The role of MicroRNAs as early biomarkers of asbestos-related lung cancer: A systematic review and meta-analysis.

BACKGROUND: Asbestos is still the leading cause of occupational cancer mortality worldwide. Asbestos-related lung cancer (LC) and malignant pleural mesothelioma (MPM) prognosis is still poor especially at advanced stage, so early diagnosis biomarkers are needed. MicroRNAs (miRNAs) have been proposed as potential early diagnostic biomarkers of asbestos-related LC and MPM. AIM: To evaluate the role of miRNAs as diagnostic and prognostic biomarkers of asbestos-related LC and MPM by performing a literature systematic review and meta-analysis. METHODS: MEDLINE, EMBASE via Ovid, PUBMED and Cochrane library databases were systematically searched up to April 2023 to identify relevant articles. A grey literature search was also conducted using the Google Scholar platform. MeSH and free text terms for 'asbestos', 'occupational exposure', 'lung cancer', 'mesothelioma' and 'miRNAs' were used to search the literature. Our systematic review protocol was registered in the PROSPERO database. Study quality was assessed via the Newcastle-Ottawa Scale. RESULTS: From the search, 331 articles were retrieved, and, after applying our selection criteria, and exclusion of one study for poor quality, 27 studies were included in the review. Most of the studies were hospital-based case-control, conducted in Europe, and evaluated MPM among men only. MiRNAs expression was measured mainly in plasma or serum. MiR-126, miR-132-3p, and miR-103a-3p were the most promising diagnostic biomarkers for MPM, and we estimated a pooled area under the curve (AUC) of 85 %, 73 %, and 50 %, respectively. In relation to MPM prognosis, miR-197­3p resulted associated with increased survival time. MiR-126, alone and combined with miR-222, was confirmed associated also to LC diagnosis, together with miR-1254 and miR-574-5p; no miRNA was found associated to LC prognosis. CONCLUSION: Based on our systematic literature review there is suggestive evidence that the expression of specific miRNAs in the blood serum or plasma are associated with asbestos-related LC and MPM diagnosis and prognosis. Further large longitudinal studies are urgently needed to validate these findings and elucidate the underlying mechanisms given the potential important implications for patients' survival.

Work-related interstitial lung disease: what is the true burden?

Interstitial lung diseases (ILDs) include a large variety of fibrotic lung conditions caused by genetic and environmental factors. Occupational exposures might also play a significant role, but the real health burden is currently unknown. Here, we aim to evaluate the role of work-related exposures in ILDs, focussing on idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP). We performed a focused review of the literature on work-related HP and IPF over the past 5 years. Using a meta-analytic approach, we quantified the occupational burden of IPF and HP, and estimated that occupational exposures to metal, silica and environmental tobacco smoke increased IPF risk with a pooled odds ratio of 1.7 (95% CI 1.42-2.03). The proportion of HP cases related to workplace exposure was 17% (95% CI 7-28). Our review supports the hypothesis that occupational exposures are a significant risk factor in the aetiopathogenesis of IPF and HP. We recommend that further research be performed to identify the underlying occupational factors and the maximum permitted exposure to reduce the associated IPF and HP burden.

Reconstructing historical exposure to asbestos: the validation of 'educated guesses'.

BACKGROUND: In both the epidemiological and legal context, the causal attribution of asbestos-related lung diseases requires retrospective exposure assessment (REA). AIMS: To assess the correlation between the retrospective assessment of occupational and anthropogenic environmental exposure to asbestos and its content in the lung tissue. METHODS: Based on the available exposure information, a team of occupational physicians retrospectively assessed cumulative exposure to asbestos in 24 subjects who died of asbestos-related diseases. The asbestos lung content was analysed using analytical scanning electron microscope (SEM-EDS). The Log10 asbestos fibre count in the autoptic samples was predicted as a function of the Log10 estimated cumulative exposure using univariate regression analysis. RESULTS: The median count of asbestos fibres by grams of dry weight (ff/gdw) in the lung tissue was 81 339 (range 0-2 135 849.06); it was 287 144 (range 0-2 135 849.06) among the occupationally exposed, and 29 671 (range 0-116 891) among the subjects who only had anthropogenic environmental and/or household exposure. Amphiboles, and particularly amosite (52%) and crocidolite (43%), were detected in all the study subjects. Chrysotile was not detected in any of the samples. Overall, the retrospective estimate of lifetime cumulative exposure to asbestos showed a moderate correlation with the total asbestos fibre count in the autoptic lung, with the regression model explaining 38-55% of the total variance. CONCLUSIONS: Detailed information on occupational, environmental and household exposure circumstances would be indispensable for experienced industrial hygienists and/or occupational physicians to reliably assess past exposure to amphiboles or mixed types of asbestos.

Issue 1 - "Update on adverse respiratory effects of outdoor air pollution". Part 1): Outdoor air pollution and respiratory diseases: A general update and an Italian perspective.

