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Biomedical subjects

H Koskinen

Publications and source records attributed to H Koskinen.

At least 19 recordsLinked to original sources
PubMed1997

Mutations, tissue accumulations, and serum levels of p53 in patients with occupational cancers from asbestos and silica exposure.

In order to determine the relationship between mutations, tissue accumulations, and serum levels of p53 in occupational cancers, we used denaturing gradient gel electrophoresis and DNA sequencing of exons 5-9 of the p53 gene, immunohistochemical analysis for tissue identification of mutant p53 protein, and enzyme-linked immunosorbent assay for serum levels of mutant p53 protein to examine for such alteration in a cohort of individuals with workplace exposure to asbestos or silica, and resultant lung cancers or mesotheliomas. DNA analysis detected mutations in 5 of 18 (28%) tumors, and tissue accumulations of protein were detected in 7 of 20 (35%) tumors; the agreement between mutational and immunohistochemical analyses was significant (kappa = 0.62, P = 0.002). Serum elevations of protein were detected in 4 of 11 (36%) cases with available serum samples; the agreement between tissue alterations and serum elevations was also significant (kappa = 0.71, P = 0.017). In addition, based on the analysis of banked samples, serum results tended to be consistent over time prior to the diagnosis of disease (positive predictive value = 0.67, negative predictive value = 0.83). These results suggest that serum levels of p53 are reasonably accurate in reflecting tissue alterations in p53 at the gene and/ or protein level and may be early biomarkers of disease risk.

Adult↗
PubMed1996

A molecular and epidemiological study on bladder cancer: p53 mutations, tobacco smoking, and occupational exposure to asbestos.

In this study, we found an unexpected association (crude odds ratio = 2.8; 95% confidence interval = 0.9-8.4) between definite work-related exposure to asbestos and carcinoma of the urinary bladder in a small group of patients (n = 28) initially recruited as referents for an epidemiological feasibility study on the occupational causes of lung cancer. We extended the study by using molecular methods to examine mutations in the p53 tumor suppressor gene in the same cases of bladder cancers. The same number of archival samples of transitional cell carcinoma, mainly of grade 3, were added to the analysis. We failed to show any association between occupational exposure to asbestos and p53 mutations among bladder cancer patients. We observed an increasing occurrence of p53 mutations in nonsmokers (5 of 17, 29%), former smokers (8 of 21, 38%), and current smokers (9 of 16, 56%) in that order; however, this was not statistically significant. The most prevalent type of mutation was G:C to A:T transition. Tumor grade was not associated with the frequency of mutations, but the higher stage (T3-T4) tumors appeared to have mutations more frequently than did the less invasive tumors (T1-T2).

Adult↗
PubMed1995

Tumour necrosis factor-alpha (TNF-alpha) in patients who have asbestosis and develop cancer.

OBJECTIVES: Concentrations of tumour necrosis factor-alpha (TNF-alpha) were assayed by radioimmunoassay in serum samples collected between 1981 and 1987 from 111 patients with asbestosis who were at a high risk of cancer. Follow up of these patients until 1993 showed that 38 had developed cancer (27 lung, three mesotheliomas, and eight diverse malignancies). RESULTS: The mean serum concentrations of TNF-alpha given in fmol/100 microliters serum in all the cases with cancer (14.1) and the cases with lung cancer (13.6) were significantly higher (P < 0.05) than the mean concentrations in the exposed controls (10.5). A positive increase was considered to be any value that was > 2 SDs above the mean of the exposed controls. 22% (six of 27) of the cases with lung cancer were positive compared with 4% (three of 73) of the exposed controls, a significant difference (P < 0.001). The serum concentrations of TNF-alpha correlated moderately with cancer (r = 0.3), lung cancer (r = 0.3), and Neu oncoproteins and epidermal growth factor receptor (EGFR) (r = 0.3, 0.5 respectively). Also, there was a significant correlation between development of cancer and severity or progression of asbestosis. There was no correlation between the concentrations of TNF-alpha and severity or progression of asbestosis. CONCLUSIONS: These results showed high concentrations of TNF-alpha in the patients who had cancer. TNF-alpha may offer an auxiliary method in early diagnosis of cancers related to asbestosis.

