Environmental Health and Preventive Medicine

Our medical research library holds 23 studies published in Environmental Health and Preventive Medicine (2005–2021). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 21 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Japanese Society for Hygiene
• Published: 1996 to the present, Japan
• Language: English
• ISSN: 1342-078X (print), 1347-4715 (electronic)
• Its record in the NLM Catalog

2020s

• Effect of IL-15 addition on asbestos-induced suppression of human cytotoxic T lymphocyte induction. N. Kumagai-Takei, Y. Nishimura, H. Matsuzaki, et al. 2021;26(1):50. PubMed · Publisher · Free full text

  Abstract

  Background: Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8+ T cells. Recently, we reported that asbestos-induced suppression of CTL induction is not due to insufficient levels of interleukin-2 (IL-2). In this study, we continue to investigate the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs and focus on interleukin-15 (IL-15) which is known to be a regulator of T lymphocyte proliferation.

  Methods: For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8+ T cells with fluorescence-labeled anti-CD3, anti-CD8, anti-CD45RA, anti-CD45RO, anti-CD25, and anti-granzyme B antibodies using flow cytometry. To examine the effect of IL-15 on the expression level of intracellular granzyme B in proliferating and non-proliferating CD8+ lymphocytes, PBMCs were stained using carboxyfluorescein diacetate succinimidyl ester (CFSE) and then washed and used for the MLR.

  Results: IL-15 addition partially reversed the decrease in CD3+CD8+ cell numbers and facilitated complete recovery of granzyme B+ cell percentages. IL-15 completely reversed the asbestos-induced decrease in percentage of granzyme B+ cells in both non-proliferating CFSE-positive and proliferating CFSE-negative CD8+ cells. The asbestos-induced decrease in the percentage of CD25+ and CD45RO+ cells in CD8+ lymphocytes was not reversed by IL-15.

  Conclusion: These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.

• Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes. N. Kumagai-Takei, Y. Nishimura, M. Maeda, et al. 2020;25(1):59. Review PubMed · Publisher · Free full text

  Abstract

  Asbestos exposure is known to cause malignant mesothelioma, which is associated with poor prognosis. We focused on and examined the effect of asbestos exposure on the differentiation and function of cytotoxic T lymphocytes (CTLs). CTLs have the ability to specifically attack tumor cells after being differentiated from naïve CD8+ T cells following antigen stimulation. Exposure to chrysotile B asbestos suppressed the differentiation of CTLs during the mixed lymphocyte reaction (MLR) and was associated with a decrease in proliferation of CD8+ T cells. Additionally, in an effort to investigate the mechanism associated with suppressed CTL differentiation upon exposure to asbestos, we focused on IL-2, a cytokine involved in T cell proliferation. Our findings indicated that insufficient levels of IL-2 are not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest potential improvement in the suppressed CTL function. Furthermore, the functional properties of peripheral blood CD8+ lymphocytes from asbestos-exposed individuals with pleural plaque (PP) and patients with malignant mesothelioma (MM) were examined. MM patients showed lower perforin levels in CD8+ lymphocytes following stimulation compared with PP-positive individuals. The production capacity of IFN-γ in the MM group tended to be lower compared with healthy volunteers or PP-positive individuals. In an effort to determine whether chronic and direct asbestos exposure affected the function of CD8+ T cells, cultured human CD8+ T cells were employed as an in vitro model and subjected to long-term exposure to chrysotile (CH) asbestos. This resulted in decreased levels of intracellular perforin and secreted IFN-γ. Those findings underlie the possibility that impaired CD8+ lymphocyte function is caused by asbestos exposure, which fail to suppress the development of MM. Our studies therefore reveal novel effects of asbestos exposure on CTLs, which might contribute towards the development and implementation of an effective strategy for the prevention and cure of malignant mesothelioma.

