Fibulin-3 as a biomarker of response to treatment in malignant mesothelioma.

BACKGROUND: Fibulin-3 is a new potential biomarker for malignant mesothelioma (MM). This study evaluated the potential applicability of fibulin-3 plasma levels as a biomarker of response to treatment and its prognostic value for progressive disease within 18 months. The potential applicability of fibulin-3 in comparison with or in addition to soluble mesothelin-related peptides (SMRP) was also assessed. PATIENTS AND METHODS: The study included 78 MM patients treated at the Institute of Oncology Ljubljana between 2007 and 2011. Fibulin-3 levels in plasma samples obtained before treatment and in various responses to treatment were measured with the enzyme-linked immunosorbent assay. RESULTS: In patients evaluated before the treatment, fibulin-3 levels were not influenced by histopathological sub-types, tumour stages or the presence of metastatic disease. Significantly higher fibulin-3 levels were found in progressive disease as compared to the levels before treatment (Mann-Whitney [U] test = 472.50, p = 0.003), in complete response to treatment (U = 42.00, p = 0.010), and in stable disease (U = 542.00, p = 0.001). Patients with fibulin-3 levels exceeding 34.25 ng/ml before treatment had more than four times higher probability for developing progressive disease within 18 months (odds ratio [OR] = 4.35, 95% confidence interval [CI] 1.56-12.13). Additionally, patients with fibulin-3 levels above 34.25 ng/ml after treatment with complete response or stable disease had increased odds for progressive disease within 18 months (OR = 6.94, 95% CI 0.99-48.55 and OR = 4.39, 95% CI 1.63-11.81, respectively). CONCLUSIONS: Our findings suggest that in addition to SMRP fibulin-3 could also be helpful in detecting the progression of MM.

Inducible nitric oxide synthase genetic polymorphism and risk of asbestosis.

Asbestos, a known occupational pollutant, may upregulate the activity of inducible nitric oxide synthase (iNOS) and thus the production of nitric oxide (NO). This study investigated whether iNOS (CCTTT)(n) polymorphism is associated with an increased asbestosis risk in exposed workers. The study cohort consisted of 262 cases with asbestosis and 265 controls with no asbestos-related disease. For each subject the cumulative asbestos exposure data were available. The number of CCTTT repeats was determined following PCR amplification of the iNOS promoter region. Logistic regression was performed to estimate asbestosis risk. The OR of asbestosis was 1.20 (95% CI = 0.85-1.69) for the LL genotype compared to the combined SL and SS genotypes and 1.26 (95% CI = 0.86-1.85) for the LL genotype compared to the SL genotype. The results of this study are borderline significant and suggest a possible role of iNOS (CCTTT)(n) polymorphism in the risk of asbestosis; however, further studies are needed.

Manganese and extracellular superoxide dismutase polymorphisms and risk for asbestosis.

Manganese and extracellular superoxide dismutases (SOD2 and SOD3) are part of the enzymatic defence against reactive oxygen species, which are involved in the pathogenesis of asbestosis. This study investigates whether SOD2Ala - 9Val and SOD3 Arg213Gly genetic polymorphisms represent risk factors for asbestosis in workers exposed to asbestos. The study included 262 cases with asbestosis and 265 controls with no asbestos-related disease. Cumulative asbestos exposure was calculated for each subject. A real-time PCR assay was introduced for genotyping. Logistic regression analysis was used to assess asbestosis risk. Asbestosis was associated with the homozygous SOD2 - 9Ala/Ala genotype (OR = 1.50, 95% CI 1.01-2.24), whereas the association for the SOD3 Arg/Gly genotype was not significant (OR = 1.63, 95% CI 0.62-4.27). The finding that the SOD2 - 9Ala/Ala genotype increases the risk for asbestosis indicates that, in addition to asbestos exposure, genetic factors may also have a significant influence on the development of asbestosis.

The influence of genetic polymorphisms of GSTP1 on the development of asbestosis.

OBJECTIVE: Genetic factors play an important role in the development of asbestosis. The aim of this study was to investigate whether genetic polymorphisms of glutathione S-transferase (GST) P1 represent a risk factor for this disease. METHODS: The study population included 262 workers with asbestosis and 265 matched controls. Information on cumulative asbestos exposure was available. A real-time PCR based on the 5' nuclease assay was designed for the analysis of GSTP1 Ile105Val and Ala114Val polymorphisms. RESULTS: Asbestosis was associated with GSTP1 genotype coding for an enzyme with high conjugation capacity versus genotypes resulting in intermediate and low enzyme activity (odds ratio = 1.49, confidence interval = 1.06-2.10). CONCLUSIONS: The key finding of the study was that GSTP1 genotype coding for an enzyme with high conjugation capacity significantly increases the risk of developing asbestosis.