Adult↗
PubMed1995

Serum oncoproteins in asbestosis patients.

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.

Asbestosis↗
PubMed1994

Detection of increased amounts of the extracellular domain of the c-erbB-2 oncoprotein in serum during pulmonary carcinogenesis in humans.

Over-expression of the c-erbB-2 oncogene-encoded p185 protein product has been implicated in the pathogenesis of a wide variety of human malignancies, including lung cancer. Over-expression of p185 can be detected immunologically by quantification of the extracellular domain of p185 (c-erbB-2 oncopeptide) in extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the c-erbB-2 oncopeptide was used to examine banked serum samples of 11 pneumoconiosis patients who subsequently developed lung cancer and serum samples from 11 hospital controls matched for age, sex, ethnic group and smoking as well as 55 unmatched general population controls. The mean serum level for the c-erbB-2 oncopeptide in human neu units/ml in the lung cancer cases (1,756 +/- 549 HNU/ml) was statistically significantly elevated (p < 0.001) in comparison to the mean level in the matched controls (976 +/- 488 HNU/ml) or the general population controls (888 +/- 655 HNU/ml). Defining a positive elevation of the serum c-erbB-2 oncopeptide as any value more than 2 standard deviations above the mean of the matched controls, 64% (7 of 11) of the lung cancer cases were positive compared to 0% (0 of 11) matched controls and 5% (3 of 55) of the unmatched controls. In addition, 4 of the 7 c-erbB-2 oncopeptide-positive cancer cases had positive serum samples prior to the time of disease diagnosis (average = 35 months). These results suggest that serum c-erbB-2 oncopeptide may be elevated at an early stage of pulmonary carcinogenesis and that further prospective study of the utility of this biomarker is warranted.

Aged↗
PubMed1994

Pancreatic cancer in industrial branches and occupations in Finland.

An examination of the risk of pancreatic cancer associated with occupation, by industrial branch and job title, was undertaken in a nationwide case-referent study in Finland. The results are based on job history information from the next-of-kin of 625 incident cases of primary malignant exocrinic pancreatic neoplasms, and of 1,700 cancer referents (stomach, colon, and rectum). All cases and referents were between 40 and 74 years at diagnosis. The diagnoses were made in 1984-87, and both cases and referents were known to be dead by April 1, 1990. The source of the cases and referents was the Finnish Cancer Registry. Increases in risk of pancreatic cancer were suggested for a small number of industrial branches and job titles, including stone mining (odds ratio 3.7), cement and building materials (11.1), pharmacists and sales associates in pharmacies (12.9), male wood machinists (4.1), male gardeners (6.7), female textile workers (5.4), and male transport inspectors and supervisors (9.4). The exposures potentially implicated are discussed. In agreement with the overall results of epidemiologic studies conducted elsewhere, direct occupational determinants probably do not account for a substantial share of the etiology of pancreatic cancer, at least in conditions resembling Finnish working environments some 15-40 years ago.

Adult↗
PubMed1994

High-resolution computed tomography in the early detection of asbestosis.

A group of 21 former asbestos sprayers was studied with high-resolution computed tomography (HRCT), and the findings were compared with radiographic, exposure and lung function variables. HRCT was superior to plain radiography in detecting parenchymal and pleural changes. It showed changes indicative of lung fibrosis, especially septal lines and parenchymal bands, in 9 of the 12 subjects (75%) with a plain radiographic category of 0/0 in the International Labour Office (ILO) 1980 classification of radiographs of pneumoconioses. The HRCT findings were classified according to a method developed by the authors, and an HRCT parenchymal score was calculated. The HRCT revealed pleural plaques in 19 of the 21 (90%) asbestos sprayers, whereas plain radiography detected pleural plaques in only 5 (24%) sprayers. Changes in the visceral pleura were detected twice as often with HRCT as with plain radiography. In the group without radiographic evidence of lung fibrosis (ILO < 1/0) and without evidence of emphysema in either the radiographs or the HRCT examination, there was a correlation between the HRCT parenchymal score and diffusion capacity (r = -0.64, P = 0.03) and total lung capacity (r = -0.61, P = 0.04). This finding indicates that parenchymal changes seen only with HRCT are of clinical importance. The study strongly suggests that for asbestos-exposed workers with an ILO classification of < 1/0 and functional impairment, an HRCT examination should always be considered.

