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Supplementary Figure 2 from Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer

Supplementary Data and Figure Legends from Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer

Asbestos is a well-known lung cancer-causing mineral fiber. In vitro and in vivo experiments have shown that asbestos can cause chromosomal damage and aberrations. Lung tumors, in general, have several recurrently amplified and deleted chromosomal regions. To investigate whether a distinct chromosomal aberration profile could be detected in the lung tumors of heavily asbestos-exposed patients, we analyzed the copy number profiles of 14 lung tumors from highly asbestos-exposed patients and 14 matched tumors from nonexposed patients using classic comparative genomic hybridization (CGH). A specific profile could lead to identification of the underlying genes that may act as mediators of tumor formation and progression. In addition, array CGH analyses on cDNA microarrays (13,000 clones) were carried out on 20 of the same patients. Classic CGH showed, on average, more aberrations in asbestos-exposed than in nonexposed patients, and an altered region in chromosome 2 seemed to occur more frequently in the asbestos-exposed patients. Array CGH revealed aberrations in 18 regions that were significantly associated with either of the two groups. The most significant regions were 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2, and 19p13.1-p13.3 (P < 0.005). Furthermore, 11 fragile sites coincided with the 18 asbestos-associated regions (P = 0.08), which may imply preferentially caused DNA damage at these sites. Our findings are the first evidence, indicating that asbestos exposure may produce a specific DNA damage profile. (Cancer Res 2006; 66(11): 5737-43)

Supplementary Figure 1 from Identification of Specific Gene Copy Number Changes in Asbestos-Related Lung Cancer

Objectives. The purpose of this study was to examine the effectiveness of intervention strategies to control mass concentrations and peak exposures of flour dust in two Finnish bakeries. The effect of the intervention on the proportion of various particle size fractions of the total particulate matter was also investigated. Methods. Mass concentrations of flour dust were measured during three working days in a pre-intervention and post-intervention study in both an industrial and a traditional bakery. Gravimetric sampling and real-time measurements were performed. Relevant intervention strategies focused on working methods were planned in collaboration with the managers of the bakeries. Results. The average mass concentration of inhalable flour dust reduced in most of the stationary locations post intervention. The reductions in exposure levels were between 39 and 45%. However, the exposure levels increased 28–55% in the breathing zone. Real-time measurements showed reductions in the peak mass concentrations in the traditional bakery post intervention. In both bakeries, the total particulate matter size fraction consisted predominantly of particles with an aerodynamic diameter lower than 1 µm and greater than 10 µm. Conclusion. Further studies are needed to plan more effective intervention measures supplemented by technical control methods in both bakeries.

Publisher Copyright: © 2021 Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Positron annihilation spectroscopy, Fourier transform-infrared absorption spectroscopy, and secondary ion mass spectrometry have been used to study the behavior of gallium vacancy-related defects and hydrogen in deuterium (D) implanted and subsequently annealed β-Ga2O3 single crystals. The data suggest the implantation generates a plethora of VGa-related species, including VGa1- and VGa2-type defects. The latter’s contribution to the positron signal was enhanced after an anneal at 300 °C, which is driven by the passivation of VGaib by hydrogen as seen from infrared measurements. Subsequent annealing near 600 °C returns the positron signal to levels similar to those in the as-received samples, which suggests that split VGa-like defects are still present in the sample. The almost complete removal of the VGaib-2D vibrational line, the appearance of new weak O-D lines in the same spectral region, and the lack of D out-diffusion from the samples suggest that the 600 °C anneal promotes the formation of either D-containing, IR-inactive complexes or defect complexes between VGaib-2D and other implantation-induced defects. The degree of electrical compensation is found to be governed by the interactions between the Ga vacancies and hydrogen.

We have applied positron annihilation spectroscopy to study a wide range of β-Ga2O3bulk crystals and thin films with various doping levels. The Doppler broadening of the 511 keV positron-electron annihilation line exhibits colossal anisotropy compared to other three-dimensional crystalline semiconductors. State-of-the-art theoretical calculations of the positron characteristics in the β-Ga2O3lattice reveal that the positron state is effectively 1-dimensional, giving rise to strong anisotropy. Strongly relaxed split Ga vacancies are found to exhibit even stronger anisotropy and to dominate the positron annihilation signals in almost all experiments. The evidence leads to the conclusion that split Ga vacancies are abundant, with concentration of 1018 cm-3 or more, in β-Ga2O3samples irrespective of conductivity.

We report a systematic first-principles study on positron annihilation parameters in the $\ensuremath{\beta}\text{\ensuremath{-}}{\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ lattice and Ga monovacancy defects complemented with orientation-dependent experiments of the Doppler broadening of the positron-electron annihilation. We find that both the $\ensuremath{\beta}\text{\ensuremath{-}}{\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ lattice and the considered defects exhibit unusually strong anisotropy in their Doppler broadening signals. This anisotropy is associated with low symmetry of the $\ensuremath{\beta}\text{\ensuremath{-}}{\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ crystal structure that leads to unusual kind of one-dimensional confinement of positrons even in the delocalized state in the lattice. In particular, the split Ga vacancies recently observed by scanning transmission electron microscopy produce unusually anisotropic positron annihilation signals. We show that in experiments, the positron annihilation signals in $\ensuremath{\beta}\text{\ensuremath{-}}{\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ samples seem to be often dominated by split Ga vacancies.

Deep-level transient spectroscopy measurements on β-Ga 2 O 3 crystals reveal the presence of three defect signatures labeled E 2 a, E 2 b, and E 3 with activation energies at around 0.66 eV, 0.73 eV, and 0.95 eV below the conduction band edge. Using secondary ion mass spectrometry, a correlation between the defect concentration associated with E 3 and the Ti concentration present in the samples was found. Particularly, it is found that E 3 is the dominant Ti-related defect in β-Ga 2 O 3 and is associated with a single Ti atom. This finding is further corroborated by hybrid functional calculations that predict Ti substituting on an octahedral Ga site, denoted as Ti GaII, to be a good candidate for E 3. Moreover, the deep level transient spectroscopy results show that the level previously labeled E 2 and attributed to Fe substituting on a gallium site (Fe Ga) consists of two overlapping signatures labeled E 2 a and E 2 b. We tentatively assign E 2 a and E 2 b to Fe substituting for Ga on a tetrahedral or an octahedral site, respectively.

We have applied positron annihilation spectroscopy to study vacancy-type defects in unintentionally doped and Si and Sn doped β-Ga 2 O 3 homoepitaxial thin films grown by metal-organic chemical vapor deposition (MOCVD). We detect Ga vacancy related defects at high concentrations in semi-insulating and highly resistive material, while conductive (ntype) material exhibits very low Ga vacancy concentrations. These findings show that Ga vacancies can act as efficient electrical compensators for n-type conductivity, but their concentrations can be suppressed by controlling the growth environment, leading to efficient n-type doping. We also note the strong anisotropy of the positron annihilation signals and give recommendation for presenting positron data obtained in β-Ga 2 O 3 .

We report a positron annihilation study using state-of-the-art experimental and theoretical methods in n-type and semi-insulating β - Ga 2 O 3. We utilize the recently discovered unusually strong Doppler broadening signal anisotropy of β - Ga 2 O 3 in orientation-dependent Doppler broadening measurements, complemented by temperature-dependent positron lifetime experiments and first principles calculations of positron-electron annihilation signals. We find that split Ga vacancies dominate the positron trapping in β - Ga 2 O 3 single crystals irrespective of the type of dopant or conductivity, implying concentrations of at least 1 × 1 0 18 c m - 3.

Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, -omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non-immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment.

We present a systematic study of the positron lifetime as a function of measurement temperature in strontium titanate ( SrTiO 3) single crystals grown in different conditions and by different synthesis methods. We combine our experimental results with state-of-the-art theoretical calculations of positron annihilation parameters. We find that the essentially omnipresent 180-190ps lifetime component is most likely the Ti Sr antisite defect, possibly coupled with one or more oxygen vacancies, supporting the importance of the Ti Sr antisite related defects in SrTiO 3.

In bakeries, high concentrations of flour dust can exist and ovens release particles into the air as well. Particle concentrations (mass, number) and number size distribution may vary considerably but the variation is not commonly studied. Furthermore, the role of the smallest size fractions is rarely considered in the exposure assessment due to their small mass. The objectives of this work were to find out how concentrations and number size distribution of fine and nanoparticles vary in a traditional Finnish bakery, and to determine the exposure of a dough maker to the nanoparticle fraction of the inhalable dust. Two measurement campaigns were carried out in a traditional, small-scale bakery. Sampling was performed at the breathing zone of the dough maker and three stationary locations: baking area, oven area, and flour depository. Both real-time measurements and conventional gravimetric sampling were conducted. Nanoparticle fraction of the inhalable dust was determined using an IOM sampler with a customized pre-cyclone. Number concentration of fine and nanoparticles, and mass concentrations of both the inhalable dust and nanoparticles were high. The nanoparticle fraction was 9–15% of the inhalable dust at the breathing zone of the dough maker. Different sources, such as ovens and doughnut baking affected the number size distribution. Flour dust contained nanoparticles but most of the fine and nanoparticles were released into the air from the oven operations. However, nanoparticles are not a primary concern in bakeries compared to health effects linked to the large flour particles such as flour-induced sensitization or asthma and development of occupational rhinitis., final draft, peerReviewed

We have previously demonstrated an association between genomic alterations in 19p13, 2p16, and 9q33.1 and asbestos exposure in patients' lung tumours. This study detected allelic imbalance (AI) in these regions in asbestos-exposed lung cancer (LC) patients' histologically normal pulmonary epithelium. We extended the analyses of tumour tissue to cover a large LC patient cohort and studied DNA copy number alteration (CNA) and AI in 19p13, 2p16, and 9q33.1 for the first time in combination. We found both CNA and AI in ?2/3 of the regions to be significantly and dose-dependently (P

Objectives: To identify biomarkers for cancer in asbestosis patients.Methods: SELDI-TOF and CART were used to identify serum biomarker profiles in 35 asbestosis patients who subsequently developed cancer and 35 did not develop cancer.Results: Three polypeptide peaks (5707.01, 6598.10, and 20,780.70 Da) could predict the development of cancer with 87% sensitivity and 70% specificity. The first two peaks were identified as KIF18A and KIF5A, respectively, and are part of the Kinesin Superfamily of proteins.Conclusions: We identified two Kinesin proteins that can be potentially used as blood biomarkers to identify asbestosis patients at risk of developing lung cancer.

The aim of this study was to introduce a new method – request-driven generation of calculation (data and model) chains – to facilitate the automatic adaptation of analysis tools to varying output demands or input supply, and consequently reducing programming efforts. The method was implemented in a prototype for a calculation algorithm based on meta-information. To demonstrate the potential of the method, the algorithm was integrated with a model library and xml-based end-user interfaces for a case study where several calculation chains were generated for the comparison of different forest inventory systems. In our application, the autonomic analysis tool automatically adapted itself to varying output requests, input data sources, and contents of the model library. To summarize, the algorithm supports sharing and re-using of models and existing analysis tools. As a stand-alone calculation system, the algorithm can be utilized as a research and development tool, e.g. when testing and comparing mod...

