Evidence Suggesting the End of Universal Domestic Asbestos Exposure in Metsovo, NW Greece.

BACKGROUND: Inhabitants of Metsovo, NW Greece, had been domestically exposed to asbestos from a gradually abandoned whitewash ("luto") that resulted in a declining epidemic of malignant mesothelioma. OBJECTIVES: We aimed to evaluate whether other sources of asbestos exposure exist following "luto" abandonment. METHODS: Chest computed tomography (CT) and bronchoalveolar lavage (BAL) were used to evaluate residual asbestos exposure in younger Metsovites through the identification of pleural calcifications and asbestos bodies, respectively. In order to provide a historical universally exposed group for comparison, we used the accumulated chest CTs and chest roentgenograms of our previous studies, performed in Metsovites with confirmed exposure but negative chest roentgenogram. As an additional external comparison group, we also assessed CT scans and chest roentgenograms of Metsovites being older than our target group obtained from the records of the Radiology Department between 2009 and 2011. In order to be able to compare our BAL findings, we sought historical controls among BAL studies performed in Metsovites with known exposure to "luto," in the 1980s-1990s, mainly to evaluate alveolitis. Those belonging to individuals of the same age range were used for further comparison. RESULTS: Twenty-two Metsovites born between 1960 and 1980 consented to undergo a chest CT scan, while another 14 CTs were retrieved from the records of the Radiology Department (among 86 of all ages), thus increasing the number of individuals studied to 36. Five of the 36 Metsovites studied were former "luto" users for a short period of time. Minimal pleural calcifications were present in 2 of them, while all chest CTs of nonusers were negative. All 8 BAL studies were negative for asbestos bodies. CONCLUSION: "Luto" use seems to have been the only source of considerable asbestos exposure in Metsovo.

The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment.

Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

Immunohistochemical expression patterns of neural and neuroendocrine markers, the neural growth factor receptors and the beta-tubulin II and IV isotypes in human thymus.

Increasing evidence suggests that neuroimmune networks play key roles in the thymic histophysiology and pathology. Prompted by this, we analyzed by immunohistochemistry the distribution of human thymic cells expressing major neural and neuroendocrine markers and neural growth factor (NGF) receptors in combination with the expression patterns of various cytokeratins. Additionally, since some beta-tubulin isotypes are preferentially expressed in neuronal cells, the immunotopographical distribution of thymic cells expressing beta-tubulin II, III and IV was analyzed. Thymic epithelial cells (TECs) expressed protein gene product 9.5 (PGP 9.5), chromogranin A (CHRA), synaptophysin (SYN), neuron-specific enolase (NSE), tyrosine hydroxylase (TH), CD56, CD57, neurofilaments (NF) (140-160 kDa), NGF receptors (TrKA and p75), beta-tubulin II and IV isotypes and cytokeratin 7, 8, 10, 13, 14, 18 and 19. PGP 9.5 was preferentially expressed in cortical TEC whereas SYN, CHRA, NSE, TH and NF 140-160 kDa were preferentially expressed in medullary TECs and Hassal corpuscles. Variable levels of expression of beta-tubulin II and IV were observed in all TEC subtypes whereas beta-tubulin III was undetectable in TECs. Subcapsular and cortical TECs display higher expression of beta-tubulin IV and lower expression of beta-tubulin II in comparison to those observed in medullary TEC and Hassal corpuscles. The diversity of the immunotopographical distibution and the expression of neural and neuroendocrine markers, the NGF receptors TrKA and p75, and the beta-tubulin II and IV isotypes in the distinct subtypes of TEC may reflect the diversity of their biological functions and/or their different stages of differentiation. The present results provide further immunohistological evidence that numerous neural and neuroendocrine factors may be required for the development and function of the human thymic microenvironment.

Decreasing prevalence of pleural calcifications among Metsovites with nonoccupational asbestos exposure.

STUDY OBJECTIVES: Twenty years ago, we reported on a very high prevalence of pleural calcifications (PCs) and malignant mesothelioma among inhabitants of Metsovo, in northwestern Greece. It was shown that both abnormalities were related to asbestos exposure from a whitewash containing tremolite. The fading use of this material has resulted in a decreased incidence of mesothelioma (one third of the original incidence). The aim of the present study was to examine whether PCs among Metsovites has followed a similar trend. DESIGN: Retrospective study. SETTINGS: University Hospital of Ioannina, a tertiary teaching hospital, "G. Hadjikosta" Hospital, a tertiary hospital in Ioannina, and Metsovo Health Center, a primary care center in the town of Metsovo. PATIENTS: Chest roentgenograms of 307 Metsovites, obtained between from 1998 to 2002 were examined. The prevalence of PCs was compared to the one noted 20 years ago. RESULTS: A significantly lower prevalence of calcifications was observed now among younger Metsovites (< 60 years of age). In both studies, there was an increasing rate of PC with age. CONCLUSIONS: The findings of the present study strengthen the incrimination of the whitewash containing tremolite in the development of PCs in Metsovites. The withdrawal of its use in the area has resulted in a null prevalence of PCs in individuals < 40 years old.

Additional proteins in BAL fluid of Metsovites environmentally exposed to asbestos: more evidence of "protection" against neoplasia?

INTRODUCTION: Inhabitants of Metsovo in northwest Greece have been exposed to asbestos from use of a tremolite-containing whitewash ("luto" soil). As a result, they have increased incidence of malignant pleural mesothelioma and pleural calcifications (PCs). However, subjects with calcifications have a much lower incidence of mesothelioma than those without. A previous study of the two groups with BAL revealed higher proportional lymphocytosis among subjects with calcifications. We suggested that BAL lymphocytosis may be somehow correlated with "protection" against neoplasia. METHODS: The present report is a study of the liquid phase of BAL in the two groups. BAL specimens of 43 Metsovites (13 subjects with PCs and 30 subjects without PCs) and two control groups were examined. We measured total protein, albumin, IgG, IgA, and interleukin-6. Proteins were analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional electrophoresis and further characterized using an appropriate computer program. RESULTS: The most interesting finding was the presence of two additional protein spots corresponding to the electrophoretic site of Ig heavy chain and C(4) component of complement. The two proteins were present in all Metsovites with PCs but in none without PCs and also in none of the control groups. CONCLUSION: This study further separates two groups of Metsovites with different reaction to asbestos, possibly as a result of different activation of alveolar macrophages. This difference leads the first group to the formation of PCs, BAL fluid lymphocytosis, and relative "protection" against malignancy, and the second group to no calcifications, no lymphocytosis, but also no protection against malignancy.

Volume and flow dependence of respiratory mechanics in mechanically ventilated COPD patients.

Volume and flow dependencies of respiratory mechanics are examined in 10 COPD patients under mechanical ventilation (MV) at 3 levels of externally applied PEEP (PEEPe). Airways pressure (Paw), flow (V') and volume (V) data are analyzed according to (1) the linear and (2) a non-linear model, accounting for volume dependence of elastance and for flow and volume dependence of resistance. The models' fitness to data is assessed by the regression errors. Non-linear modelling fits significantly better to data, while the difference of fitness decreases with PEEPe. Linear mechanics are not significantly different between the 3 levels of PEEPe. A positive volume dependence of elastance observed at 0, decreases at 5 and increases again at 10 hPa of PEEPe. A seriously negative volume dependence of resistance at 0 turned to positive with PEEPe. These dependencies of respiratory mechanics during COPD under MV, show that the present non-linear respiratory mechanical monitoring may help for better and less risky adjustment of PEEPe.

Soluble adhesion molecules E-cadherin, intercellular adhesion molecule-1, and E-selectin as lung cancer biomarkers.

BACKGROUND: Altered levels of circulating adhesion molecules found in several carcinomas, including lung cancer, reflect local loss of diffusion barriers and tumor volume and can be potentially used as biomarkers. In the present study, we investigated the role of soluble E-cadherin (sE-cad), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-sel) as biomarkers in lung cancer. METHODS: Sixty-two patients with recently diagnosed lung cancer, 42 with small cell lung cancer (SCLC), and 20 with non-small cell lung cancer (NSCLC), as well as 29 healthy volunteers were enrolled. Blood samples were collected at the time of diagnosis and measurement of soluble adhesion molecules in the serum samples was performed by enzyme-linked immunoassay using monoclonal antibodies against E-cadherin, E-selectin, and ICAM-1. RESULTS: Serum levels of sE-cad, sE-sel, and sICAM-1 in both SCLC and NSCLC were significantly elevated compared with control subjects (P < .001). In addition, patients with SCLC or NSCLC with distant metastasis had a marked increase of sE-Cad (P < .001), but no such correlation with sE-sel and sICAM-1 was found. CONCLUSIONS: Our findings suggest that sE-cad, sE-sel, and sICAM-1 have an adjunctive diagnostic role in lung cancer. Furthermore, sE-cad may also have a prognostic role and could be a useful biomarker in the prediction of lung cancer outcome.

Proteome analysis of bronchoalveolar lavage in individuals from Metsovo, nonoccupationally exposed to asbestos.

Inhabitants of Metsovo, NW Greece, have been exposed to an asbestos whitewash, resulting in malignant pleural mesothelioma (MPM) and pleural calcifications (PCs). Interestingly, those with PCs (PC(+)) are less prone to MPM. They also have lymphocytic alveolitis, and differences in bronchoalveolar lavage (BAL) proteins, compared with those without pleural calcifications (PC(-)). This may mean a different response to the fiber leading to different susceptibility to neoplasia. To further evaluate this, a proteomic analysis of BAL proteins was performed. Proteomic analysis (2D-electrophoresis/Mass Spectrometry) of BAL in Metsovites nonoccupationally exposed to asbestos revealed increased albumin fragments, alpha1-antitrypsin, S100-A9 and HSP27, suggesting ongoing inflammation. In those without pleural calcifications, increased expression of acid ceramidase, glutathione-S-transferase and presence of calcyphosin, all involved in cell cycle regulation and death as well as in the detoxification of mutagenic and toxic agents, lend further support to our thesis of possible "protection against neoplasia" in Metsovites with pleural calcifications.