Investigating the Relationship between Epigenetic Age and Cardiovascular Risk in a Population with Overweight/Obesity.

Introduction: Cardiovascular diseases stand as the leading global cause of mortality. Major modifiable risk factors encompass overweight/obese conditions, high blood pressure, elevated LDL cholesterol, diabetes, smoking, secondhand smoke exposure, unhealthy diet, and physical inactivity. In the present study, we explored the relationship between cardiovascular risk factors and epigenetic age (DNAm age), an estimate reflecting an individual's actual physiological functionality and overall health. Additionally, we assessed the association between DNAm age acceleration and cardiovascular risk, as evaluated through the Framingham risk score (FRS). Methods: The study includes 190 subjects with overweight/obese conditions. We calculated their DNAm age using Zbiec-Piekarska et al.'s DNAm age estimator on five sets of CpGs analyzed in the peripheral leucocytes. Linear regression models were employed to test the associations. Results: Various parameters contributing to increased cardiovascular risk were associated with DNAm age acceleration, such as systolic blood pressure (ß = 0.045; SE = 0.019; p = 0.019), heart rate (ß = 0.096; SE = 0.032; p = 0.003), blood glucose (ß = 0.025; SE = 0.012; p = 0.030), glycated hemoglobin (ß = 0.105; SE = 0.042; p = 0.013), diabetes (ß = 2.247; SE = 0.841; p = 0.008), and menopausal conditions (ß = 2.942; SE = 1.207; p = 0.016), as well as neutrophil (ß = 0.100; SE = 0.042; p = 0.018) and granulocyte (ß = 0.095; SE = 0.044; p = 0.033) counts. Moreover, DNAm age acceleration raised the FRS (∆% 5.3%, 95% CI 0.8; 9.9, p = 0.019). Conclusion: For the first time, we report that cardiovascular risk factors accelerated DNAm age in a selected population of hypersusceptible individuals with overweight or obesity. Our results highlight the potential of DNAm age acceleration as a biomarker of cumulative effects in cardiovascular risk assessment.

Mortality and cancer incidence in a population exposed to TCDD after the Seveso, Italy, accident (1976-2013).

OBJECTIVES: The Seveso accident (1976) caused the contamination with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in an area north of Milan, Italy. We report the results of the update of mortality and cancer incidence in the exposed population through 2013. METHODS: The study cohort includes subjects living in three contaminated zones with decreasing TCDD soil concentrations (zone A, B and R) and in a surrounding uncontaminated territory (reference). Poisson models stratified/adjusted for gender, age and period were fitted to calculate rate ratios (RRs) and 95% CIs. RESULTS: In zone A in males, we found elevated mortality from circulatory diseases in the first decade after the accident (17 deaths, RR 2.00, 95% CI 1.24 to 3.23). In females, mortality from diabetes mellitus was increased, with a positive trend across zones. Incidence of soft tissue sarcoma was increased in males in zone R in the first decade (6 cases, RR 2.62, 95% CI 1.01 to 6.83). In females in zone B, there was an excess of non-Hodgkin's lymphoma after 30 years (6 cases, RR 2.87, 95% CI 1.14 to 7.23). Multiple myeloma was increased in the second decade in females in zone B (4 cases, RR 5.09, 95% CI 1.82 to 14.2) and in males in zone R (11 cases, RR 2.15, 95% CI 1.08 to 4.26). In males in zone R, there was a leukaemia excess after 30 years (23 cases, RR 2.02, 95% CI 1.04 to 3.93). CONCLUSIONS: Although with different patterns across gender, zone and time, we confirmed previous results of increased cardiovascular diseases, diabetes, soft tissue sarcoma, and lymphatic and haematopoietic cancers.

Environmental and Lifestyle Cancer Risk Factors: Shaping Extracellular Vesicle OncomiRs and Paving the Path to Cancer Development.

Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m2 (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future.

Second Primary Cancers in a Population-Based Mesothelioma Registry.

BACKGROUND: The presence of a second primary cancer (SPC) in patients with pleural mesothelioma (PM) may impact overall survival and suggest a common mechanism of carcinogenesis or an underlying germline genetic alteration. METHODS: We evaluated the occurrence of SPCs within PM cases collected from 2000 to 2018 by the Lombardy Mesothelioma Registry and their prognostic implications. Kaplan-Meier analysis was performed to estimate median survival times, together with univariate and multivariate Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) of death. RESULTS: The median overall survival (OS) of the entire study population (N = 6646) was 10.9 months (95% CI: 10.4-11.2); patient age and histotype were the strongest prognostic factors. No substantial survival difference was observed by the presence of an SPC (10.5 months in 1000 patients with an SPC vs. 10.9 months in 5646 patients in the non-SPC group, HR 1.03, p = 0.40). Shorter OS in the SPC group was only observed in 150 patients with the non-epithelioid subtype (median OS of 5.4 vs. 7.1 months, HR 1.21, p = 0.03). CONCLUSIONS: The diagnosis of an SPC did not influence the outcome of PM patients in the overall study population but was associated with shorter OS in non-epithelioid cases. Further studies are needed to clarify the role of SPCs as markers of genetic susceptibility in mesothelioma.