Background National disparities in asbestos use will likely lead to an unequal burden of asbestos diseases. Objectives As economic status may be linked to asbestos use, we assessed, globally, the relationship between indicators of national economic development and asbestos use. Methods For the 135 countries that have ever used asbestos, per capita asbestos use (kilograms per capita per year) was compared with per capita gross domestic product (GDP) in 1990 Geary–Khamis dollars (GKD) for the period 1920–2003. Countries were grouped into three income levels (high, middle, and low) that were adapted from the 2003 World Bank categories. Results The historical pattern of asbestos use followed the environmental Kuznets curve in which use by high-income countries peaked when incomes attained 10,000–15,000 GKD and essentially ceased at income levels over 20,000 GKD. Currently, middle- and low-income countries are increasing their use of asbestos, closely following the paths once traced by higher income countries. Conclusions Developing countries have the opportunity to eliminate asbestos use sooner than high-income countries and thus reduce the future burden of asbestos diseases.

Five to seven percent of lung tumours are estimated to occur because of occupational asbestos exposure. Using cDNA microarrays, we have earlier detected asbestos exposure-related genomic regions in lung cancer. The region at 2p was one of those that differed most between asbestos-exposed and non-exposed patients. Now, we evaluated genomic alterations at 2p22.1-p16.1 as a possible marker for asbestos exposure. Lung tumours from 205 patients with pulmonary asbestos fibre counts from 0 to 570 million fibres per gram of dry lung, were studied by fluorescence in situ hybridisation (FISH) for DNA copy number alterations (CNA). The prevalence of loss at 2p16, shown by three different FISH probes, was significantly increased in lung tumours of asbestos-exposed patients compared with non-exposed (P=0.05). In addition, a low copy number loss at 2p16 associated significantly with high-level asbestos exposure (P=0.02). Furthermore, 27 of the tumours were studied for allelic imbalances (AI) at 2p22.1–p16.1 using 14 microsatellite markers and also AI at 2p16 was related to asbestos exposure (P=0.003). Our results suggest that alterations at 2p16 combined with other markers could be useful in diagnosing asbestos-related lung cancer.

Various growth factors, including platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta, have been implicated in the pathogenesis of asbestos-induced disease. PDGF and TGF-beta levels were determined by enzyme-linked immunosorbent assays in the banked serum samples of a cohort of workers with asbestosis, and the relationships of the growth factor levels to the subsequent development of cancer and to the radiographic severity and progression of asbestosis in the cohort were examined. Serum levels of PDGF and TGF-beta were found to be unrelated to the development of cancer, and serum levels of PDGF were found to be unrelated to the severity and progression of asbestosis. However, serum levels of TGF-beta were found to be statistically significantly related to disease severity (p = 0.01), increasing approximately 2.4-fold from ILO radiographic category 0 to category 3, and they were marginally related to disease progression (p = 0.07), in multivariate analysis controlling for other contributory factors including cumulative asbestos exposure. This suggests that serum TGF-beta may be a useful biomarker for asbestos-induced fibrotic disease.

Background In response to the health risks posed by asbestos exposure, some countries have imposed strict regulations and adopted bans, whereas other countries have intervened less and continue to use varying quantities of asbestos. Objectives This study was designed to assess, on a global scale, national experiences of recent mortality from pleural mesothelioma, historical trends in asbestos use, adoption of bans, and their possible interrelationships. Methods For 31 countries with available data, we analyzed recent pleural mesothelioma (International Classification of Diseases, 10th Revision) mortality rates (MRs) using age-adjusted period MRs (deaths/million/year) from 1996 to 2005. We calculated annual percent changes (APCs) in age-adjusted MRs to characterize trends during the period. We characterized historical patterns of asbestos use by per capita asbestos use (kilograms per capita/year) and the status of national bans. Results Period MRs increased with statistical significance in five countries, with marginal significance in two countries, and were equivocal in 24 countries (five countries in Northern and Western Europe recorded negative APC values). Countries adopting asbestos bans reduced use rates about twice as fast as those not adopting bans. Turning points in use preceded bans. Change in asbestos use during 1970–1985 was a significant predictor of APC in mortality for pleural mesothelioma, with an adjusted R2 value of 0.47 (p < 0.0001). Conclusions The observed disparities in global mesothelioma trends likely relate to country-to-country disparities in asbestos use trends.

We give a general description of a class of contrastive constructions, intended to capture what is common to contrastive knowledge, belief, hope, fear, understanding and other cases where one expre...

The potential for a global epidemic of asbestos-related diseases is a growing concern. Our aim was to assess the ecological association between national death rates from diseases associated with asbestos and historical consumption of asbestos.We calculated, for all countries with data, yearly age-adjusted mortality rates by sex (deaths per million population per year) for each disease associated with asbestos (pleural, peritoneal, and all mesothelioma, and asbestosis) in 2000-04 and mean per head asbestos consumption (kg per person per year) in 1960-69. We regressed death rates for the specified diseases against historical asbestos consumption, weighted by the size of sex-specific national populations.Historical asbestos consumption was a significant predictor of death for all mesothelioma in both sexes (adjusted R2=0.74, p0.0001, 2.4-fold [95% CI 2.0-2.9] mortality increase was predicted per unit consumption increase for men; 0.58, p0.0001, and 1.6-fold [1.4-1.9] mortality increase was predicted for women); for pleural mesothelioma in men (0.29, p=0.0015, 1.8-fold [1.3-2.5]); for peritoneal mesothelioma in both sexes (0.54, p0.0001, 2.2-fold [1.6-2.9] for men, 0.35, p=0.0008, and 1.4-fold for women [1.2-1.6]); and for asbestosis in men (0.79, p0.0001, 2.7-fold [2.2-3.4]). Linear regression lines consistently had intercepts near zero.Within the constraints of an ecological study, clear and plausible associations were shown between deaths from the studied diseases and historical asbestos consumption, especially for all mesothelioma in both sexes and asbestosis in men. Our data strongly support the recommendation that all countries should move towards eliminating use of asbestos.

