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Background The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is described as a potential biomarker for NSCLC (non-small cell lung cancer). Diagnostic biomarkers need to be detectable in easily accessible body fluids, should be characterized by high specificity, sufficient sensitivity, and robustness against influencing factors. The aim of this study was to evaluate the performance of MALAT1 as a blood based biomarker for NSCLC. Results MALAT1 was shown to be detectable in the cellular fraction of peripheral human blood, showing different expression levels between cancer patients and cancer-free controls. For the discrimination of NSCLC patients from cancer-free controls a sensitivity of 56% was calculated conditional on a high specificity of 96%. No impact of tumor stage, age, gender, and smoking status on MALAT1 levels could be observed, but results based on small numbers. Conclusions The results of this study indicate that MALAT1 complies with key characteristics of diagnostic biomarkers, i.e., minimal invasiveness, high specificity, and robustness. Due to its relatively low sensitivity MALAT1 might not be feasible as a single biomarker for the diagnosis of NSCLC in the cellular fraction of blood. Alternatively, MALAT1 might be applicable as a complementary biomarker within a panel in order to improve the entire diagnostic performance.

For the detection of malignant mesothelioma no single biomarker with reasonable sensitivity and specificity has been described so far. Mesothelin, the most prominent blood-based biomarker, is characterized by high specificity but low sensitivity. It might be reasonable to combine biomarkers of different molecular classes in order to improve the overall performance. The aim of this study was to assess the performance of the combination of mesothelin and miR-103a-3p as blood-based biomarker for mesothelioma. Mesothelin concentration in plasma and miR-103a-3p levels in the cellular blood fraction were analyzed in 43 male mesothelioma patients and 52 male controls formerly exposed to asbestos. For the discrimination of epithelioid and biphasic mesothelioma from asbestos-exposed controls mesothelin and miR-103a-3p showed 74% and 89% sensitivity and 85% and 63% specificity, respectively. For the combination of mesothelin and miR-103a-3p a sensitivity of 95% and a specificity of 81% were calculated. The results of this study show that the combination of mesothelin and miR-103a-3p improves the diagnostic performance of individual blood-based biomarker to detect malignant mesothelioma. The obtained results indicate that the use of biomarkers of different molecular classes might be a reasonable approach to assemble a biomarker panel.

Background Smoking intensity, which is generally based on self-reported average cigarettes per day (CPD), is a major behavioural risk factor and strongly related to socioeconomic status (SES). To assess the validity of the CPD measure, correlations with objective markers of tobacco smoke exposure – such as urinary nicotine metabolites – were examined. Yet, it remains unclear, whether this correlation is affected by SES, which may indicate imprecise or biased self-reports of smoking intensity. Methods We investigated the role of SES in the association between CPD and nicotine metabolites in current smokers among the participants of the population-based, prospective Heinz Nixdorf Recall Study. We determined urinary cotinine and additionally trans-3′-hydroxy-cotinine. SES was assessed by the International Socio-Economic Index of occupational status, and education. We calculated correlations (Pearson’s r) between logarithmised CPD and cotinine in subgroups of SES and analysed SES and further predictors of cotinine in multiple linear regression models separately by gender. Results Median reported smoking intensity was 20 CPD in male and 19 CPD in female smokers. Men showed higher cotinine concentrations (median 3652 μg/L, interquartile range (IQR) 2279–5422 μg/L) than women (3127 μg/L, IQR 1692–4920 μg/L). Logarithmised CPD correlated moderately with cotinine in both, men and women (Pearson’s r 0.4), but correlations were weaker in smokers with lower SES: Pearson’s r for low, intermediate, and high occupational SES was 0.35, 0.39, and 0.48 in men, and 0.28, 0.43, and 0.47 in women, respectively. Logarithmised CPD and urinary creatinine were main predictors of cotinine in multiple regression models, whereas SES showed a weak negative association in women. Results were similar for trans-3′-hydroxy-cotinine. Conclusions Decreasing precision of self-reported CPD was indicated for low SES in men and women. We found no strong evidence for biased self-reports of smoking intensity by SES.

