta-dihydroxycholestanol, 7alpha-hydroxycholesterol, 5beta,6beta-epoxycholesterol, 5alpha,6alpha-epoxycholesterol, 24-dihydrolanosterol, and lanosterol. We evaluated Spearman correlations and intraclass correlation coefficients (ICCs) between quantifiable concentrations measured in repeat samples taken one-year apart to estimate within-person reproducibility. RESULTS: Spearman correlations (ICCs) over one year ranged from 0 (ICC=0.10) for 5beta,6beta-epoxycholesterol and 0.10 (ICC=0.20) for 5alpha,6alpha-epoxycholesterol, representing low within-person stability, to 0.81 (ICC=0.75) for 27-hydroxycholesterol and 0.86 (ICC=0.91) for 24S-hydroxycholesterol, representing relatively high within-person stability. Correlations between oxysterols and lanosterol ranged from 0.01 between 24S-hydroxycholesterol and lanosterol to 0.70 between 5alpha,6alpha-epoxycholesterol and 5beta,6beta-epoxycholesterol. CONCLUSIONS: Our results demonstrate that for 27-hydroxycholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 7alpha-hydroxycholesterol and lanosterol, a single serum measurement can reliably estimate average levels over a one-year period. Circulating oxysterols are of increasing interest in epidemiologic studies of chronic disease risk including cancer and cardiovascular disease. Our data suggest that within-person stability of oxysterols differs depending on the individual oxysterol evaluated. We identified four oxysterols and lanosterol as stable over time to inform the use of circulating oxysterols in epidemiologic studies.
    Type of Publication: Journal article published
    PubMed ID: 29108727
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  • 2
    Abstract: CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to 4 matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated towards the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed 〈2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; phet =0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 29159934
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  • 3
    Abstract: BACKGROUND: Testicular germ cell tumors (TGCT) were suggested to have a prenatal environmentally related origin. The potential endocrine disrupting properties of certain solvents may interfere with the male genital development in utero. OBJECTIVES: We aimed to assess the association between maternal and paternal occupational exposures to organic solvents during the prenatal period and TGCT risk in their offspring. METHODS: This registry-based case control study included TGCT cases aged 14-49 y (n=8,112) diagnosed from 1978 to 2012 in Finland, Norway, and Sweden. Controls (n=26,264) were randomly selected from the central population registries and were individually matched to cases on year and country of birth. Occupational histories of parents prior to the child's birth were extracted from the national censuses. Job codes were converted into solvent exposure using the Nordic job-Nordic Occupational Cancer Study Job-Exposure Matrix. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Overall, no association was found between prenatal maternal exposure to solvents and TGCT risk. In subset analyses using only mothers for whom occupational information was available in the year of or in the year prior to the child's birth, there was an association with maternal exposure to aromatic hydrocarbon solvents (ARHC) (OR=1.53; CI: 1.08, 2.17), driven by exposure to toluene (OR=1.67; CI: 1.02, 2.73). No association was seen for any paternal occupational exposure to solvents with the exception of exposure to perchloroethylene in Finland (OR=2.42; CI: 1.32, 4.41). CONCLUSIONS: This study suggests a modest increase in TGCT risk associated with maternal prenatal exposure to ARHC. https://doi.org/10.1289/EHP864.
    Type of Publication: Journal article published
    PubMed ID: 28893722
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  • 4
    Abstract: The World Cancer Research Fund International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure-cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-Commissioned validation study. In Stage 1, a "hypothesis-free" approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In Stage 2, a systematic review was conducted on the insulin-like growth factor 1 receptor chosen as intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness-IGF1R association and modest evidence linking IGF1R to breast cancer, therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic review by integrating evidence from mechanistic studies on exposure-cancer associations. Based on our experience, we provide recommendations for future users.
    Type of Publication: Journal article published
    PubMed ID: 28754794
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