Restructuring of a Textile Manufacturing Company and Workers' Health.

Organizational restructuring is associated with greater mortality and morbidity of the workers affected by it. We examined the quality of workers' health at a textile manufacturing company after restructuring, comparing three groups of workers: workers who remained (survivors), workers who lost their jobs and later found new jobs (the reemployed), and unemployed workers. A total of 1046 workers participated in a telephonic survey. The data were processed using SPSS and the R package version 1.2 of prLogistic. The differences between groups were calculated using the chi-square test and adjusted prevalence ratios. The comparison between the three groups shows significantly poorer mental health of the unemployed, who more often than survivors and the reemployed reported depression, as well as significant differences in elevated blood pressure, cholesterol level, and cardiac disorders. The reemployed, who were nonetheless in better health compared to the unemployed, reported poor mental health or depression more often in comparison to survivors. Higher morbidity of the unemployed and reemployed could be influenced by numerous factors associated with restructuring.

Glutathione S-transferases GSTM1 and GSTT1 polymorphisms and asbestosis.

OBJECTIVE: In a nested case-control study, the authors investigated whether the deletion polymorphism of glutathione S-transferases GSTM1 and GSTT1 represents a risk factor for the development of asbestosis. METHODS: In total, 262 cases with asbestosis and 265 controls, selected from a cohort of 2080 workers occupationally exposed to asbestos, were genotyped for GSTM1 and GSTT1-null alleles. Cumulative exposure for each subject was available. RESULTS: Asbestosis was associated with cumulative exposure (odds ratio [OR]=3.21, confidence interval [CI] 2.43-4.23) and GSTT1-null genotype (OR=0.61, CI 0.40-0.94), but not with GSTM1-null genotype (OR=1.01, CI 0.71-1.43). The risk of GSTM1-null and GSTT1-null genotype for asbestosis did not change after adjustment by cumulative exposure, smoking, gender, and age. CONCLUSIONS: An important finding of this study is that GSTT1 gene deletion might have a protective effect on the development of asbestosis.

Personality traits in miners with past occupational elemental mercury exposure.

In this study, we evaluated the impact of long-term occupational exposure to elemental mercury vapor (Hg0) on the personality traits of ex-mercury miners. Study groups included 53 ex-miners previously exposed to Hg0 and 53 age-matched controls. Miners and controls completed the self-reporting Eysenck Personality Questionnaire and the Emotional States Questionnaire. The relationship between the indices of past occupational exposure and the observed personality traits was evaluated using Pearson's correlation coefficient and on a subgroup level by machine learning methods (regression trees). The ex-mercury miners were intermittently exposed to Hg0 for a period of 7-31 years. The means of exposure-cycle urine mercury (U-Hg) concentrations ranged from 20 to 120 microg/L. The results obtained indicate that ex-miners tend to be more introverted and sincere, more depressive, more rigid in expressing their emotions and are likely to have more negative self-concepts than controls, but no correlations were found with the indices of past occupational exposure. Despite certain limitations, results obtained by the regression tree suggest that higher alcohol consumption per se and long-term intermittent, moderate exposure to Hg0 (exposure cycle mean U-Hg concentrations > 38.7 < 53.5 microg/L) in interaction with alcohol remain a plausible explanation for the depression associated with negative self-concept found in subgroups of ex-mercury miners. This could be one of the reason for the higher risk of suicide among miners of the Idrija Mercury Mine in the last 45 years.

The impact of long-term past exposure to elemental mercury on antioxidative capacity and lipid peroxidation in mercury miners.