Adult↗
PubMed1994

The detection of increased amounts of the extracellular domain of the epidermal growth factor receptor in serum during carcinogenesis in asbestosis patients.

Overexpression of the epidermal growth factor receptor (EGFr) has been implicated in the pathogenesis of a wide variety of human malignancies and may be related to asbestos-induced carcinogenesis. Overexpression of the EGFr can be detected immunologically by quantitation of the extracellular domain (ECD) in the extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the EGFr ECD was used to examine banked serum samples of 38 asbestosis patients who subsequently developed cancer, 72 age-sex-race-smoking-asbestos exposure matched asbestosis controls without cancer, and 20 age-sex-race-smoking matched nonasbestosis noncancer controls. The mean serum level for the EGFr ECD in the cancer cases (636 +/- 299 fmol/ml) was statistically significantly elevated (P < 0.05) in comparison to the mean level in the asbestosis controls (546 +/- 147 fmol/ml) or the nonasbestosis controls (336 +/- 228 fmol/ml). Defining a positive elevation of the serum EGFr ECD as any value more than 2 standard deviations above the nonasbestosis control mean, 7 (18%) of the cancer cases were positive compared to 4 (6%) of the asbestosis controls and one (5%) of the nonasbestosis controls. In addition, all of these cancer cases had positive serum samples prior to the time of disease diagnosis (average = 5.1 years). These results suggest that serum EGFr ECD may be elevated at an early stage of carcinogenesis in some asbestosis patients and that further prospective study of the utility of this biomarker is warranted.

Adult↗
PubMed1994

Increased incidence of lung and skin cancer in Finnish silicotic patients.

Cancer incidence during 1953 to 1991 in 811 Finnish silicotic patients diagnosed between 1936 and 1977 was evaluated. In comparison with the general population, excesses were observed for all cancers (standardized incidence ratio, 1.7 [95% confidence interval, 1.4 to 1.9]), all lung cancers (2.9 [2.4 to 3.5]), squamous cell lung cancers (3.3 [2.3 to 4.5]), and skin cancers: melanoma (3.0 [0.8 to 7.6]) and nonmelanoma (2.9 [1.2 to 6.1]). Confounding by tobacco smoking did not explain the lung cancer increment. The consistency of the association between silicosis and lung cancer across a large number of studies suggests that silicosis represents a direct or indirect lung cancer hazard. The skin cancer excess, a relatively novel finding, may be explained either by carcinogens in foundries, or silica-induced lowering of immunocompetence, which would lead to a more pronounced effect of solar ultraviolet radiation.

Adult↗
PubMed1992

Serum oncoproteins and growth factors in asbestosis and silicosis patients.

Levels of 9 different oncoproteins and growth factors were assayed by immunoblotting with monoclonal antibodies in 91 serum samples collected between March 1983 and August 1987 from 46 pneumoconiosis patients (36 asbestosis, 10 silicosis) at high risk for the development of cancer. Follow-up of these patients through June 1991 showed that 18 had developed cancer (11 lung, 2 pleural mesothelioma, 2 transitional-cell carcinomas of the urinary bladder, 1 osteosarcoma, 1 non-Hodgkin's lymphoma, 1 adenocarcinoma of the gallbladder). Increased serum levels of ras oncogene-related protein (p21) were found in 7 of the 18 patients who developed cancer (5 lung, 2 pleural mesothelioma) versus 2 of the 28 patients without cancer, a statistically significant difference (p = 0.012). In addition, 6 of the 7 p21-positive cancer cases had positive serum samples prior to clinical diagnosis of disease (average = 16.3 months, range = 3-26 months prior to diagnosis), suggesting that elevated serum p21 levels may be a useful marker for earlier detection in a significant percentage of respiratory malignancies. Finally, elevated serum levels of PDGF-related protein were detected significantly more frequently in advanced pneumoconiosis cases (ILO radiographic classification of 2/1 or greater) than in less advanced cases (80% vs. 41.9%; p = 0.016), and there was a tendency for these PDGF-positive patients to have progression of their disease (68.2% vs. 41.7%; p = 0.065), suggesting that elevated serum PDGF levels may be a marker for the development of severe and progressive pneumoconioses.

Aged↗
PubMed1992

Parenchymal and pleural fibrosis in construction workers.

Exposure to mineral dust was studied among construction workers (N = 437) with the aid of a questionnaire and a chest X-ray examination of the lungs. The results of the questionnaire showed that 81% of the construction workers had been exposed to asbestos. Exposure had occurred in all of the occupational groups studied. Pleural plaques and/or lung fibrosis (ILO greater than or equal to 1/1) were found in 26% of the examined workers; the prevalence varied from 18 to 40% among the various occupational groups. Comparison with a representative sample of the Finnish male population from another investigation indicates that the frequency of lung fibrosis (ILO greater than or equal to 1/1) is at least two times higher among the examined construction workers than among the general population. It seems likely that exposure to asbestos dust can be considered an etiological factor for an appreciable number of the X-ray findings.

Adult↗
PubMed1992

Localized pleural plaques and lung cancer.

In a mass chest radiography survey conducted in 1971 for 7,986 residents of three Finnish communities, 604 subjects (7.6%) with pleural plaques but not other asbestos-related radiographic signs were identified. The same number of referents, each individually matched to each plaque carrier on sex, birth year, and community, was selected from among persons in the same source population with no pleural plaques. The two groups were followed for investigation of incidence of lung cancer during 1972-1989. Twenty-eight of those with plaques and 25 referents contracted lung cancer (crude conditional RR = 1.1; CL95 = 0.7, 1.9). The application of the proportional hazards model, with adjustment for sex, age, and residence, resulted in a hazard ratio of 1.1 (CL = 0.6, 1.8). The risk ratio estimate may be biased; hence, the result is inconclusive in regard to the predictive assessment of lung cancer risk among carriers of pleural plaques.

Adult↗
PubMed1987

Urinary chlorophenols in sawmill workers.

The concentration of urinary chlorophenol was assayed for 230 sawmill workers. Information on the work tasks was obtained through questionnaires from occupational health centres. The workers were divided into three groups on the basis of the type of exposure: (1) those with skin absorption as the main route, (2) those with skin and respiratory route of equal importance and (3) those with respiratory tract as the main route. The concentrations of urinary chlorophenol were higher in workers with skin absorption as the main route (median concentration: 7.8 mumol l-1; range 0.1 to 210.9 mumol l-1) than in those with both routes of equal importance (1.4 mumol l-1; range 0.1 to 47.8 mumol l-1, P less than 0.001) or in those with mainly respiratory route (0.9 mumol l-1; range 0.1 to 13.3 mumol l-1, P less than 0.001). The urinary chlorophenol concentration was below 15 mumol l-1 in all workers with the lungs as the main absorption route. In nine out of 112 workers whose main absorption route was the skin, the urinary chlorophenol values were above 50 mumol l-1. Six were loaders when the through-dipping method was used. In two of them urinary chlorophenol concentrations were as high as 170.8 and 210.9 mumol l-1. These results emphasize the need to develop and use simple methods of protection against skin contact with chlorophenols.

Administration, Inhalation↗
PubMed1986

Serum angiotensin-converting enzyme and lysosomal enzymes in tobacco workers.

The activities of angiotensin-converting enzyme (ACE) in people with extrinsic allergic alveolitis (EAA) have been both increased and decreased. These observations suggest that pulmonary macrophages or endothelial cells participate in the disease process. Exposure to molds in the tobacco industry has recently been suspected to be associated with chronic extrinsic allergic alveolitis. In the present study, we analyzed the serum activities of ACE and two lysosomal enzymes, beta-N-acetylglycosaminidase (NAG) and beta-glucuronidase (GLU), among 57 tobacco workers. The tobacco workers not exposed had serum ACE levels similar to those of the reference population workers not occupationally exposed to dust (N = 127). The tobacco workers' serum levels of NAG (16.0 +/- 2.0 units/L and GLU (2.4 +/- 0.7 units/L) were higher than among the referents (NAG, 9.1 +/- 2.0 units/L; GLU, 1.0 +/- 0.6 units/L; p less than 0.01). Fifteen tobacco workers with respiratory symptoms compatible with pulmonary diseases caused by organic dust had a trend toward increased ACE, NAG, and GLU levels. The mean level of ACE in serum was higher among the workers with (25.8 +/- 4.5 units/L) than among those without pulmonary fibrosis (20.7 +/- 7.5 units/L; p less than 0.025). The mean ACE level was also higher among workers with the highest exposure to molds (24.6 +/- 7.1 units/L) compared to those with the mildest exposure (18.3 +/- 5.7 units/L; p less than 0.05). Tobacco workers with or without antibodies against one or more microbes had similar mean levels of ACE, NAG, and GLU. All of these findings indicate that raw tobacco dust and its contaminants may cause allergic or toxic reactions or both, reflected by the serum levels of ACE, NAG, and GLU.

Acetylglucosaminidase↗
PubMed1985

Symptoms and clinical findings in patients with silicosis.

Respiratory symptoms, radiographic findings, and lung function were analyzed in 144 Finnish patients with silicosis. The prevalence of persistent phlegm production in these patients was 46% and that of dyspnea 87%. Impairment of the vital capacity (VC) and the diffusion capacity (DLCO) (less than 80% of predicted values) were found in 46 and 47% of the patients with simple silicosis, respectively. The mean DLCO was lower in patients with advanced simple silicosis (category 3) than in those with slight simple silicosis (categories 1 and 2). In category 3 the DLCO was impaired in 9 out of 12 patients, the impairment being below 65% of the predicted values in six of the nine. All patients with large opacities showed impairment in their lung function tests. Twenty-eight of the silicosis patients had referents matched for exposure to silica dust, age, and gender. The referents had no radiographic signs of silicosis. The patients experienced dyspnea more often than their referents, whereas no difference was found in the prevalence of persistent phlegm production. The mean values of VC, forced expiratory volume in 1 s (FEV1.0), and DLCO were lower in the patients than in the referents. The results indicate a high prevalence of dyspnea, restrictive impairment of lung function, and impaired diffusion capacity in the patients with simple or complicated (ie, large radiographic opacities) silicosis. The DLCO proved to be a rather sensitive lung function parameter for advanced simple silicosis.

Adult↗
PubMed1984

Toxicity of polymethylmethacrylate thermodegradation products.

Polymethylmethacrylate was thermally degraded in air at 300 degrees C and the volatile decomposition products studied with gas chromatography-mass spectrometry. The main product was monomeric methacrylate, although many other compounds existed among the products. Electron spin resonance spectroscopy revealed the presence of free radicals. Wistar rats were exposed to the fumes of the plastic (300 degrees C) and their lungs and brain studied for biochemical effects. In the lung, the activity of 7-ethoxycoumarin O-deethylase decreased and an initial inhibition of glutathione peroxidase and superoxide dismutase was observed. The contents of reduced nonprotein sulfhydryl groups were decreased in the lung and brain. The exposures enhanced the activities of acetylcholine esterase, creatine kinase and NADPH-diaphorase in the brain. Scanning electron microscopy of the exposed lungs showed disorganization of ciliated cells, and the epithelial serous cells (Clara cells) were damaged.

Animals↗