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Despite advances in understanding of the biology of malignant pleural mesothelioma (MPM), the prognosis of this malignancy remains poor. Although asbestos still remains the main pathogenic agent of MPM, other asbestos-like fibers such as fluoro-edenite (FE) fibers, induce MPM. Notable incidence and mortality rates of MPM have been found in Biancavilla, Italy, where FE fibers have been extracted from building materials for >50 years. Cyclic adenosine monophosphate (cAMP) is a secondary messenger that plays a key role in several physiological and pathological mechanisms regulating protein kinase A (PKA) and the CREB pathway. Hyperactivation of the cAMP/PKA/CREB pathway is involved in many neoplastic processes, including tumor cell proliferation, invasion and metastatic spread. The present study investigated immunohistochemical expression of cAMP in patients with FE-induced MPM, which included six males and four females with an age range of 50-93 years. There was high immunoexpression of cAMP in 5 out of 10 tumors while the remaining 5 cases showed low immunoexpression. In addition, there was a correlation between cAMP overexpression and decreased survival times (mean overall survival times, 7.5 months in high expression group vs. 18 months in low expression group).

Background An increased incidence of pleural mesotheliomas in Biancavilla (Italy) was attributed to the environmental exposure to fluoro-edenite (FE). Results from the Ramazzini Institute (RI) in vivo long-term study confirmed the evidence that exposure to FE fibres is correlated with an increase of malignant pleural mesotheliomas in Sprague–Dawley rats. Recently asbestosis-like features were substantiated in Biancavilla residents without known occupational exposures. Aim of this work was to establish whether FE induce lung fibrosis with a pathogenetic mechanism similar to other asbestiform fibres. Methods Original slides from the RI study were systematically re-examined to characterize the FE-induced lesions. Quantitative analysis of lung fibrosis was assessed following the Ashcroft method. Immunohistochemical analysis of protein involved in fibrotic responses and histochemical staining for FE-fibres identification were performed. Results Like asbestos, FE caused fibrotic lesions, pleural plaques or nodules and mesotheliomas. A significant increase of lung fibrosis ( p  < 0.001) was observed in the FE-treated groups compared to untreated controls. In the fibrotic responses to FE, vimentin was the most expressed protein, followed by collagen-I and alpha-SMA. Finally, ferruginous bodies, characterized by iron deposits and ferritin expression, were observed in FE-induced lesions. Conclusions This study confirmed that FE exposure promotes the onset of fibrotic lesions at pleural level, as fibrous plaques or nodules and fibrosis, through a mechanism similar to other form of asbestos. These results combined with epidemiological study reported in Biancavilla residents, corroborate the need to promote health and epidemiological surveillance plans of respiratory diseases in population living in FE contaminated sites.

Several decades have passed since Wagner et al demonstrated a causal link between asbestos fibre inhalation and the development of pleural mesothelioma in 1960. It was later suggested that pleural plaques are a benign consequence of exposure to these fibres. Most recently, a significant association between exposure to asbestos and cancer diagnosed at various sites, such as the peritoneum, stomach, pharynx, colon and ovaries has been demonstrated. The great concerns about public health that arose from the scientific evidence presented above have led to the banning of asbestos in several countries. Over the years, the suspicion that particles with a high aspect ratio may have asbestos-like pathogenicity has been supported by increasing evidence. Natural occurring minerals, as well as man-made fibres, have proven capable of inducing either chronic inflammation of serous membranes, or, in some cases, the development of peritoneal and pleural mesothelioma. The pathogenic role of both fluoro-edenite and carbon nanotubes, two 'asbestos-like' fibres is summarized and discussed in this review. The data presented herein support the notion that occupational exposure to these two types of fibre contributes to the development of different types of cancer.

The Serine and Arginine-Rich Splicing Factor 1 (SRSF1) has a proto-oncogenic function, being associated with angiogenesis and frequently overexpressed in many human malignant neoplasms. Its immunohistochemical expression has never been investigated in malignant pleural mesothelioma (MPM). We evaluated SRSF1 immunoexpression and its possible relation to angiogenesis in a selected cohort of 10 fluoro-edenite(FE)-induced MPM cases. Methods: Immunohistochemical analyses with an anti-SRSF1 antibody were performed. We interpreted the cases as positive if tumor cell nuclei were stained; a semi-quantitative analysis of the cases was performed by evaluating the intensity of staining and the percentage of tumor positive cells. A microvessel density (MVD) count was also performed. Results: High and low immunoexpressions of SRSF1 were seen in six and four MPMs, respectively. A trend of shorter overall survival was found in FE-induced MPM patients with SRSF1 overexpression. In addition, a significant association between high-MVD and high SRSF1 immunoexpression (p = 0.0476) was found. Conclusions: SRSF1 appears to be involved in MPM pathogenesis and its immunoexpression may represent a prognostic biomarker capable of identifying subgroups of patients with different prognosis. However, given the preliminary nature of the present study, further investigations on larger series, and additional in vitro studies, are required to validate our findings.