Asbestos is a pulmonary carcinogen known to give rise to DNA and chromosomal damage, but the exact carcinogenic mechanisms are still largely unknown. In this study, gene expression arrays were performed on lung tumor samples from 14 heavily asbestos-exposed and 14 non-exposed patients matched for other characteristics. Using a two-step statistical analysis, 47 genes were revealed that could differentiate the tumors of asbestos-exposed from those of non-exposed patients. To identify asbestos-associated regions with DNA copy number and expressional changes, the gene expression data were combined with comparative genomic hybridization microarray data. As a result, a combinatory profile of DNA copy number aberrations and expressional changes significantly associated with asbestos exposure was obtained. Asbestos-related areas were detected in 2p21-p16.3, 3p21.31, 5q35.2-q35.3, 16p13.3, 19p13.3-p13.1 and 22q12.3-q13.1. The most prominent of these, 19p13, was further characterized by microsatellite analysis in 62 patients for the differences in allelic imbalance (AI) between the two groups of lung tumors. 79% of the exposed and 45% of the non-exposed patients (P=0.008) were found to be carriers of AI in their lung tumors. In the exposed group, AI in 19p was prevalent regardless of the histological tumor type. In adenocarcinomas, AI in 19p appeared to occur independently of the asbestos exposure.

Asbestos is a well-known lung cancer-causing mineral fiber. In vitro and in vivo experiments have shown that asbestos can cause chromosomal damage and aberrations. Lung tumors, in general, have several recurrently amplified and deleted chromosomal regions. To investigate whether a distinct chromosomal aberration profile could be detected in the lung tumors of heavily asbestos-exposed patients, we analyzed the copy number profiles of 14 lung tumors from highly asbestos-exposed patients and 14 matched tumors from nonexposed patients using classic comparative genomic hybridization (CGH). A specific profile could lead to identification of the underlying genes that may act as mediators of tumor formation and progression. In addition, array CGH analyses on cDNA microarrays (13,000 clones) were carried out on 20 of the same patients. Classic CGH showed, on average, more aberrations in asbestos-exposed than in nonexposed patients, and an altered region in chromosome 2 seemed to occur more frequently in the asbestos-exposed patients. Array CGH revealed aberrations in 18 regions that were significantly associated with either of the two groups. The most significant regions were 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2, and 19p13.1-p13.3 (P < 0.005). Furthermore, 11 fragile sites coincided with the 18 asbestos-associated regions (P = 0.08), which may imply preferentially caused DNA damage at these sites. Our findings are the first evidence, indicating that asbestos exposure may produce a specific DNA damage profile. (Cancer Res 2006; 66(11): 5737-43)

The complexations of two ammonium ions (guests) with two resorcarenes (hosts) were investigated using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry. Although the two guests and the two hosts were noticeably similar, the quantity of the corresponding supramolecular complexes formed varied significantly due to the differences in host conformations and guest ability to form non-covalent interactions.

High mobility group A (HMGA) proteins play an important role in the regulation of transcription, differentiation, and neoplastic transformation. In this work, the expression of HMGA 1 and 2 in 152 lung carcinomas of mainly non-small-cell histological type has been studied by immunohistochemistry in order to evaluate their feasibility as lung cancer markers. In 17 lung cancer cases, the related bronchial epithelial changes were also studied for HMGA1 and 2 expression. RNA expression of HMGA1a and b isoforms and of HMGA2 was determined by real-time semi-quantitative RT-PCR in 23 lung carcinomas. High expression of HMGA1 and HMGA2 at both mRNA and protein levels was detected in lung carcinomas, compared with normal lung tissue. Nuclear immunostaining for HMGA1 and 2 proteins also occurred in hyperplastic, metaplastic, and dysplastic bronchial epithelium. Increased nuclear expression of HMGA1 and 2 correlated with poor survival (for adenocarcinomas, HMGA1, p = 0.006; HMGA2, p = 0.05). While the expression of HMGA2 was significantly associated with cell proliferation (p = 0.008), HMGA1 expression did not show any association with proliferation or apoptotic index. Sequencing of HMGA2 transcripts from tumours with very high expression showed a normal full-length transcript. As HMGA proteins were expressed in about 90% of lung carcinomas and their expression was inversely associated with survival, they may provide useful markers for lung cancer diagnosis and prognosis. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

We explored the impact of cancer diagnosis on the employment status of 46 312 working-aged people with cancer, alive on 31 December 1997 in Finland, and an equal number of age- and gender-matched referents. In general, 50% of the cancer patients were employed, in comparison to 55% of their referents. People with cancer were slightly less often employed, mainly because of their higher retirement rate: 34% of the cancer patients and 27% of the referents had retired. People with lung cancer as well as those with cancer of the nervous system were less likely to be employed. Our results suggest that cancer diagnosis does not usually lead to unemployment or early retirement, even though the employment rate of the people with cancer varied greatly according to the cancer site. Early retirement is common among people with highly disabling cancer or poor prognosis, but in general, the employment of cancer survivors seems optimistic. Copyright © 2004 John Wiley & Sons, Ltd.

To identify new potential diagnostic markers for lung cancer, the expression profiles of 37 lung tumours were analysed using cDNA arrays. Seven samples were from small-cell lung cancer (SCLC), two from large-cell neuroendocrine tumours (LCNEC), and 28 from other non-small-cell lung cancers (mainly squamous cell cancer and adenocarcinoma). Principal component analysis and the permutation test were used to detect differences in the gene expression profiles and a set of genes was found that distinguished high-grade neuroendocrine carcinomas (SCLC and LCNEC) from other lung cancers. In addition, several genes, such as caveolin-1 (CAV1) and caveolin-2 (CAV2), were constantly deregulated in all types of tumour sample, compared with normal tissue. The expression of these two genes was investigated further at the protein level on a tissue microarray containing tumours from 161 patients and normal tissues. Immunostaining for CAV1 was negative in 48% of tumours, whereas 28% of the tumours did not express CAV2. Lack of CAV1 protein expression was not caused by methylation or mutation. In stage I adenocarcinomas, CAV2 protein expression correlated with shorter survival. In conclusion, the present study was able to identify genes that have not previously been implicated in lung cancer by the combined use of two different array techniques. Some of these genes may provide novel diagnostic markers for lung cancer. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The expression patterns of cancer-related genes in 13 cases of squamous cell lung cancer (SCC) were characterized and compared with those in normal lung tissue and 13 adenocarcinomas (AC), the other major type of nonsmall cell lung cancer (NSCLC). cDNA array was used to screen the gene expression levels and the array results were verified using a real-time reverse-transcriptase-polymerase chain reaction (RT-PCR). Thirty-nine percent of the 25 most upregulated and the 25 most downregulated genes were common to SCC and AC. Of these genes, DSP, HMGA1 (alias HMGIY), TIMP1, MIF, CCNB1, TN, MMP11, and MMP12 were upregulated and COPEB (alias CPBP), TYROBP, BENE, BMPR2, SOCS3, TIMP3, CAV1, and CAV2 were downregulated. The expression levels of several genes from distinct protein families (cytokeratins and hemidesmosomal proteins) were markedly increased in SCC compared with AC and normal lung. In addition, several genes, overexpressed in SCC, such as HMGA1, CDK4, IGFBP3, MMP9, MMP11, MMP12, and MMP14, fell into distinct chromosomal loci, which we have detected as gained regions on the basis of comparative genomic hybridization data. Our study revealed new candidate genes involved in NSCLC.

Information about asbestos issues at the national level was compiled for ten Asian countries (China, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, and Vietnam) regarding 1) bans and consumption levels; 2) occupational exposure limits (OELs) and medical follow-up schemes; and 3) statistics and compensation status of asbestosis and mesothelioma victims. Only Singapore and recently Japan have adopted a total ban an asbestos. China, a major producer of chrysotile, showed an increasing consumption trend, which was typical of the less industrialized countries. Considerable differences between countries existed in OELs (0.1 to 5.0 fibers/mL) and medical follow-up of exposed workers. National statistics for asbestosis and mesothelioma were available for only the industrialized countries, where reported cases as well as compensated cases were relatively few. There is need to improve the quality and quantity of information, but the available information attests to unfavorable conditions in the less industrialized countries. Hence the experience of industrialized countries regarding asbestos and its use should be utilized to the fullest to improve the situation worldwide.

Objectives Cancer risk has been estimated for asbestos production workers or other heavily exposed asbestos workers in numerous studies. The bulk of the asbestos epidemic results come, however, from past intermittent exposures during asbestos product use. This study concentrated on estimating the risk of cancer in such a population. Methods Altogether 23 285 men and 930 women invited to a nationwide screening campaign for benign asbestos-related diseases in 1990-1992 were followed for cancer through the Finnish Cancer Register up to 1998. Standardized incidence ratios (SIR) were calculated in comparison with the total Finnish population. Results Altogether 1392 cases of cancer were found among the men. The risk was slightly, but significantly elevated for lung cancer [SIR 1.14, 95% confidence interval (95% CI) 1.01-1.26), mesothelioma (SIR 2.77, 95% CI 1.66-4.31), and prostate cancer (SIR 1.21, 95% CI 1.09-1.34). The risk of lung cancer was slightly higher among the invited nonparticipants (SIR 1.48, 95% CI 1.20-1.79) than among the participants (SIR 1.02, 95% CI 0.88-1.17). About 98% of the lung cancers occurred in current or ex-smokers. Conclusions In a population of long-term construction workers, the risk of lung cancer and mesothelioma was increased, but considerably lower than among insulators, asbestos sprayers, or patients with asbestosis. As it was not possible to follow most of the invited nonparticipants in the original screening study, selection bias by smoking or other life-style factors possibly correlated to the individual's decision to participate in the health screening cannot be excluded.

Study objectives To determine the risk of asthma among patients with occupationally induced rhinitis. Design Patients with confirmed occupational rhinitis were followed for asthma incidence through register linkage. Patients with other occupational diseases were used as a reference population. Subjects Patients entered into the Finnish Register of Occupational Diseases in from 1988 to 1999 for occupational rhinitis (n = 3,637) or other occupational disease (n = 31,457) were observed until December 31, 2000, through two national registers of individuals who were eligible for the reimbursement of asthma medication and the Population Register Center. Methods Incidence rates of asthma were calculated, and a log-linear model, adjusted for age, gender, and occupation, was used to estimate the relative risks (RRs) of asthma among those with occupational rhinitis compared to those with other occupational diseases. Results There were 420 and 972 incident cases of asthma, respectively, among those with occupational rhinitis and the reference population. The crude RR of asthma was 4.8 (95% confidence interval [CI], 4.3 to 5.4) for all patients with occupational rhinitis, 5.4 (95% CI, 4.8 to 6.2) for those with occupational rhinitis accepted for compensation, and 3.7 (95% CI, 3.1 to 4.5) for patients with unaccepted occupational rhinitis. The RR varied according to occupation and was the highest among farmers and wood workers, both groups having a sevenfold risk. The risk was especially high during the year following notification, but a roughly threefold risk persisted several years thereafter. Conclusions Patients with occupationally induced rhinitis have a high risk of asthma, but further studies are needed to establish the effect of preventive interventions.

