Abstract
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 ...controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Background
Skin prick testing (SPT) is an important step in the diagnosis of IgE‐mediated occupational allergic diseases. The outcome of SPT is related to the quality of allergen extracts. Thus, the ...aim of the study was to assess different commercially available SPT solutions for selected occupational allergens.
Methods
SPT was performed in 116 bakers, 47 farmers and 33 subjects exposed to natural rubber latex (NRL), all with work‐related allergic symptoms. The SPT solutions from different manufacturers (n = 3–5) for wheat flour, rye flour, soy, cow hair/dander, storage mites (Tyrophagus putrescentiae, Lepidoglyphus destructor, Acarus siro) and NRL were analysed with respect to their protein and antigen contents. SPT was carried out in 16 allergy centres in six European countries using standardized procedures. Specific IgE values were used as the gold standard to calculate the sensitivity and specificity of SPT solutions. The optimal cut‐point for each SPT solution was determined by Youden Index.
Results
Protein and antigen contents and patterns of the SPT solutions varied remarkably depending on the manufacturer. While SPT solutions for wheat flour and soy reached overall low sensitivities, sensitivities of other tested SPT solutions depended on the manufacturer. As a rule, solutions with higher protein and antigen content showed higher sensitivities and test efficiencies.
Conclusions
There is a wide variability of SPT solutions for occupational allergens, and the sensitivity of several solutions is low. Thus, improvement and standardization of SPT solutions for occupational allergens is essential.
There is limited evidence regarding the exposure‐effect relationship between lung‐cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung‐cancer risks in relation to quantitative ...indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case‐control studies from Europe and Canada, including 16 901 lung‐cancer cases and 20 965 control subjects. A measurement‐based job‐exposure‐matrix estimated job‐year‐region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19‐1.47) and 1.29 (95% CI 1.15‐1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48‐2.24) and 1.29 (95% CI 0.60‐2.86), respectively. In men, excess lung‐cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson‐type of error structure, which may cause differential bias of risk estimates.
What's new?
Occupational exposure to hexavalent chromium (Cr(VI)) and nickel is associated with increased lung‐cancer risk. Little is known, however, about quantitative exposure‐effect relationships between lung cancer and Cr(VI) or nickel. Here, quantitative exposure‐effect relationships were investigated using secondary measurement data from different regions and time periods across a wide range of jobs, with adjustment for smoking habits. Lung‐cancer risk was elevated even at low cumulative exposure levels to Cr(VI) or nickel, particularly in men and regardless of smoking habits. The findings warrant ongoing surveillance for carcinogenic risks of occupational metal exposure.
CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, ...which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.
CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.
Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)) than it was for ER-negative disease (1.32 95%CI, 0.93 to 1.88; P = .12; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.
These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents.
We investigated the ...pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking.
In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI).
All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46;
= 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8).
Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently ...tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers.
138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis.
CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group. The opposite was found for RARB (p<0.001). RASSF1 methylation increased with tumor type and grade (p<0.001) with strongest methylation in neuroendocrine tumors (NET).
Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade. RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET. L1RE1 in combination with either RARB or RASSF1 could function as biomarkers for separating lung cancer and non-cancerous tissue and could be useful for samples of limited size such as biopsies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Optimizing treatment planning is essential for advances in patient care and outcomes. Precisely tailored therapy for each patient remains a yearned-for goal. Cardiovascular modelling has the ...potential to simulate and predict the functional response before the actual intervention is performed. The objective of this study was to proof the validity of model-based prediction of haemodynamic outcome after aortic valve replacement. In a prospective study design virtual (model-based) treatment of the valve and the surrounding vasculature were performed alongside the actual surgical procedure (control group). The resulting predictions of anatomic and haemodynamic outcome based on information from magnetic resonance imaging before the procedure were compared to post-operative imaging assessment of the surgical control group in ten patients. Predicted vs. post-operative peak velocities across the valve were comparable (2.97 ± 1.12 vs. 2.68 ± 0.67 m/s; p = 0.362). In wall shear stress (17.3 ± 12.3 Pa vs. 16.7 ± 16.84 Pa; p = 0.803) and secondary flow degree (0.44 ± 0.32 vs. 0.49 ± 0.23; p = 0.277) significant linear correlations (p < 0.001) were found between predicted and post-operative outcomes. Between groups blood flow patterns showed good agreement (helicity p = 0.852, vorticity p = 0.185, eccentricity p = 0.333). Model-based therapy planning is able to accurately predict post-operative haemodynamics after aortic valve replacement. These validated virtual treatment procedures open up promising opportunities for individually targeted interventions.
Using an ethnobotanical approach in combination with in vivo-guided fractionation as a means for lead discovery, cryptolepine was isolated as an antihyperglycemic component of Cryptolepis ...sanguinolenta. Two syntheses of cryptolepine, including an unambiguous synthesis, are reported. The hydroiodide, hydrochloride, and hydrotrifluoromethanesulfonate (hydrotriflate) salts of cryptolepine were synthesized, and a comparison of their spectral properties and their in vitro activities in a 3T3-L1 glucose transport assay is made. Cryptolepine and its salt forms lower blood glucose in rodent models of type II diabetes. While a number of bioactivities have been reported for cryptolepine, this is the first report that cryptolepine posesses antihyperglycemic properties.
Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, ...inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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