Background Malignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin. Methods For a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype. Results Calretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10–3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30–4.00). Conclusions Calretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study.

Olfactory impairment is increasingly recognized as an early symptom in the development of Parkinson's disease. Testing olfactory function is a non-invasive method but can be time-consuming which restricts its application in clinical settings and epidemiological studies. Here, we investigate odor identification as a supportive diagnostic tool for Parkinson's disease and estimate the performance of odor subsets to allow a more rapid testing of olfactory impairment. Odor identification was assessed with 16 Sniffin' sticks in 148 Parkinson patients and 148 healthy controls. Risks of olfactory impairment were estimated with proportional odds models. Random forests were applied to classify Parkinson and non-Parkinson patients. Parkinson patients were rarely normosmic (identification of more than 12 odors; 16.8%) and identified on average seven odors whereas the reference group identified 12 odors and showed a higher prevalence of normosmy (31.1%). Parkinson patients with rigidity dominance had a twofold greater prevalence of olfactory impairment. Disease severity was associated with impairment of odor identification (per score point of the Hoehn and Yahr rating OR 1.87, 95% CI 1.26-2.77). Age-related impairment of olfaction showed a steeper gradient in Parkinson patients. Coffee, peppermint, and anise showed the largest difference in odor identification between Parkinson patients and controls. Random forests estimated a misclassification rate of 22.4% when comparing Parkinson patients with healthy controls using all 16 odors. A similar rate (23.8%) was observed when only the three aforementioned odors were applied. Our findings indicate that testing odor identification can be a supportive diagnostic tool for Parkinson's disease. The application of only three odors performed well in discriminating Parkinson patients from controls, which can facilitate a wider application of this method as a point-of-care test.

ObjectivesCalretinin and mesothelin are molecular markers for the detection of malignant mesothelioma at early stages. Our objective was the re-evaluation of factors influencing calretinin and mesothelin concentrations in plasma of cancer-free men in order to minimise false-positive tests when using commercial assays approved for clinical diagnostics.SettingThis re-evaluation used data and archived blood samples of the population-based Heinz Nixdorf Recall Study (HNRS) collected from 2011 to 2014.ParticipantsThe present analysis comprised of 569 cancer-free men at the time of blood sampling (median age 70 years) from HNRS.Primary and secondary outcomesMesothelin plasma concentration was determined using ELISA and CLEIA (chemiluminescent enzyme immunoassay). Calretinin plasma concentration was assessed using ELISA.ResultsCompared with the previous determination of concentrations, we detected less false-positive tests using the commercial assays. In this analysis, we found nine false-positive calretinin tests using the ELISA (specificity 98.4%, 95% CI 97.0% to 99.2%) and 24 false-positive mesothelin tests using both ELISA and CLEIA (specificity 95.8%, 95% CI 93.8% to 97.2%). We confirmed renal dysfunction as major predictor of elevated marker concentrations. Mesothelin was additionally affected by bronchitis. Furthermore, elevated inflammation values and hypertension only affected the mesothelin concentration determined by ELISA.ConclusionsThe newly available assays of calretinin and mesothelin approved for clinical diagnostics showed high specificities in the population-based cohort of elderly men without a malignant disease. The current evaluation provides a basis to consider influencing factors in order to further improve the diagnostic procedure.

The aim of this study was to estimate average occupational exposure to inhalable nickel (Ni) using the German exposure database MEGA. This database contains 8052 personal measurements of Ni collected between 1990 and 2009 in adjunct with information on the measurement and workplace conditions. The median of all Ni concentrations was 9 μg/m 3 and the 95th percentile was 460 μg/m 3 . We predicted geometric means (GMs) for welders and other occupations centered to 1999. Exposure to Ni in welders is strongly influenced by the welding process applied and the Ni content of the used welding materials. Welding with consumable electrodes of high Ni content (>30%) was associated with 10-fold higher concentrations compared with those with a low content (<5%). The highest exposure levels (GMs ≥20 μg/m 3 ) were observed in gas metal and shielded metal arc welders using welding materials with high Ni content, in metal sprayers, grinders and forging-press operators, and in the manufacture of batteries and accumulators. The exposure profiles are useful for exposure assessment in epidemiologic studies as well as in industrial hygiene. Therefore, we recommend to collect additional exposure-specific information in addition to the job title in community-based studies when estimating the health risks of Ni exposure.