Microanalysis of Fe3+/ΣFe in geological samples using synchrotron-based X-ray absorption spectroscopy has become routine since the introduction of standards and model compounds. Existing calibrations commonly use least-squares linear combinations of pre-edge data from standard reference spectra with known coordination number and valence state acquired on powdered samples to avoid preferred orientation. However, application of these methods to single mineral grains is appropriate only for isometric minerals and limits their application to analysis of in situ grains in thin sections. In this work, a calibration suite developed by acquiring X-ray absorption near-edge spectroscopy (XANES) data from amphibole single crystals with the beam polarized along the major optical directions (X, Y, and Z) is employed. Seven different methods for predicting %Fe3+ were employed based on (1) area-normalized pre-edge peak centroid, (2) the energy of the main absorption edge at the location where the normalized edge intensity has the highest R2 correlation with Fe3+/ΣFe, (3) the ratio of spectral intensities at two energies determined by highest R2 correlation with Fe3+/ΣFe, (4) use of the slope (first derivative) at every channel to select the best predictor channel, (5 and 6) partial least-squares models with variable and constant numbers of components, and (7) least absolute shrinkage and selection operator models. The latter three sophisticated multivariate analysis techniques for predicting Fe3+/ΣFe show significant improvements in accuracy over the former four types of univariate models. Fe3+/ΣFe can be measured in randomly oriented amphibole single crystals with an accuracy of ±5.5-6.2% absolute. Multivariate approaches demonstrate that for amphiboles main edge and EXAFS regions contain important features for predicting valence state. This suggests that in this mineral group, local structural changes accommodating site occupancy by Fe3+ vs. Fe2+ have a pronounced (and diagnostic) effect on the XAS spectra that can be reliably used to precisely constrain Fe3+/ΣFe.

•In Italy, between 2003 and 2014, 16,086 persons died for malignant mesothelioma.•Mesothelioma annual mortality rates: 3.65/100,000 in men, 1.09 in women.•81.8% of mesothelioma deaths in men and 79.5% in women are pleural mesothelioma.•High risks were detected close industrial asbestos sources.•Occupational, environmental, domestic asbestos exposure routes can be hypothesized. Malignant mesothelioma (MM) is causally linked to asbestos exposure with an estimated etiological fraction of 80% or more. Standardized rates of all mesothelioma (C45, ICD-10) and malignant pleural mesothelioma (C45.0, ICD-10) mortality in Italy were computed at national and regional levels, for the period 2003–2014. Standardized Mortality Ratios (SMRs, with 95% Confidence Intervals) were calculated for each of the 8047 Italian municipalities, for both diseases, with respect to Regional figures. A geographical clustering analysis at municipal level was performed, applying SatScan methods. In Italy, 16,086 persons (about 1,340/year) died for MM, in analysed period. National Standardized rates of MM mortality are 3.65/100,000 in men and 1.09/100,000 in women, with an increasing annual trend, among male population. The highest rates were found in men from Northern Regions. Significant clusters (p < 0.10) were found corresponding to areas that hosted major asbestos-cement plants, naval shipyards, petrochemical plants and refineries. Furthermore, excesses were found corresponding to chemical and textile industries; the latter involving, particularly, female population. Excesses were found also in areas near the chrysotile mine of Balangero, and in Biancavilla, a town with a stone quarry contaminated by fluoro-edenitic fibres; an excess of MM mortality was observed among male population living in a minor island where a Navy shipyard is located. Mortality for mesothelioma in Italy is still increasing, twenty-six years after the asbestos ban. Epidemiological surveillance of mesothelioma mortality allows to detect the temporal trend of the disease and highlights previously unknown or underestimated sources of asbestos exposure.

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

Fluoro-edenite (FE) is an asbestiform fiber identified in Biancavilla (Sicily, Italy). Environmental exposure to FE has been associated with a higher incidence of malignant mesothelioma (MM). The present study aimed to validate the predicted diagnostic significance of hsa-miR-323a-3p, hsa-miR-101-3p, and hsa-miR-20b-5p on a subset of MM patients exposed to FE and matched with healthy controls. For this purpose, MM tissues vs. nonmalignant pleura tissues were analyzed through droplet digital PCR (ddPCR) to evaluate differences in the expression levels of the selected miRNAs and their MM diagnostic potential. In addition, further computational analysis has been performed to establish the correlation of these miRNAs with the available online asbestos exposure data and clinic-pathological parameters to verify the potential role of these miRNAs as prognostic tools. ddPCR results showed that the three analyzed miRNAs were significantly down-regulated in MM cases vs. controls. Receiver operating characteristic (ROC) analysis revealed high specificity and sensitivity rates for both hsa-miR-323a-3p and hsa-miR-20b-5p, which thus acquire a diagnostic value for MM. In silico results showed a potential prognostic role of hsa-miR-101-3p due to a significant association of its higher expression and increased overall survival (OS) of MM patients.

Fluoro-edenite (FE), an asbestiform fiber, is responsible for many respiratory pathologies: chronic obstructive diseases, pleural plaques, fibrosis, and malignant mesothelioma. Macrophage migration inhibitory factor (MIF) is one of the first cytokines produced in response to lung tissue damage. Heme oxygenase-1 (HO-1) is a protein with protective effects against oxidative stress. It is up regulated by several stimuli including pro-inflammatory cytokines and factors that promote oxidative stress. In this research, the in vivo model of sheep lungs naturally exposed to FE was studied in order to shed light on the pathophysiological events sustaining exposure to fibers, by determining immunohistochemical lung expression of MIF and HO-1. Protein levels expression of HO-1 and MIF were also evaluated in human primary lung fibroblasts after exposure to FE fibers in vitro. In exposed sheep lungs, MIF and HO-1 immunoexpression were spread involving the intraparenchymal stroma around bronchioles, interstitium between alveoli, alveolar epithelium and macrophages. High MIF immunoexpression prevails in macrophages. Similar results were obtained in vitro, but significantly higher values were only detected for HO-1 at concentrations of 50 and 100 μg/mL of FE fibers. MIF and HO-1 expressions seem to play a role in lung self-protection against uncontrolled chronic inflammation, thus counteracting the strong link with cancer development, induced by exposure to FE. Further studies will be conducted in order to add more information about the role of MIF and HO-1 in the toxicity FE-induced.

Background: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos-related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated. Methods: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as ≥50% of tumor cells showing membranous staining. Results: Six cases showed AQP1 expression in ≥50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months. Conclusions: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator.