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Untargeted metabolomics faces significant challenges in standardization due to variability introduced by sample preparation and analytical workflows. We systematically evaluated the impact of biological matrices, extraction protocols, and chromatographic configurations to establish a mechanism-informed framework aimed at improving reproducibility in large-scale clinical and epidemiological studies. Three extraction protocols were compared using an in-house pooled heparin plasma: monophasic protein precipitation with isopropanol (IPA), methanol:acetonitrile (MeOH:ACN), and a modified Matyash biphasic method. The most reproducible protocol was then applied to four blood matrices. Samples were analysed using untargeted metabolomics on hydrophilic interaction liquid chromatography (HILIC) and reversed-phase (RP) HPLC columns, with mass spectrometry data processed using Compound Discoverer. Both IPA and MeOH:ACN extractions achieved over 80% of features with coefficient of variation (CV%) ≤ 30% for both RP and HILIC, whereas the Matyash method showed higher variability, with a larger proportion of metabolites exhibiting CV% > 30%. Across matrices, RP chromatography detected over 80% of metabolites with CV% < 30%, while HILIC showed higher variability, with at least 20% of metabolites above this threshold. Among matrices, serum and heparin plasma outperformed EDTA and citrate in reproducibility. We propose a standardized workflow in which monophasic extractions combined with RP chromatography maximize reproducibility and metabolite coverage, minimizing methodological artefacts and providing a reliable framework for robust biological discovery in large-scale untargeted metabolomics studies.

Breast cancer (BC) is the leading cause of cancer death in women. Adipokines, and other inflammation molecules linked to adiposity, are suspected to be involved in breast carcinogenesis, however prospective findings are inconclusive. In a prospective nested case-control study within the EPIC-Varese cohort, we used conditional logistic regression to estimate rate ratios (RRs) for BC, with 95% confidence intervals (CI), in relation to plasma levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6, leptin, and adiponectin, controlling for BC risk factors. After a median 14.9 years, 351 BC cases were identified and matched to 351 controls. No marker was significantly associated with BC risk overall. Significant interactions between menopausal status and CRP, leptin, and adiponectin were found. Among postmenopausal women, high CRP was significantly associated with increased BC risk, and high adiponectin with significantly reduced risk. Among premenopausal women, high TNF-α was associated with significantly increased risk, and high leptin with reduced risk; interleukin-6 was associated with increased risk only in a continuous model. These findings constitute further evidence that inflammation plays a role in breast cancer. Interventions to lower CRP, TNF-α, and interleukin-6 and increase adiponectin levels may contribute to preventing BC.

Background Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. Methods This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). Results In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m 2 ) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m 2 ) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09–0.47). Conclusions Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.

Background Growing evidence raises concern about possible associations of high selenium exposure with diabetes in selenium-replete populations such as the US. In countries with lower selenium status, such as Italy, there is little epidemiological evidence on the association between selenium and diabetes. This study examined the prospective association between dietary selenium intake and risk of type 2 diabetes. Methods The ORDET cohort study comprised a large sample of women from Northern Italy (n = 7,182). Incident type 2 diabetes was defined as a self-report of a physician diagnosis, use of antidiabetic medication, or a hospitalization discharge. Dietary selenium intake was measured by a semi-quantitative food-frequency questionnaire at the baseline examination (1987-1992). Participants were divided in quintiles based on their baseline dietary selenium intake. Results Average selenium intake at baseline was 55.7 μg/day. After a median follow-up of 16 years, 253 women developed diabetes. In multivariate logistic regression analyses, the odds ratio for diabetes comparing the highest to the lowest quintile of selenium intake was 2.39, (95% CI: 1.32, 4.32; P for linear trend = 0.005). The odds ratio for diabetes associated with a 10 μg/d increase in selenium intake was 1.29 (95% CI: 1.10, 1.52). Conclusions In this population, increased dietary selenium intake was associated with an increased risk of type 2 diabetes. These findings raise additional concerns about the association of selenium intake above the Recommended Dietary Allowance (55 μg/day) with diabetes risk.