Limited information is available on the effects of chronic mercury exposure in relation to the risk of cardiovascular disease (CVD). It is known from in vitro and in vivo studies that Hg can promote lipid peroxidation through promotion of free radical generation, and interaction with antioxidative enzymes and reduction of bioavailable selenium. The objective of the study was to test the hypothesis that long-term past occupational exposure to elemental Hg (Hg0) can modify antioxidative capacity and promote lipid peroxidation in miners. The study population comprised 54 mercury miners and 58 workers as the control group. The miners were examined in the post-exposure period. We evaluated their previous exposure to Hg0, the putative appearance of certain nonspecific symptoms and signs of micromercurialism, as well as the main behavioural and biological risk factors for CVD, and determined: 1) Hg and Se levels in blood and urine, 2) antioxidative enzymes, Cu/Zn superoxide dismutase (CuZn-SOD), catalase (CAT), and selenoenzyme glutathione peroxidase (GSH-Px) activity in erythrocytes as indirect indices of free radical activity, 3) pineal hormone melatonin (MEL) in blood and urine, and 4) lipid hydroperoxides (LOOHs) and malondialdehyde (MDA) as lipid peroxidation products. The mercury miners were intermittently exposed to Hg0 for periods of 7 to 31 years. The total number of exposure periods varied from 13 to 119. The cumulative U-Hg peak level varied from 794-11,365 microg/L. The current blood and urine Hg concentrations were practically on the same level in miners and controls. Miners showed some neurotoxic and nephrotoxic sequels of micromercurialism. No significant differences in behavioural and biological risk factors for CVD were found between miners and controls. A weak correlation (r = 0.36, p < 0.01) between systolic blood pressure and average past exposure U-Hg level was found. The mean P-Se in miners (71.4 microg/L) was significantly lower (p < 0.05) than in the controls (77.3 microg/L), while the mean U-Se tended to be higher (p < 0.05) in miners (16.5 microg/g creatinine) than in the controls (14.0 microg/g creatinine). Among antioxidative enzyme activities, only CAT in erythrocytes was significantly higher (p < 0.01) in miners (3.14 MU/g Hb) than in the controls (2.65 MU/g Hb). The mean concentration of B-MEL in miners (44.3 ng/L) was significantly higher (p < 0.01) than in the controls (14.9 ng/L). The mean value of U-MEL sulphate (31.8 microg/L) in miners was significantly lower (p < 0.01) than in the control group (46.9 microg/L). Among the observed lipid peroxidative products, the mean concentration of U-MDA was statistically higher (p < 0.01) in miners (0.21 micromol/mmol creatinine) than in the controls (0.17 micromol/mmol creatinine). In the group of miners with high mercury accumulation and the presence of some nonspecific symptoms and signs of micromercurialism, the results of our study partly support the assumption that long-term occupational exposure to Hg0 enhances the formation of free radicals even several years after termination of occupational exposure. Therefore, long-term occupational exposure to Hg0 could be one of the risk factors for increased lipid peroxidation and increased mortality due to ischaemic heart disease (ICH) found among the mercury miners of the Idrija Mine.

Soluble mesothelin-related peptides levels in patients with malignant mesothelioma.

Soluble mesothelin-related peptides (SMRP) are a potential tumor marker for malignant mesothelioma. The aim of this study was to determine the differences in SMRP levels in patients with malignant mesothelioma before treatment and in various responses to treatment and to investigate whether SMRP level could be useful in evaluating tumor response to treatment. The study included patients with malignant mesothelioma treated at the Institute of Oncology Ljubljana between March 2007 and December 2009. Blood samples were collected before treatment and/or in various responses to treatment. SMRP levels were determined using ELISA assay based upon a combination of two monoclonal antibodies. Mann-Whitney test was used to determine the differences in SMRP levels in various responses to treatment. Median SMRP was 2.80 nmol/L (range 0.00-34.80) before treatment, 0.00 nmol/L (range 0.00-0.00) in complete response, 0.48 nmol/L (range 0.00-4.40) in partial response, 1.65 nmol/L (range 0.00-20.71) in stable disease and 7.15 nmol/L (range 0.44-31.56) in progressive disease. Pre-treatment SMRP levels were significantly higher than in stable disease, partial response and complete response (p=0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p< 0.001). Our findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment.

Asbestosis and catalase genetic polymorphism.

Catalase (CAT) is part of the enzymatic defense system against reactive oxygen species (ROS), known to be involved in the pathogenesis of asbestosis. This study investigates whether CAT -262 C>T genetic polymorphism influences the risk of asbestosis in workers occupationally exposed to asbestos.The nested case-control study included 262 cases with asbestosis and 265 controls with no asbestos-related disease. Data on cumulative asbestos exposure and smoking were available. A real-time PCR assay was introduced for genotyping CAT -262 C>T promoter polymorphism.A slightly elevated risk of asbestosis was observed in subjects with the CAT -262 TT genotype compared to others (OR=1.36, CI 0.70-2.62). This risk did not change substantially after adjustment by sex, age, and smoking, but the involvement of cumulative asbestos exposure changed the OR to 1.91 (CI 0.93-3.91). These findings indicate that the CAT -262 TT genotype may be slightly associated with an increased risk of asbestosis. No synergistic effect was found between cumulative asbestos exposure and the CAT -262 TT genotype, but cumulative asbestos exposure acted as a confounder. These results are an important contribution to understanding the interactions between genetic and environmental factors that may modify the risk of asbestosis.