2010s

• Adverse health effects of asbestos: solving mysteries regarding asbestos carcinogenicity based on follow-up survey of a Chinese factory. E. Yano. 2018;23(1):35. Review PubMed · Publisher · Free full text

  Abstract

  The present review summarizes the results of several follow-up studies assessing an asbestos product manufacturing plant in Chongqing, China, and discusses three controversial issues related to the carcinogenicity of asbestos. The first issue is the amphibole hypothesis, which asserts that the carcinogenicity of asbestos is limited to amphiboles, such as crocidolite, but not serpentines, such as chrysotile. However, considering the possible multiple component of asbestos carcinogenicity in the presence of tobacco smoke or other carcinogens, chrysotile cannot be regarded as non-carcinogenic. Additionally, in a practical sense, it is not possible to assume "pure" chrysotile due to its ubiquitous contamination with tremolite, which is a type of amphibole. Thus, as the International Agency for Research on Cancer (IARC) assessed, all forms of asbestos including chrysotile should be regarded carcinogenic to humans (Group 1). The second issue is the chrysotile/tremolite paradox, which is a phenomenon involving predominant levels of tremolite in the lung tissues of individuals who worked in locations with negligible levels of tremolite due to the exclusive use of chrysotile. Four possible mechanisms to explain this paradox have been proposed but this phenomenon does not support the claim that amphibole is inert. The final issue discussed is the textile mystery, i.e., the higher incidence of cancer in asbestos textile plants compared to asbestos mines where the same asbestos was produced and the exposure levels were comparable. This phenomenon was first reported in North America followed by UK and then in the present observations from China. Previously, levels of fiber exposure were calculated using a universal converting coefficient to estimate the mass concentration versus fiber concentration. However, parallel measurements of fiber and mass concentrations in the workplace and exposed air indicated that there are wide variations in the fiber/mass ratio, which unjustifies the universal conversion. It is possible that contamination by airborne non-fibrous particles in mines with mass fiber conversion led to the overestimation of fiber concentrations and resulted in the textile mystery. Although the use and manufacturing of asbestos has been banned in Japan, more than 10 million tons of asbestos had been imported and the majority remains in existing buildings. Thus, efforts to control asbestos exposure should be continued.

• Inflammation and cancer. M. Murata. 2018;23(1):50. Review PubMed · Publisher · Free full text

  Abstract

  Infection and inflammation account for approximately 25% of cancer-causing factors. Inflammation-related cancers are characterized by mutagenic DNA lesions, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine. Our previous studies demonstrated the formation of 8-oxodG and 8-nitroguanine in the tissues of cancer and precancerous lesions due to infection (e.g., Opisthorchis viverrini-related cholangiocarcinoma, Schistosoma haematobium-associated bladder cancer, Helicobacter pylori-infected gastric cancer, human papillomavirus-related cervical cancer, Epstein-Barr virus-infected nasopharyngeal carcinoma) and pro-inflammatory factors (e.g., asbestos, nanomaterials, and inflammatory diseases such as Barrett's esophagus and oral leukoplakia). Interestingly, several of our studies suggested that inflammation-associated DNA damage in cancer stem-like cells leads to cancer development with aggressive clinical features. Reactive oxygen/nitrogen species from inflammation damage not only DNA but also other biomacromolecules, such as proteins and lipids, resulting in their dysfunction. We identified oxidatively damaged proteins in cancer tissues by 2D Oxyblot followed by MALDI-TOF/TOF. As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species. Dysfunction of anti-oxidative proteins due to this damage might increase oxidative stress. Such damage in biomacromolecules may form a vicious cycle of oxidative stress, leading to cancer development. Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers. We examined epigenetic alterations, DNA methylation and microRNA dysregulation, in Epstein-Barr virus-related nasopharyngeal carcinoma in the endemic area of Southern China and found several differentially methylated tumor suppressor gene candidates by using a next-generation sequencer. Among these candidates, we revealed higher methylation rates of RAS-like estrogen-regulated growth inhibitor (RERG) in biopsy specimens of nasopharyngeal carcinoma more conveniently by using restriction enzyme-based real-time PCR. This result may help to improve cancer screening strategies. We profiled microRNAs of nasopharyngeal carcinoma tissues using microarrays. Quantitative RT-PCR analysis confirmed the concordant downregulation of miR-497 in cancer tissues and plasma, suggesting that plasma miR-497 could be used as a diagnostic biomarker for nasopharyngeal carcinoma. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses. These changes may be useful biomarkers in liquid biopsy for early detection and prevention of cancer.

• Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos. H. Matsuzaki, N. Kumagai-Takei, S. Lee, et al. 2017;22(1):53. Review PubMed · Publisher · Free full text

  Abstract

  The immunological effects of asbestos exposure on various lymphocytes such as the regulatory T cell (Treg), responder CD4+ T helper cell (Tresp), CD8+ cytotoxic T lymphocytes (CTL), and natural killer (NK) cells were investigated. Results show that asbestos exposure impairs antitumor immunity through enhancement of regulatory T cell function and volume, reduction of CXCR3 chemokine receptor in responder CD4+ T helper cells, and impairment of the killing activities of CD8+ cytotoxic T lymphocytes (CTL) and NK cells. These findings were used to explore biological markers associated with asbestos exposure and asbestos-induced cancers and suggested the usefulness of serum/plasma IL-10 and TGF-β, surface CXCR3 expression in Tresp, the secreting potential of IFN-γ in Tresp, intracellular perforin level in CTL, and surface expression NKp46 in NK cells. Although other unexplored cytokines in serum/plasma and molecules in these immunological cells, including Th17, should be investigated by experimental procedures in addition to a comprehensive analysis of screening methods, biomarkers based on immunological alterations may be helpful in clinical situations to screen the high-risk population exposed to asbestos and susceptible to asbestos-related cancers such as mesothelioma.

• Elemental and immunohistochemical analysis of the lungs and hilar lymph node in a patient with asbestos exposure, a pilot study. Y. Koga, T. Satoh, K. Kaira, et al. 2016;21(6):492-500. PubMed · Publisher · Free full text

  Abstract

  Objectives: Studies have shown that inhaled mine dust, such as asbestos, can be translocated to various organs including the lymph nodes. Recently, we have established a protocol that enables us to identify inhaled elements using paraffin embedded lung specimens by in-air microparticle-induced X-ray emission (micro-PIXE). However, little research has examined the concentration of these inhaled fibers in various organs or the mechanisms of their translocation. In this study, we compared the concentration of inhaled fibers in the lung parenchyma to the concentration in the hilar lymph node as well as to determine the elemental spatial distribution of the inhaled fibers in a patient with occupational asbestos exposure.

  Methods: Lung tissues and hilar lymph node in a patient with asbestos exposure were used in this study. Elemental analysis was performed by in-air micro-PIXE. Immunohistochemical analysis was performed using anti CD163, smooth muscle actin, vimentin and β-catenin antibody.

  Results: The analysis revealed that the amount of inhaled silicon was approximately 6 times higher in the lymph node than in the lungs. The spatial analysis showed that silicon, iron and aluminium were co-localized in the hilar lymph node. The immunohistochemical analysis showed localized agreement of the inhaled fibers with macrophages, smooth muscle actin, and vimentin in the hilar lymph node.

  Conclusions: This study showed that in-air micro-PIXE could be useful for analyzing the elemental distribution and quantification of inhaled fibers in the human body. Furthermore, immunohistochemistry in combination with in-air micro-PIXE analyses may help to determine the mechanism of mine dust distribution in vivo.

• Environmental factors and human health: fibrous and particulate substance-induced immunological disorders and construction of a health-promoting living environment. T. Otsuki, H. Matsuzaki, S. Lee, et al. 2016;21(2):71-81. Review PubMed · Publisher · Free full text

  Abstract

  Among the various scientific fields covered in the area of hygiene such as environmental medicine, epidemiology, public health and preventive medicine, we are investigating the immunological effects of fibrous and particulate substances in the environment and work surroundings, such as asbestos fibers and silica particles. In addition to these studies, we have attempted to construct health-promoting living conditions. Thus, in this review we will summarize our investigations regarding the (1) immunological effects of asbestos fibers, (2) immunological effects of silica particles, and (3) construction of a health-promoting living environment. This review article summarizes the 2014 Japanese Society for Hygiene (JSH) Award Lecture of the 85th Annual Meeting of the JSH entitled "Environmental health effects: immunological effects of fibrous and particulate matter and establishment of health-promoting environments" presented by the first author of this manuscript, Prof. Otsuki, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan, the recipient of the 2014 JSH award. The results of our experiments can be summarized as follows: (1) asbestos fibers reduce anti-tumor immunity, (2) silica particles chronically activate responder and regulatory T cells causing an unbalance of these two populations of T helper cells, which may contribute to the development of autoimmune disorders frequently complicating silicosis, and (3) living conditions to enhance natural killer cell activity were developed, which may promote the prevention of cancers and diminish symptoms of virus infections.

• Erratum to: High-risk mesothelioma relation to meteorological and geological condition and distance from naturally occurring asbestos. A. Abakay, A.C. Tanrikulu, M.S. Imamoglu, et al. 2016;21(2):91. PubMed · Publisher · Free full text

• High-risk mesothelioma relation to meteorological and geological condition and distance from naturally occurring asbestos. A. Abakay, A.C. Tanrikulu, M. Ayhan, et al. 2016;21(2):82-90. PubMed · Publisher · Free full text

  Abstract

  Objectives: Very few studies have investigated the incidence and risk of malignant mesothelioma (MM) associated with distinct sources of asbestos exposure, especially exposure to naturally occurring asbestos (NOA).

  Methods: Subjects were MM, lung, and breast cancer patients who were diagnosed and followed in Diyarbakir Province between 2008 and 2013. The birthplaces of patients were displayed on a geologic map. Geological and meteorological effects on MM were analyzed by logistic regression.

  Results: A total of 180 MM, 368 breast, and 406 lung cancer patients were included. The median distance from birthplace to ophiolites was 6.26 km for MM, 31.06 km for lung, and 34.31 km for breast cancer (p < 0.001). The majority of MM cases were seen within 20 km from NOA areas. The MM incidence inside of NOA was 1059/100.000, and out of NOA was 397/100.000; this difference was significant (p = 0.014). The largest concentration of MM residential areas was within ± 30° (34 residential areas 36.6%) of the dominant wind direction. Most MM patients were found in or near the dominant wind direction, especially in the acute angle defined by the dominant wind direction. MM incidence was directly proportional to {[area of NOA (km(2))] * [cosine α of wind direction angle]} and was inversely proportional to the square of the distance (R = 0.291, p = 0.023).

  Conclusions: MM was higher near NOA and in the downwind direction. MM incidence and risk were affected by geological and meteorological factors.

• Prognostic value of the lymphocyte-to-monocyte ratio and other inflammatory markers in malignant pleural mesothelioma. A.C. Tanrikulu, A. Abakay, H. Komek, et al. 2016;21(5):304-311. PubMed · Publisher · Free full text

  Abstract

  Objectives: Inflammation plays a role in malignant pleural mesothelioma (MPM) prognosis and symptoms. We investigated the roles of the new and old inflammatory indexes and markers in MPM prognosis.

  Methods: Two hundred and ninety-two MPM patients (167 male and 125 female) were included in this retrospective study. Demographic parameters were collected from the patients' files. Kaplan-Meier curves and multivariate Cox regression analyses were used for the analysis of prognosis.

  Results: The mean age of the patients was 58.4 years. The mean survival time was 14.6 ± 13.0 months. Twenty-four potential prognostic factors associated with a poor outcome were calculated in the univariate analysis, and 16 potential prognostic factors were associated with a poor prognosis. These 16 potential prognostic factors were also analyzed in multivariate analysis. Multivariate analysis showed that increased age, stage 3-4 disease, the non-epithelial type, a low Karnofsky performance score, a high white blood cell count, and a low lymphocyte-to-monocyte ratio (LMR) were associated with a poor prognosis. The results of the multivariate analysis showed that a decreased LMR was associated with poor survival. Patients with LMR ≤2.6 had poor survival compared with those with LMR >2.6 (mean 9.6 vs. 17.0 months, respectively; p = 0.004).

  Conclusions: LMR is an independent marker of prognosis in patients with MPM and is superior to the other inflammation-based markers. The inexpensive nature and easy reproducibility of the hemogram should encourage the use of the LMR in clinical practice.

• Mesothelin (MSLN) methylation and soluble mesothelin-related protein levels in a Chinese asbestos-exposed population. M. Yu, Y. Zhang, Z. Jiang, et al. 2015;20(5):369-78. PubMed · Publisher · Free full text

  Abstract

  Objectives: This study investigated the mesothelin (MSLN) methylation and its relationship with soluble mesothelin-related protein (SMRP) levels in participants stratified by asbestos exposure scenarios and benign asbestos-related diseases (ARDs).

  Methods: The presence of benign ARDs was confirmed through chest X-ray and the asbestos exposure history was obtained using a standardized questionnaire in this study, including 262 participants. Sera SMRP were measured using MESOMARK, and MSLN methylation in genomic DNA extracted from whole blood was detected by real-time methylation-specific PCR. Covariates were compared with SMRP concentrations using correlation analysis and the potential covariates affecting SMRP were determined by multiple linear regression analysis, and the distribution of methylation status was analyzed by Chi-square test.

  Results: There was a trend toward elevation of SMRP values in healthy individuals exposed to asbestos as compared with those without asbestos exposure. The highest median level of SMRP was 1.3 nM in subjects with asbestosis, followed by cases with pleura plaque and asbestosis (1.2 nM), pleura plaque (0.9 nM), healthy subjects with occupational exposure (0.9 nM), non-occupational exposure (0.8 nM), and mixed exposure (0.8 nM). Within asbestosis cases, those with higher profusion scores had higher SMRP values than those with lower profusion scores (1.6 vs. 0.8 nM). Based on multi-regression analysis, the trend toward elevation of SMRP remained significant in subjects with occupational exposure or in those with asbestosis, as compared with healthy subjects without exposure (p < 0.01), although body mass index had an effect on SMRP (p < 0.0001). Regardless of the differences in SMRP levels among these subgroups, MSLN methylation ranged from 80.5 to 92.5 %, with no significant difference. The elevated level of SMRP in asbestosis with higher profusion scores could not be attributed to low MSLN methylation status.

  Conclusions: Our findings suggest that the elevation of SMRP is related to asbestos exposure and benign ARDs especially for cases with high profusion scores, which is independent of MSLN methylation.

• Silica exposure and altered regulation of autoimmunity. S. Lee, H. Matsuzaki, N. Kumagai-Takei, et al. 2014;19(5):322-9. Review PubMed · Publisher · Free full text

  Abstract

  Silica particles and asbestos fibers, which are known as typical causatives of pneumoconiosis, induce lung fibrosis. Moreover, silicosis patients often complicate with autoimmune diseases, and asbestos-exposed patients suffer from malignant diseases such as pleural mesothelioma and lung cancer. We have been conducting experimental studies to investigate altered regulation of self-tolerance caused by silica exposure, including analyses using specimens such as plasma and immunocompetent cells obtained from silicosis patients, as a means of examining the supposition that silica exposure induces molecular and cellular biological alterations of immune cells. These approaches have resulted in the detection of several specific autoantibodies, alterations of CD95/Fas and its related molecules, and evidence of chronic activation of responder T cells and regulatory T cells following silica exposure. In this review, we present details of our investigations as an introduction to scientific approaches examining the immunological effects of environmental and occupational substances.

• Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases. Y. Nishimura, M. Maeda, N. Kumagai-Takei, et al. 2013;18(3):198-204. Review PubMed · Publisher · Free full text

  Abstract

  Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-β) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma.

• Cytotoxicity and solubility evaluation of two types of whiskers by cell magnetometry. Y. Kudo, Y. Aizawa. 2011;16(5):327-34. PubMed · Publisher · Free full text

  Abstract

  Objectives: We investigated two types of whiskers, an antimony-containing tin-oxide-coated aluminum borate whisker (CABW) and an aluminum borate whisker (ABW), which are asbestos substitutes, in order to evaluate the safety of these fibers.

  Methods: The cytotoxicity and solubility of CABW and ABW were evaluated by cell magnetometry, LDH assay and solubility test.

  Results: ABW was found to be cytotoxic by cell magnetometry and slightly less soluble than CABW. In addition, it was found that the solubility of both fibers was intermediate between that of chrysotile and rock wool, as compared to our previous test results. Regarding the LDH assay, no significant difference was found among the fibers tested. These findings suggested that CABW, the surface of which is coated with antimony-containing tin oxide, had lower cytotoxicity and slightly higher solubility than ABW.

  Conclusions: This study was only a short-term cytotoxicity and solubility study. Therefore, further safety assessment should be carried out in long-term experiments to examine the half-life of these fibers and monitor the potential development of lung carcinoma or mesothelioma after intratracheal instillation of these fibers in rats.