No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semi-quantitative real-time RT-PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The down-regulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

We wanted to explore the risk of asthma among male workers of the construction industry. All Finnish male construction industry workers and all those employed in administrative work were followed for asthma incidence through a register linkage in 1986 through 1998. Age-adjusted relative risks (RR) were estimated for 24 construction occupations. The risk was increased in nearly all construction occupations studied, but it was highest among welders and flame cutters (RR 2.34), asphalt roofing workers (RR 2.04), plumbers (RR 1.90), and brick layers and tile setters (RR 1.83). Only 45 (2%) of the cases of asthma among construction workers had been recognized as occupational asthma. Construction industry workers have an increased risk of adult-onset persistent asthma and cases of occupational asthma caused by well-established causative agents have only a minor contribution to this overall asthma excess.

The target set to the research was to develop open data transfer for bridge information modeling. Open data transfer was studied and tested to find software-independent solution to produce contents of bridge design data from initial data to engineering design. As a result of the research it was found that information of the technical bridge structures and other infrastructure refer to the bridge is able to produce using open data formats, which are IFC and Inframodel. In information modeling based design the model includes almost all of the information set in requirements by bridge design manuals and guidelines. However for software used in bridge and infra engineering design there are still limited possibilities to execute data transfer using open data formats between different technical design areas.

Induction of a polycyclic aromatic hydrocarbon-metabolizing cytochrome P450 isoform CYP1A1 is regulated by aromatic hydrocarbon receptor (AHR). High inducibility of CYP1A1, possibly due to genetic polymorphisms, has been considered to be a risk factor for lung cancer in tobacco smokers. The relationship between low or high pulmonary expression of CYP1A1 and polymorphic genotypes of CYP1A1 and AHR was investigated in 73 active smokers. CYP1A1 expression was determined in surgical lung samples by measuring ethoxyresorufin O-deethylase (EROD) activity and by immunostaining for CYP1A1 protein. The most common allelic variants of CYP1A1 and AHR in Finns, i.e. the MspI variant (CYP1A1*2A), I462V variant (CYP1A1*2B), and -459C to T variant of CYP1A1 and the R554K variant (AHR*2) of AHR were studied using polymerase chain reaction based methods. EROD activity correlated positively with the daily cigarette consumption (r = 0.45). There was additional variation in EROD activity independent of the amount of smoking e.g. among those who smoked one pack per day until the day of operation, EROD activity ranged from 4-142 (median 48) pmol/min/mg. The frequencies of the MspI, 462V, and -459T variant alleles of CYP1A1 and 554K variant allele of AHR were 0.158, 0.055, 0.055 and 0.075, respectively. No differences were observed in the frequencies of polymorphic genotypes between the smokers with low and those with high expression, when the relationship was studied using a regression analysis adjusted for cigarette consumption. Our results thus indicate that the interindividual variation of CYP1A1 levels in smokers' lung tissue is not attributable to genetic polymorphisms of CYP1A1 or AHR tested in this study.

Frequent DNA copy number gain at 3q, with minimal overlapping area at 3q24-qter, has previously been reported in squamous cell carcinoma of the lung (SQCC), implicating the importance of genes at 3q in the tumorigenesis of SQCC. To further characterize the gain of DNA sequences at 3q, we performed interphase fluorescence in situ hybridization (FISH) analysis on 16 paraffin-embedded SQCC tumor samples that had previously been studied by comparative genomic hybridization (CGH). Eleven yeast artificial chromosome (YAC) probes located at 3q25∼q27 and a chromosome 3-specific centromeric probe were used in the analysis. All SQCC tumors showed increase in DNA sequence copy number with 9 – 11 probes. In 5 tumors (31%) the number of centromeric signals varied from 3 to 5 and the YAC/centromeric signal ratio was 1.0, suggesting that the increase in DNA sequence copy number at 3q in these cases resulted from polysomy of chromosome 3. In 11 tumors (69%), the YAC/centromeric signal ratio varied between 1.5 and 4.7, indicating that the increase in DNA sequence copy number was due to intrachromosomal gain of DNA sequences at 3q. In each case, several YACs showed increased number of signals, demonstrating that the gained area was relatively large. Our findings therefore suggest that multiple genes located at 3q25∼q27 are involved in the tumorigenesis of SQCC.

Objectives: To study the asbestos-associated risk of lung cancer according to the histological type of cancer, the time of and time since diagnosis of asbestosis, the asbestos-associated risk for cancers other than lung cancer or mesothelioma, and the predictive value of asbestos-related pleural abnormalities as regards the risk of cancer. Methods: Finnish patients with asbestosis (n=1,376) or asbestos-related benign pleural disease (n=4,887) notified as an occupational disease since 1964 were followed-up through the Finnish Cancer Registry for cancer in 1967–95. Results: Compared with the total cancer incidence in Finland, men with asbestosis had a raised risk of lung cancer (standardized incidence ratio [SIR]=6.7; 95% confidence interval [CI]=5.6–7.9), mesothelioma (SIR=32, CI=14–60) and cancer of the larynx (SIR=4.2, CI=1.4–9.8). The risk of lung cancer was similarly raised for all histological types of lung cancer (the highest in insulators) and did not change markedly over time of notification or duration of follow-up. Men with benign pleural disease had a raised risk of mesothelioma (SIR=5.5, CI=1.5–14) and a slightly elevated risk of lung cancer (SIR=1.3, CI=1.0–1.8). Among women with asbestosis, significant excess was found for lung cancer and mesothelioma. Conclusion: Asbestosis and asbestos-related benign pleural disease seem to possess different predictive values as regards the risk of lung cancer.

Glutathione S-transferases (GSTs) are known to take part in detoxification of many potentially carcinogenic compounds. Therefore, polymorphisms of the GST genes have been considered as potentially important modifiers of individual risk of environmentally induced cancers. The association between lack of glutathione S-transferase M1 gene (GSTM1 null genotype) and susceptibility to smoking-related lung cancer has been actively studied, with contradictory results. In contrast, little is known about the more recently found polymorphisms in GSTM3, GSTP1 and GSTT1 genes with respect to individual responses to environmental exposures. In this study, we determined the genotype distribution of all these genes, and their combinations, among 208 Finnish lung cancer patients and 294 population controls. None of the genotypes studied had a statistically significant effect on lung cancer risk, when studied separately. However, a significant association was observed for concurrent lack of the GSTM1 and GSTT1 genes and susceptibility to squamous cell carcinoma. For that cell type, the risk was more than 2-fold when compared with that of individuals having other genotype combinations (OR = 2.3; 95% CI = 1.0–5.3; p = 0.05). Moreover, the risk was mostly attributable to patients with smoking history of 40 pack-years or less (OR = 2.9; 95% CI = 1.1–7.7; p = 0.03). In contrast, this genotype combination did not affect the risk for other histological types of lung cancer, and the other genotype combinations had no effects on individual susceptibility to this malignancy. The overall role of GST polymorphisms in modifying the lung cancer risk may therefore be more limited than has been so far anticipated. Int. J. Cancer 77:516–521, 1998. © 1998 Wiley-Liss, Inc.

Study objectives To explore whether the progression of asbestosis correlates with the risk of lung cancer among patients with asbestosis. Design A group of 85 asbestosis patients (78 men and 7 women) were radiographically followed up between 1979 and 1987. Two or three posteroanterior radiographs taken from each patient in 1978 to 1979, 1983 to 1984, and 1986 to 1987 were classified according to the International Labour Office 1980 classification and were used to divide the patients into progressors and nonprogressors. Follow-up for cancer was done automatically through the files of the Finnish Cancer Registry from the time of determination of the progression status to December 31, 1994. Predictors of lung cancer risk were studied with a logistic regression model, and the standardized incidence ratio (SIR) was calculated for lung cancer. Results Of the 24 male patients with progressive small opacity profusion, 11 (46%) developed lung cancer, as opposed to 5 (9%) of the 54 male patients without progression. The SIR for lung cancer was 37 (95% confidence interval, 18 to 66) for the progressors and 4.3 (1.4 to 9.9) for the nonprogressors. In both groups, all the lung cancer cases occurred among smokers or exsmokers. None of the seven female patients showed progressive small opacity profusion. One of them developed lung cancer. In the logistic regression model including all 85 asbestosis patients, radiographic progression of small opacity profusion (p=0.0009) and current smoking (0.0021) were significant predictors of lung cancer morbidity. Conclusions Asbestosis patients with radiographic progression of small opacity profusion over a few years are at a higher risk of lung cancer than those with a less aggressive course of the disease. The progression of pulmonary fibrosis may be an independent risk factor that, in addition to smoking history and the intensity of asbestos exposure, could be used to estimate lung cancer risk.

We performed a comparative genomic hybridization study on 25 samples of adenocarcinoma and 19 samples of squamous cell carcinoma of the lung to detect recurrent changes in the genetic material. DNA copy number changes were found in 16 squamous cell carcinoma samples and 17 adenocarcinoma samples. The most common changes were gains of DNA sequences in 3q (43%), 1q (34%), 8q (32%), 5p, (30%), 7p (25%), and 12p (25%). Of the squamous cell carcinoma samples with DNA copy number changes, 94% (15/16) had a gain in 3q (minimal common region of overlap q24-qter), whereas only 24% (4/17) of the adenocarcinoma samples with DNA copy number changes showed a gain in 3q (q22-qter) (P< 0.001). Six high-level amplifications in 3q (q26.2-q26.3) were detected in the squamous cell carcinoma samples but none were observed in the adenocarcinoma samples. Our results suggest that amplification of genes in 3q may be important in the tumorigenesis of squamous cell carcinoma but not necessarily of adenocarcinoma. Genes Chromosomes Cancer 22:79–82, 1998. © 1998 Wiley-Liss, Inc.

Human pulmonary tissues are known to contain enzymes mediating procarcinogen activation. Peripheral blood lymphocytes and bronchoalveolar macrophages (BAMs) have been used as surrogates for the lung in studies involving cytochrome P450 (CYP) parameters, including CYP1A1 inducibility in relation to susceptibility to lung cancer. In this study, a comprehensive view of the expression patterns of xenobiotic-metabolizing CYP forms in human BAMs and peripheral blood lymphocytes was obtained by using gene-specific reverse transcriptase–polymerase chain reaction analysis. These patterns were compared with that in the whole lung. MRNAs of CYP2B6/7, CYP2C, CYP2E1, CYP2F1, CYP3A5, and CYP4B1 were detected in all seven BAM samples studied; however, only the mRNA of CYP2E1 was found consistently in all eight lymphocyte samples. The amounts of amplification products of CYP2B6/7, CYP2C, CYP3A5, and CYP4B1 were low and inconsistent, indicating low levels of expression in lymphocytes. Consistent with previous knowledge, mRNAs of CYP1A1, CYP2B6/7, CYP2E1, CYP2F1, CYP3A5, and CYP4B1 were detected in whole-lung tissue. These results give an overall picture of the expression of CYP genes in the xenobiotic-metabolizing families CYP1, CYP2, and CYP3 in BAMs, peripheral blood lymphocytes, and whole-lung tissue and will aid in directing future studies on the respective protein products. The differences in the CYP gene expression patterns between lung and lymphocytes cast additional doubt on the use of lymphocytes as a surrogate for the lung. Mol. Carcinog. 20:224–230, 1997. © 1997 Wiley-Liss, Inc.

Objectives The study analyzed the recent trend in the incidence of mesothelioma in Finland and evaluated the coverage of reporting work-related mesothelioma. Methods The incidence of mesothelioma in 1960--1995 was retrieved from the Finnish Cancer Registry, and the number of asbestos-associated work-related mesotheliomas were taken from the Finnish Register of Occupational Diseases. Results The annual number of mesotheliomas increased rapidly in 1975--1990. In the 1990s, the age-adjusted incidence remained relatively stable for Finnish men. The annual number of cases still increased among men over 65 years of age, but decreased slightly among men under 55 years of age and among women. About 35 annual cases were diagnosed among the men and 10--15 among women in the mid-1990s. The reporting of work-related mesotheliomas improved during the Finnish asbestos program in 1987--1992. In 1993--1995 about 30 annual cases (ie, about 90% of all pleural and 50% of the peritoneal mesotheliomas in men) were reported to be work-related. Conclusion The increasing trend in the incidence of mesothelioma in Finland slowed down in the 1990s, and the maximum of asbestos-related cases in the early 2000s will probably be clearly less than the 100 annual cases estimated in the early 1990s. If the observed trend continues up to 2010, about 40--50 cases among men and 10--20 among the women will then be diagnosed annually. Altogether 40--50 of these cases would be related to occupational asbestos exposure.

To evaluate current occupational exposure and its associations with asthma control, exacerbations, and severity in middle-aged men with asthma from youth.We used the Finnish Defence Force registers, 1986 to 1990, to select conscripts with asthma to represent mild or moderate asthmatic group (asthma group 1; N = 505), men who were exempted from military service to represent relatively severe asthmatic group (asthma group 2; N = 393), and a control group without asthma (N = 1500). A questionnaire was sent out in 2009.The current self-reported or expert-evaluated exposure to asthma-aggravating factors differed only slightly between the asthmatic groups and the controls. In asthma group 2, being a manual worker or self-employed (odds ratio, 4.5; 95% confidence interval, 1.2 to 16.3) significantly associated with asthma exacerbations.Current work may associate with the asthma outcome of middle-aged men with relatively severe asthma in their youth.

In Finland, unlike other countries, anthophyllite asbestos has been widely used due to its domestic production in 1918-1975. In this particular context, the aim of the present study was to analyse the relationship between asbestos bodies (ABs) in bronchoalveolar lavage (BAL) fluid and the concentration of ABs and the different amphibole asbestos fibres in lung tissue. Sixty five BAL lung tissue sample pairs from patients with pulmonary disease were analysed. The concentration of ABs in BAL fluid and lung tissue was determined with optical microscopy, and the concentration, type and dimensions of asbestos fibres in lung tissue with scanning electron microscopy. There was a significant correlation between the concentrations of ABs in BAL fluid and in lung tissue (r = 0.72; p < 0.001), between the concentrations of ABs and amphibole asbestos fibres in lung tissue (r = 0.73; p < 0.001), and between the concentration of ABs in BAL fluid and the concentration of amphibole asbestos fibres in lung tissue (r = 0.64; p < 0.001). In patients who had been exposed mainly to commercial anthophyllite, significantly higher concentrations of ABs were observed per total pulmonary amphibole fibre burden, as compared to patients whose main exposure was to crocidolite/amosite. The anthophyllite fibres in lung tissue were longer than the crocidolite/amosite fibres. The relationship between asbestos body counts in lung tissue and in bronchoalveolar lavage fluid was similar to previous international observations. When using the asbestos body count to predict the underlying total pulmonary amphibole asbestos burden in Finnish patients, however, it should be borne in mind that the relationship between the two parameters seems to be different with anthophyllite as compared to crocidolite/amosite fibres.

In 1987-1992, the Finnish Institute of Occupational Health (FIOH) implemented a nationwide asbestos program aimed at preventing asbestos-related risks in good cooperation with governmental authorities, industry, trade unions, the health care and insurance systems, and mass media. The goals were to minimize all exposure to asbestos, identify people exposed at work, and improve the diagnostics of asbestos diseases, especially cancers. The program entailed several concrete actions and extensive dissemination of information, training, services, and scientific research. As proposed by the State Asbestos Committee, new use of asbestos products was banned and strict regulations were applied to renovation and inspection of old buildings. The screening study of asbestos-induced diseases included 18,943 current and retired workers from house building, shipyard, and asbestos industries. Pleural and parenchymal changes were found in 4,133 persons (22%), who were referred to further clinical examinations as suspected cases of an occupational disease. It was estimated that past exposure of asbestos among the Finnish population of 5 million causes > 150 mesotheliomas and lung cancers annually, totalling > 2,000 asbestos-induced cancer deaths by the year 2010. Although several major control actions were made or started during the program, the bulk of the preventive work still lies ahead.

Asthma often begins in childhood or early adulthood and is a common disease among conscripts. The identification of long-term predictive factors for persistent asthma may lead to improved treatment opportunities and better disease control.Our aim was to study the prognostic factors of the severity of asthma among 40-year-old male conscripts whose asthma began in youth.We studied 119 conscripts who were referred to the Central Military Hospital during 1987-1990 due to asthma and who attended a follow-up visit approximately 20 years later. Asthma severity was evaluated during military service according to the medical records, and 20 years later during a follow-up visit using Global Initiative for Asthma guidelines. We used the results of lung function and allergy tests at baseline as predictors of current persistent asthma.Compared with baseline, asthma was less severe at follow-up: 11.8% of subjects were in remission, 42.0% had intermittent asthma, 10.9% had mild persistent asthma, and 35.3% had moderate/severe persistent asthma (p.001). In multivariate models, a positive exercise test at baseline yielded an odds ratio (OR) of 3.2 (95% CI 1.0-9.8, p = .046), a decreased FEV1/FVC % predicted an OR of 4.0 (95% CI 1.7-9.3, p = .002), and a decreased FEF50% % predicted an OR of 2.8 (95% CI 1.3-6.4, p = .012) for current persistent asthma.About half of the men had persistent asthma at the 20-year follow-up. Positive exercise tests and obstructive spirometry results were related to the persistence of asthma and may be useful long-term prognostic factors for asthma severity.