ROS-mediated TNF-α and MIP-2 gene expression in alveolar macrophages exposed to pine dust

BACKGROUND: Respiratory symptoms, impaired lung function, and asthma have been reported in workers exposed to wood dust in a number of epidemiological studies. The underlying pathomechanisms, however, are not well understood. Here, we studied the effects of dust from pine (PD) and heat-treated pine (HPD) on the release of reactive oxygen species (ROS) and inflammatory mediators in rat alveolar macrophages. METHODS: Tumour necrosis factor-alpha (TNF-α) and macrophage inflammatory protein-2 (MIP-2) protein release, TNF-α and MIP-2 mRNA expression, and generation of ROS were studied as end points after treatment of rat alveolar macrophages with PD or HPD. In a separate series of experiments, the antioxidants glutathione and N-acetyl-L-cysteine were included in combination with wood dust. To determine the endogenous oxidative and antioxidant capacity of wood dusts, electron spin resonance (ESR) spectroscopy was used. RESULTS: After 4 h incubation, both PD and HPD elicited a significantly (p < 0.05) increased mRNA expression of TNF-α and MIP-2 as well as a concentration-dependent release of TNF-α and MIP-2 protein. Interestingly, PD induced a significantly higher TNF-α and MIP-2 production than HPD. Moreover, a significantly increased ROS production was observed in alveolar macrophages exposed to both PD and HPD. In the presence of the antioxidants glutathione and N-acetyl-L-cysteine, the PD- and HPD-induced release of ROS, TNF-α, and MIP-2 was significantly reduced. Finally, electron spin resonance analyses demonstrated a higher endogenous antioxidant capacity of HPD compared to PD. Endotoxin was not present in either dust sample. CONCLUSION: These results indicate that pine dust is able to induce expression of TNF-α and MIP-2 in rat alveolar macrophages by a mechanism that is, at least in part, mediated by ROS

THL and FIOH in the Finnish research and development field : Report for the international evaluations of the National Institute for Health and Welfare (THL) and the Finnish Institute of Occupational Health (FIOH/TTL)

This report has been produced for the international evaluations of the THL and the FIOH, which were carried out in 2014 by independent international evaluation groups of experts, appointed by the Ministry of Social Affairs and Health of Finland

THL and FIOH in the Finnish research and development field

Report for the international evaluations of the National Institute for Health and Welfare (THL) and the Finnish Institute of Occupational Health (FIOH/TTL). This report has been produced for the international evaluations of the THL and the FIOH, which were carried out in 2014 by independent international evaluation groups of experts, appointed by the Ministry of Social Affairs and Health of Finland

Computed tomography in the evaluation of malignant pleural mesothelioma-Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival

Objectives: Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival. Materials and methods: As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings. Results: The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT. Conclusion. In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses.Peer reviewe

Hot spot mutations in Finnish non-small cell lung cancers

Objectives: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Materials and methods: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Results: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PlIC3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Conclusion: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

Occurrence of sinonasal intestinal‐type adenocarcinoma and non‐intestinal‐type adenocarcinoma in two countries with different patterns of wood dust exposure

Sinonasal intestinal-type adenocarcinoma is strongly associated with hardwood dust exposure. Non-intestinal-type adenocarcinoma is a rarer and less well-known subtype considered not to be related with wood dust exposure. We determined the relative numbers of these two tumor types in 56 sinonasal adenocarcinoma patients in France and Finland, relating them with carefully assessed wood dust exposure histories. Diagnostic workup including immunohistochemistry for the intestinal markers CDX2 and CK20 indicated that the proportions of the two tumors differed significantly between France and Finland. In Finnish samples non-intestinal adenocarcinomas were more common than intestinal-type adenocarcinomas (12 non-intestinal vs. nine intestinal), while in the French samples the reverse was true (six non-intestinal vs. 29 intestinal). Such remarkably dissimilar occurrence of these tumors in France and Finland presumably reflects different pathogenetic circumstances in the two countries, and perhaps their different patterns of wood dust exposure. In France the main source of wood dust is from hardwoods. In Finland it is derived from softwoods. This is the first systematic comparison of the occurrence of intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma in two countries with different wood usage. It appears to be the first systematic study on differences in wood dust exposure between intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma.</p

Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing

Background Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM. MethodsExome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM. ResultsIn asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs. ConclusionBAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.Peer reviewe

Development of physical and psychosocial job exposure matrices

Job exposure matrices (JEM) provide systematic collections of job-related exposures, including detailed information on exposures in individual occupational titles. The matrices can be used by the social insurance system and employment offices to provide data on job specific work requirements. The matrices may also be used vocational rehabilitation. Furthermore, they can be used to define priorities for workplace interventions and to identify high-risk target groups. Although the matrix was based on Finnish data it could be applicable, with some modifications, in other countries with a similar occupational structure and level of technology

Evaluation of the validity of job exposure matrix for psychosocial factors at work

Objective: To study the performance of a developed job exposure matrix (JEM) for the assessment of psychosocial factors at work in terms of accuracy, possible misclassification bias and predictive ability to detect known associations with depression and low back pain (LBP). Materials and Methods: We utilize

Genome-Wide Meta-Analysis of Sciatica in Finnish Population

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (pPeer reviewe