Introduction Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson’s disease (PD) in small-scale retrospective case–control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case–control study within a large European prospective cohort. Methods A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. Results Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1–41.0) vs. 24.7 (16.6–38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98–2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40–5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09–2.18). Conclusion The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

BackgroundChronic inflammation from visceral obesity contributes to metabolic disorders and cancer through cytokine imbalance. Accurate cytokine measurement is crucial to understand these links. This study examined challenges in quantifying interleudin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, and adiponectin in historical biobank samples with limited volumes and varying plasma anticoagulants.MethodsLuminex-MAGPIX platform was used to evaluate three analytical aspects. Single-well precision was assessed via intra- and inter-assay coefficients of variability (CVs). Plasma matrix effects were examined by pairwise comparison of analyte concentrations across citrate, heparin, and EDTA plasma from 10 volunteers. Cytokine stability was tested after one freeze-thaw cycle (analysis of variance).ResultsSingle-well measurements showed good precision (CV <10% intra-assay, <15% inter-assay). Plasma matrix affected absolute concentrations. In particular, all analytes were lower in citrate than in EDTA and heparin, but relative relationships and subject-specific rankings remained preserved. Pearson correlation coefficients for IL-6, leptin, and adiponectin were high across matrices (r-range = 0.952-0.999), whereas correlations for TNF-α were lower (r-range = 0.897-0.972). Freeze-thaw stability was analyte- and matrix-dependent: leptin remained stable in heparin and EDTA but decreased 9.5% in citrate; adiponectin was stable in citrate but decreased in heparin (-9.0%) and EDTA (-11.8%). IL-6 and TNF-α were unaffected.ConclusionIL-6, TNF-α, leptin, and adiponectin were accurately quantified using single-well Luminex assays and showed reasonable tolerance to a single freeze-thaw cycle, offering a practical strategy for preserving valuable specimens. Although plasma anticoagulant affected absolute concentrations, the preservation of relative analyte rankings permits their use in most study designs but limit absolute value comparisons.

Colorectal cancer is the third most common cancer worldwide. Diet has been hypothesized as involved in colorectal cancer etiology, but few studies on the influence of total dietary antioxidant intake on colorectal cancer risk have been performed. We investigated the association between colorectal cancer risk and the total antioxidant capacity (TAC) of the diet, and also of intake of selected antioxidants, in 45,194 persons enrolled in 5 centers (Florence, Naples, Ragusa, Turin and Varese) of the European Prospective Investigation into Cancer and Nutrition (EPIC) Italy study. TAC was estimated by the Trolox equivalent antioxidant capacity (TEAC) assay. Hazard ratios (HRs) for developing colorectal cancer, and colon and rectal cancers separately, adjusted for confounders, were estimated for tertiles of TAC by Cox modeling, stratifying by center. Four hundred thirty-six colorectal cancers were diagnosed over a mean follow-up of 11.28 years. No significant association between dietary TAC and colorectal cancer incidence was found. However for the highest category of TAC compared to the lowest, risk of developing colon cancer was lower (HR: 0.63; 95% CI: 0.44-0.89, P trend: 0.008). By contrast, increasing TAC intake was associated with significantly increasing risks of rectal cancer (2nd tertile HR: 2.09; 95%CI: 1.19-3.66; 3rd tertile 2.48 95%CI: 1.32-4.66; P trend 0.007). Intakes of vitamin C, vitamin E, and ß-carotene were not significantly associated with colorectal cancer risk. Further prospective studies are needed to confirm the contrasting effects of high total antioxidant intake on risk of colon and rectal cancers.

Metabolic syndrome (defined as at least three among abdominal obesity, high blood triglycerides, low high-density lipoprotein cholesterol, high blood glucose, and high blood pressure) is emerging as a risk factor for breast cancer; however few studies - most confined to postmenopausal women - have investigated associations between breast cancer risk and metabolic syndrome. The purpose of this study was to examine the association between metabolic syndrome and its components, and risk of breast cancer in postmenopausal and premenopausal women. We performed a case-cohort study on 22,494 women recruited in 1993-1998 to four Italian centres (Turin, Varese, Naples, Ragusa) of the European Prospective Investigation into Cancer and Nutrition (EPIC) and followed-up for up to 15 years. A random subcohort of 565 women was obtained and 593 breast cancer cases were diagnosed. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Prentice-weighted Cox proportional hazards models. Presence of metabolic syndrome was associated with significantly increased breast cancer risk in all women (HR 1.52, 95%CI 1.14-2.02). When the analyses were repeated separately for menopausal status, the association was limited to postmenopausal women (HR 1.80, 95%CI 1.22-2.65) and absent in premenopausal women (HR 0.71, 95%CI 0.43-1.16); P for interaction between metabolic syndrome and menopausal status was 0.001. Of metabolic syndrome components, only high blood glucose was significantly associated with increased breast cancer risk in all women (HR 1.47, 95%CI 1.13-1.91) and postmenopausal women (HR 1.89, 95%CI 1.29-2.77), but not premenopausal women (HR 0.80, 95%CI 0.52-1.22; P interaction=0.004). These findings support previous data indicating that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women, but not in premenopausal women, and suggest that prevention of metabolic syndrome through lifestyle changes could confer protection against breast cancer.

In Europe, evidence on the relationship between socioeconomic position (SEP) and air pollution exposure is mixed. We assessed the association between individual SEP (education and occupation) and air pollution in the Turin and Varese European Prospective Investigation into Cancer and Nutrition cohorts. This cross-sectional study included participants enrolled between 1992–1998, categorised by three educational (high, medium, and low) and three occupational (high-, medium-, and low-skilled) levels. Air pollution exposure (2008–2011) at residential addresses was estimated using Land Use Regression models. Nitrogen dioxide (NO2) and nitrogen oxide (NOx) data were available for both cohorts; particulate matter (PM2.5, PM10) only for Turin. Linear regression models (adjusted for sex, age, and marital status) estimated associations between SEP and annual mean pollutant concentrations (µg/m3), stratified by cohort. In Varese, lower education was associated with lower NOx exposure. In Turin, medium and low education were also linked to lower NOx exposure, though without a clear gradient. In both cohorts, individuals in medium- and low-skilled occupations had lower nitrogen exposure than those in high-skilled jobs. Associations between SEP and PM exposure in Turin were weak to null. In conclusion, lower SEP was associated with slightly lower nitrogen exposure; no clear link was found with PM.

Background The risk of breast cancer has been associated with various lifestyle factors, yet the evidence regarding how lifestyle modifications affect this risk remains limited. This study examines the relationship between changes in the Healthy Lifestyle Index (HLI) and postmenopausal breast cancer risk in women participating in the European Prospective Investigation into Cancer (EPIC). Methods HLI scores (ranging from 0 to 16) were computed based on smoking habits, alcohol consumption, body mass index (BMI), and physical activity levels, using data from baseline and follow-up questionnaires, which were separated by a median interval of 10  (IQR: 5.2–12.0) years. Among the 125,746 women included in the analyses, 2,175 developed breast cancer over a median follow-up period of nearly 4  (IQR: 2.9–8.4) years starting from the date of the second lifestyle questionnaire. Cox proportional hazards models were employed to estimate hazard ratios (HRs) and confidence intervals (CIs) for the relationship between changes in HLI and postmenopausal breast cancer risk, analysed both overall and by estrogen receptor (ER) status. Individual components of the HLI were also analysed, with sensitivity analyses addressing potential reverse causation by delaying the start of follow-up by 1 to 3 years. Results Each unit increase in the HLI—reflecting a healthier lifestyle—was not associated with the overall risk of postmenopausal breast cancer. Among individual components, only a one-unit increase in the BMI score, corresponding to a shift towards a healthier BMI, was inversely associated with overall (HR = 0.936; 95% CI 0.880–0.996) and ER-positive (HR = 0.930; 95% CI 0.865–1.000) postmenopausal breast cancer risks. Conclusions Lifestyle changes, as measured by the HLI, during mid-adulthood were not significantly associated with the risk of postmenopausal breast cancer. More specifically, the results of this study suggested that a shift towards a healthier BMI may contribute to breast cancer prevention. Further research involving diverse and larger study populations and lifestyle assessments at earlier life stages could provide deeper insights.