Objective Some epidemiological and animal data indicate that night work might increase the risk for breast cancer. We have investigated the risk in a German population-based case-control study known as GENICA (Gene ENvironment Interaction and breast CAncer). Methods The GENICA study involved interviews to assess shift work information in 857 breast cancer cases and 892 controls. We estimated risks of employment status and night shift characteristics using conditional logistic regression models, adjusting for potential confounders. Resampling and bootstrapping were applied to adjust the risk estimates for a potential selection bias. Results Among 1749 women, 56 cases and 57 controls worked in night shifts for ≥ 1 year, usually in the healthcare sector (63.0% of controls). Female night workers were more frequently nulliparous and low-educated than day workers (28.6% versus 17.8% and 12.3% versus 9.2%, respectively). Fewer women in night work had ever used post-menopausal hormone therapy (35.7% versus 51.9%). Having ever done shift or night work was not associated with an elevated breast cancer risk when compared to women employed in day work only [odds ratio (OR) 0.96, 95% confidence interval (95% CI) 0.67-1.38 and OR 0.91, 95% CI 0.55-1.49, respectively). Women who reported > 807 night shifts, the third quartile of the distribution among controls, experienced a breast cancer risk of 1.73 (95% CI 0.71-4.22). Night work for ≥ 20 years was associated with an OR of 2.48 (95% CI 0.62-9.99) based on 12 cases and 5 controls. Conclusions Long-term night work was associated with a modestly, but not significantly, increased breast cancer risk, while having ever done night work was not. The precision of the results was limited by a low prevalence of night work in this study population.

We investigated airborne and internal exposure to manganese (Mn) and iron (Fe) among welders. Personal sampling of welding fumes was carried out in 241 welders during a shift. Metals were determined by inductively coupled plasma mass spectrometry. Mn in blood (MnB) was analyzed by graphite furnace atom absorption spectrometry. Determinants of exposure levels were estimated with multiple regression models. Respirable Mn was measured with a median of 62 (inter-quartile range (IQR) 8.4–320) μ g/m 3 and correlated with Fe ( r =0.92, 95% CI 0.90–0.94). Inhalable Mn was measured with similar concentrations (IQR 10–340  μ g/m 3 ). About 70% of the variance of Mn and Fe could be explained, mainly by the welding process. Ventilation decreased exposure to Fe and Mn significantly. Median concentrations of MnB and serum ferritin (SF) were 10.30  μ g/l (IQR 8.33–13.15  μ g/l) and 131  μ g/l (IQR 76–240  μ g/l), respectively. Few welders were presented with low iron stores, and MnB and SF were not correlated ( r =0.07, 95% CI −0.05 to 0.20). Regression models revealed a significant association of the parent metal with MnB and SF, but a low fraction of variance was explained by exposure-related factors. Mn is mainly respirable in welding fumes. Airborne Mn and Fe influenced MnB and SF, respectively, in welders. This indicates an effect on the biological regulation of both metals. Mn and Fe were strongly correlated, whereas MnB and SF were not, likely due to higher iron stores among welders.

Objective Malignant mesothelioma is an aggressive cancer of the serous membranes. For the detection of the tumor at early stages non- or minimally-invasive biomarkers are needed. The circulating biomarkers miR-132-3p, miR-126-3p, and miR-103a-3p were analyzed in a nested case–control study using plasma samples from 17 prediagnostic mesothelioma cases and 34 matched asbestos-exposed controls without a malignant disease. Results Using prediagnostic plasma samples collected in median 8.9 months prior the clinical diagnosis miR-132-3p, miR-126-3p, and miR-103a-3p revealed 0% sensitivity on a defined specificity of 98%. Thus, the analyzed miRNAs failed to detect the cancer in prediagnostic samples, showing that they are not feasible for the early detection of malignant mesothelioma. However, the miRNAs might still serve as possible markers for prognosis and response to therapy, but this needs to be analyzed in appropriate studies.