OBJECTIVE: to summarize the main updated evidence about the health effects of air pollution and to focus on Italian epidemiological experiences on the respiratory effects. RESULTS: the recent literature indicates that there is strong evidence for causal relationships between PM2.5 air pollution exposure and all-cause mortality as well as mortality from acute lower respiratory infections, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lung cancer. A growing body of evidence also suggests causal relationships with type II diabetes and impacts on neonatal mortality from low birth weight and short gestation as well as neurologic effects in both children and adults. Italy, a Southern European country, faces a more threatening air pollution challenge because of the effects of both anthropogenic pollutants and natural dust (particulate matter, PM). The 2020 Report of the European Environment Agency highlighted the number of premature deaths in Italy attributable to main pollutants: 52,300 for PM2.5, 10,400 for NO2 and 3,000 for O3 in 2018. In Italy, original time series and analytical epidemiological studies showed increased cardio-respiratory hospital admissions and mortality and increased risk of respiratory diseases in people living in urban areas. CONCLUSIONS: adverse health effects of air pollutants, even at low levels, have been confirmed by recent epidemiological studies. Further studies should focus on the potential link between air pollution exposure and respiratory infections. This topic has become particularly important in the current SARS-COV-2 pandemic. Based on strong scientific evidence, the Italian government, which hosts the Global Alliance against Chronic Respiratory Diseases (GARD)-Italy at the Ministry of Health, the scientific respiratory societies and the patients' associations, as well as others in the health sector and civil society, must increase their engagement in advocacy for clean air policies, especially in light of the new Air Quality Guidelines of the World Health Organization.

Shift rotation scheme, sleepiness and sleep quality in night-shift workers.

BACKGROUND: Shift rotation schemes can influence workers' tolerance of night-shift work and its impact on health. AIMS: This study was aimed to assess the influence of shift work rotation schemes on sleepiness and sleep quality. METHODS: We conducted a cross-sectional study of 145 male workers, 77 from a ceramic tile factory on a fixed, forward-rotating shift work scheme, and 68 from a dockyard company, working on-call night shifts. Participants self-administered the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) questionnaires and provided data on demographic and lifestyle variables. We set two logistic regression models to predict the risk of daytime sleepiness and poor sleep quality as a function of night-shift work and on-call night shifts, adjusting for personal and lifestyle covariates. RESULTS: Marital status, body mass index, smoking and alcohol intake did not affect ESS and PSQI scores, nor did they differ between the two cohorts. Night-shift workers from both cohorts were more likely to have a PSQI score ≥6, suggestive of poor sleep quality, with no variation between the two cohorts. ESS scores suggestive of daytime sleepiness were strongly associated with on-call night shifts among dockyard workers for (odds ratio = 13.4; 95% confidence interval 2.9-63.9), in respect the regular, forward-rotating night-shift work among ceramic tile factory workers. DISCUSSION: Daytime sleepiness occurred more frequently among dockyard workers working on-call night shifts. Poor sleep quality occurred more frequently among night-shift workers, but it did not differ between the two companies.

Comparative proteomic profiling of Hodgkin lymphoma cell lines.

Classical Hodgkin lymphoma (cHL) is a malignancy with complex pathogenesis. The hallmark of the disease is the presence of large mononucleated Hodgkin and bi- or multinucleated Reed/Sternberg (H/RS) cells. The origin of HRS cells in cHL is controversial as these cells show the coexpression of markers of several lineages. Using a proteomic approach, we compared the protein expression profile of cHL models of T- and B-cell derivation to find proteins differentially expressed in these cell lines. A total of 67 proteins were found differentially expressed between the two cell lines including metabolic proteins and proteins involved in the regulation of the cytoskeleton and/or cell migration, which were further validated by western blotting. Additionally, the expression of selected B- and T-cell antigens was also assessed by flow cytometry to reveal significant differences in the expression of different surface markers. Bioinformatics analysis was then applied to our dataset to find enriched pathways and networks, and to identify possible key regulators. In the present study, a proteomic approach was used to compare the protein expression profiles of two cHL cell lines. The identified proteins and/or networks, many of which not previously related to cHL, may be important to better define the pathogenesis of the disease, to identify novel diagnostic markers, and to design new therapeutic strategies.

[Incidence of malignant mesothelioma and asbestos exposure in the Lombardy region, Italy, 2000-2008]. / Incidenza del mesotelioma maligno ed esposizione ad amianto in Lombardia, 2000-2008.

We evaluated the trend of incidence and asbestos exposure of malignant mesothelioma (MM) in 2000-2008 in the Lombardy Region (Italy). We recorded 2,816 MMs (1,793 men, 1,023 women). The age-standardized rates (x 100,000/year) were 3.4 (men) and 1.4 (women) (standard population: Europe). We found a 3.0% and 0.9% increase per year of number of cases and rate, respectively. Exposure was obtained in 2,671 cases (94.9%). Occupational exposure to asbestos was found for 1,296 (72.3%) men and 377 (36.9%) women, non-occupational exposure in 141 (13.8%) women and 58 (3.2%) men. The exposure profile within gender did not vary over years.

Kinetics of peg-filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

Peg-filgrastim is a form of G-CSF with a sustained duration of action due to self-limited clearance. We administered 6 mg peg-filgrastim to 18 autograft recipients on day +1 after transplantation for hematologic malignancies. Plasma samples were collected at baseline and during transplantation. Hematopoietic recovery and clinical outcomes were compared to the historical data of 54 patients not receiving G-CSF. Patients receiving peg-filgrastim achieved a serum level of 115 000 pg/ml on day +2, 24 h after drug administration. Drug level maintained a plateau until day +8 and, after day +10, declined concomitantly with myeloid recovery. Patients experienced prompt neutrophil recovery: days +9 and +10 to 500 and 1000 neutrophils per microliter, and 4 days with an absolute neutrophil count <100 cells per microliter. Duration of antibiotic therapy was significantly shortened, but we did not observe significant differences in other end points. In conclusion, peg-filgrastim was well tolerated and efficacious, and hastened myeloid recovery.

Formation of PML/RAR alpha high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RAR alpha-mediated retinoic acid response.

Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukaemia (APL) patients by triggering terminal differentiation of neoplastic cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results from the recombination of the PML and the RA receptor alpha (RAR alpha) genes (PML/RAR alpha fusion protein). Ectopic expression of PML/RAR alpha into haemopoietic cell lines results in increased response to RA-induced differentiation. By structure-function analysis of PML/RAR alpha-mediated RA-differentiation, we demonstrated that fusion of PML and RAR alpha sequences and integrity of the PML dimerization domain and of the RAR alpha DNA binding region are required for the effect of PML/RAR alpha on RA-differentiation. Indeed, direct fusion of the PML dimerization domain to the N- or C-terminal extremities of RAR alpha retained full biological activity. All the biologically active PML/RAR alpha mutants formed high molecular weight complexes in vivo. Functional analysis of mutations within the PML dimerization domain revealed that the capacity to form PML/RAR alpha homodimers, but not PML/RAR alpha-PML heterodimers, correlated with the RA-response. These results suggest that targeting of RAR alpha sequences by the PML dimerization domain and formation of nuclear PML/RAR alpha homodimeric complexes are crucial for the ability of PML/RAR alpha to mediate RA-response.

Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia.

The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.

[Comparison between automatic substraction devices and computer subtraction in radioisotope pancreatography]. / Confronto fra dispositivi automatici di sottrazione e sottrazione al computer nella pancreatografia radioisotopica.

Reference is made to several indicative cases in a personal series. Their comparative examination with a scanner and a gamma camera computer showed that: a) noticeably different findings were given by the two methods with regard to cystic, neoplastic, and inflammatory lesions of the pancreas, whereas; b) computerised subtraction was much more sensitive in lesions due to cysts and pancreatitis, even though there was no significant difference between the two methods in the case of neoplasia.

[Current role of pancreatic scintiscanning in the study of pancreatic symptomatology]. / Ruolo attuale della scintigrafia pancreatica nel contesto della semeiologia del pancreas.

A brief reference is made to the part once assigned to scintiscanning as a method of approach to diseases of the pancreas. It is felt that the lack of confidence now displayed in this technique is based preconceptions. A new diagnostic approach is therefore proposed and briefly described. The advantages and disadvantages of the diagnostic techniques included in the proposed scheme are examined. The view is expressed that a fresh assessment should be made of nuclear pancreatography, since it is still a fundamental diagnostic tool.

[Radiopaque hemithorax, with special reference to scintigraphic methods]. / L'emitorace radiopaco con particolare riguardo alle metodiche scintigrafiche.

Radioopaque hemithorax is frequently observed. The various situations in which it may occur are examined aetiopathologically, along with the general and specifically radiological methods used for its investigation. Particular attention is given to the employment of radio-isotopes for this purpose and the methods involved. Results obtained with perfusion are noteworthy, and even more so those achieved with positive tracers such as 67Ga citrate and 57Co Blm, especially in the differential diagnosis of pleural effusion and mesothelioma through what is described as the "paradox effect".

[Scintigraphic diagnosis of pancreatic diseases: random analysis of 100 patients]. / La diagnostica scintigrafica delle pancreopatie: analisi randomizzata di 100 pazienti.

After a brief statement on the procedure of selection of the patients, the article describes how the cases were studied, since some difficulties arose through the lack of homogeneity of the subjects. The cases are then commented and an effort is made to evidence the outstanding data which can be deduced, and in particular a study is made of the percentage of overall unreliability of scintillographic examination, the "false positives" and the "false negatives", which are rather low. The Authors conclude with the consideration that scintiscanning of the pancreas now constitutes a valid method of investigation of pancreatic pathology.