2000s

• Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases. S. Murakami, Y. Nishimura, M. Maeda, et al. 2009;14(4):216-22. PubMed · Publisher · Free full text

  Abstract

  This review is partly composed of the presentation "Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases" delivered during the symposium "Biological effects of fibrous and particulate substances and related areas" organized by the Study Group of Fibrous and Particulate Studies of the Japanese Society of Hygiene and held at the 78th Annual Meeting in Kumamoto, Japan. In this review, we briefly introduce the results of recent immunological analysis using the plasma of silica and asbestos-exposed patients diagnosed with silicosis, pleural plaque, or malignant mesothelioma. Thereafter, experimental background and speculation concerning the immunological pathophysiology of silica and asbestos-exposed patients are discussed.

• Asbestos and malignant mesothelioma: foreword. Reviews of a symposium entitled "Malignant Mesothelioma" organized by the Study Group on Fibrous and Particulate Substances of the 77th Annual Meeting of the Japanese Society for Hygiene, 2007. T. Otsuki. 2008;13(2):53-4. PubMed · Publisher · Free full text

• Current therapies for malignant pleural mesothelioma. T. Nakano. 2008;13(2):75-83. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a highly lethal tumor derived from mesothelial cells, and its global incidence is increasing because of widespread exposure of numerous individuals to asbestos in the last 50 years. Mesothelioma is largely untreatable with any of the therapeutic modalities. Recently, a novel multitargeted antifolate pemetrexed has shown promising activity against malignant pleural mesothelioma, producing response rates of up to 40% when used in combination with cisplatin. In a large phase III study, use of a combination of pemetrexed and cisplatin was associated with significantly improved survival time and with greater antitumor activity compared with cisplatin alone. This combination also gave a significant response rate of approximately 50% in patients with epithelioid malignant pleural mesothelioma. These clinical benefits of pemetrexed-cisplatin doublet have changed the perception of mesothelioma chemotherapy. Other combinations, including gemcitabine in combination with cisplatin, have also shown encouraging response rates. Prognosis depends on gender, clinical stage of the tumor, histological subtype, platelet count, leukocyte counts, and performance status. Radiotherapy can palliate mesothelioma patients with chest pain, and has been indicated to be of benefit for the prevention of malignant seeding along the tract of a chest tube or needle biopsy. Trimodality treatment using extrapleural pneumonectomy, radiation and chemotherapy has shown promising therapeutic value. The development of chemotherapeutic regimens and the favorable outcomes of trimodality have led to new combined modality trials. In Japan, multicenter national trials against mesothelioma will begin in the near future.

• Diagnostic tumor marker of asbestos-related mesothelioma. O. Hino, M. Maeda. 2008;13(2):71-4. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is an aggressive tumor arising from the mesothelium, and is usually associated with previous exposure to asbestos. The incubation period of the tumor may be described as 30-40 years, and the prognosis is dismal. We previously discovered the Erc (Expressed in renal carcinoma) gene in the Eker rat model (Tsc2 gene mutant) and it was a homolog of the human mesothelin/MPF gene. We developed a novel ELISA system (N-ERC/mesothelin). Recently, we found that N-ERC/mesothelin was a potentially useful diagnostic marker for asbestos-related mesothelioma.

• Immunological alterations found in mesothelioma patients and supporting experimental evidence. Y. Miura, Y. Nishimura, M. Maeda, et al. 2008;13(2):55-9. PubMed · Publisher · Free full text

  Abstract

  It is common knowledge that exposure to asbestos causes asbestos-related diseases, such as asbestosis, lung cancer and malignant mesothelioma, not only in people who have had long-term contact with asbestos in their work environment but also in residents living near factories that handle asbestos. Since the summer of 2005, these revelations turned into a large medical problem and caused and social unrest. We have focused on the immunological effects of both asbestos and silica on the human immune system. In this brief review, we introduce immunological alterations found in patients with malignant mesothelioma and describe the experimental background in which these were found. Analyzing the immunological effects of asbestos may improve our understanding of the biological effects of asbestos.

• Molecular biology of malignant mesothelioma. Y. Sekido. 2008;13(2):65-70. PubMed · Publisher · Free full text

  Abstract

  Human malignancies develop via a multi-step that involves the accumulation of several key gene alterations with associated genetic and epigenetic events. Although malignant mesothelioma (MM) has been demonstrated to be clearly correlated with asbestos exposure, it remains poorly understood how asbestos fibers confer key gene alterations and induce cellular transformation in normal mesothelial cells, which results in the acquisition of malignant phenotypes, including deregulated cell proliferation and invasion. Malignant mesothelioma presents with the frequent inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) on chromosome 9p21 and neurofibromatosis type 2 (NF2) on chromosome 22q12, with the latter being responsible for the NF2 familial cancer syndrome. In contrast, MM shows infrequent mutation of the p53 gene, which is one of the most frequently mutated tumor suppressor genes in human malignancies. Genetic abnormalities of oncogenes have also been studied in MM, but no frequent mutations have been identified, including the epidermal growth factor receptor (EGFR) and K-RAS genes. Recent studies have suggested the activation of other receptor tyrosine kinases, including Met, and the deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, although the alterations responsible for their activation are still not clear. Thus, further genome-wide studies of genetic and epigenetic alterations as well as detailed analyses of deregulated signaling cascades in MM are necessary to determine the molecular mechanisms of MM, which would also provide some clues for establishing a new molecular target therapy for MM.

• Pathology of mesothelioma. K. Inai. 2008;13(2):60-4. PubMed · Publisher · Free full text

  Abstract

  The incidence of mesothelioma has been gradually increasing in Japan, and the underlying factor for this is considered to be the increase in the amount of asbestos imported into Japan between 1960 and 1975. Mesothelioma can be roughly divided into localized and diffuse types, but the former is extremely rare. In making a diagnosis of mesothelioma, it is important to confirm the location of tumor and the specific gross findings before histological examination. Mesothelioma can be categorized histologically as epithelioid type, sarcomatoid type, biphasic type, desmoplastic type, among others. It can take many forms; consequently, there are many diseases to be differentiated when the diagnosis of mesothelioma is based on histological analyses. Immunohistochemical stains are useful for making a diagnosis, but the correct combination of antibodies as positive or negative markers should be selected and a comprehensive assessment of the staining results is necessary. The accuracy of the pathological diagnosis is very important to the patients because they can be receive official compensation or relief when the diagnosis of mesothelioma is confirmed. Under present conditions, both clinicians and pathologists must make a concerted effort to improve the accuracy of the diagnosis of mesothelioma.

• Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006) : -Pathophysiological Development and Immunotoxicology: what we have found from research related to silica and silicate such as asbestos-. T. Otsuki, Y. Miura, M. Maeda, et al. 2007;12(4):153-60. PubMed · Publisher · Free full text

  Abstract

  Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

• Behavior of new type of rock wool (HT wool) in lungs after exposure by nasal inhalation in rats. Y. Kudo, K. Shibata, T. Miki, et al. 2005;10(5):239-48. PubMed · Publisher · Free full text

  Abstract

  Objectives: Previous types of rock wool has been recently replaced with high-temperature wool (HT wool). HT wool is characterized by a chemical composition with a higher concentration of Al(2)O(3) and a lower concentration of SiO(2), lower biopersistence, and a higher melting point than previous types of rock wool. To evaluate the safety of HT wool, an asbestos substitute, we examined the biopersistence of HT wool in the lungs, based on changes in fiber count according to the length and fiber size (length and width), by performing a nose-only inhalation exposure study in rats.

  Methods: Male Fischer 344 rats were exposed to fibers at the target exposure concentration of 30 mg/m(3) continuously for 3 hours daily for 5 consecutive days. Rats were sacrificed shortly after exposure, and 1, 2, and 4 weeks after exposure, and their lung tissues were incinerated at a low temperature. Then, fiber counts and sizes in the lungs were analyzed using a phase contrast microscope.

  Results: The fiber count in the lungs 4 weeks after exposure significantly decreased from the baseline value (shortly after exposure). The half-life of fibers calculated from the approximation curve was 34 days for all fibers and 11 days for fibers longer than 20 μm.

  Conclusions: Both the length and width significantly decreased 4 weeks after exposure, probably because fibers were ingested by alveolar macrophages, discharged to outside of the body by mucociliary movement, or lysed by body fluid. In future studies, it is necessary to examine the long-term persistence of fibers in the lungs.

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