Metabolomic profiles in night shift workers: A cross-sectional study on hospital female nurses.

Background and aim: Shift work, especially including night shifts, has been found associated with several diseases, including obesity, diabetes, cancers, and cardiovascular, mental, gastrointestinal and sleep disorders. Metabolomics (an omics-based methodology) may shed light on early biological alterations underlying these associations. We thus aimed to evaluate the effect of night shift work (NSW) on serum metabolites in a sample of hospital female nurses. Methods: We recruited 46 nurses currently working in NSW in Milan (Italy), matched to 51 colleagues not employed in night shifts. Participants filled in a questionnaire on demographics, lifestyle habits, personal and family health history and work, and donated a blood sample. The metabolome was evaluated through a validated targeted approach measuring 188 metabolites. Only metabolites with at least 50% observations above the detection limit were considered, after standardization and log-transformation. Associations between each metabolite and NSW were assessed applying Tobit regression models and Random Forest, a machine-learning algorithm. Results: When comparing current vs. never night shifters, we observed lower levels of 21 glycerophospholipids and 6 sphingolipids, and higher levels of serotonin (+171.0%, 95%CI: 49.1-392.7), aspartic acid (+155.8%, 95%CI: 40.8-364.7), and taurine (+182.1%, 95%CI: 67.6-374.9). The latter was higher in former vs. never night shifters too (+208.8%, 95%CI: 69.2-463.3). Tobit regression comparing ever (i.e., current + former) and never night shifters returned similar results. Years worked in night shifts did not seem to affect metabolite levels. The Random-Forest algorithm confirmed taurine and aspartic acid among the most important variables in discriminating current vs. never night shifters. Conclusions: This study, although based on a small sample size, shows altered levels of some metabolites in night shift workers. If confirmed, our results may shed light on early biological alterations that might be related to adverse health effects of NSW.

Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare highly aggressive tumor strongly associated with asbestos exposure and characterized by poor prognosis. Currently, diagnosis is based on invasive techniques, thus there is a need of identifying non-invasive biomarkers for early detection of the disease among asbestos-exposed subjects. In the present study, we measured the plasmatic concentrations of Mesothelin, Fibulin-3, and HMGB1 protein biomarkers, and of hsa-miR-30e-3p and hsa-miR-103a-3p Extracellular-Vesicles- embedded micro RNAs (EV-miRNAs). We tested the ability of these biomarkers to discriminate between MPM and PAE subjects alone and in combination. METHODS: the study was conducted on a population of 26 patients with MPM and 54 healthy subjects with previous asbestos exposure (PAE). Mesothelin, Fibulin-3, and HMGB1 protein biomarkers were measured by the enzyme-linked immunosorbent assay (ELISA) technique; the levels of hsa-miR-30e-3p and hsa-miR-103a-3p EV-miRNAs was assessed by quantitative real-time PCR (qPCR). RESULTS: the most discriminating single biomarker resulted to be Fibulin-3 (AUC 0.94 CI 95% 0.88-1.0; Sensitivity 88%; Specificity 87%). After investigating the different possible combinations, the best performance was obtained by the three protein biomarkers Mesothelin, Fibulin-3, and HMGB1 (AUC 0.99 CI 95% 0.97-1.0; Sensitivity 96%; Specificity 93%). CONCLUSIONS: the results obtained contribute to identifying new potential non-invasive biomarkers for the early diagnosis of MPM in high-risk asbestos-exposed subjects. Further studies are needed to validate the evidence obtained, in order to assess the reliability of the proposed biomarker panel.

The Relationship between Exposure to Airborne Particulate and DNA Adducts in Blood Cells in an Urban Population of Subjects with an Unhealthy Body Mass Index.

Bulky DNA adducts are a combined sign of aromatic chemical exposure, as well as an individual's ability to metabolically activate carcinogens and repair DNA damage. The present study aims to investigate the association between PM exposure and DNA adducts in blood cells, in a population of 196 adults with an unhealthy BMI (≥25). For each subject, a DNA sample was obtained for quantification of DNA adducts by sensitive32P post-labelling methods. Individual PM10 exposure was derived from daily mean concentrations measured by single monitors in the study area and then assigned to each subject by calculating the mean of the 30 days (short-term exposure), and of the 365 (long-term exposure) preceding enrolment. Multivariable linear regression models were used to study the association between PM10 and DNA adducts. The majority of analysed samples had bulky DNA adducts, with an average value of 3.7 ± 1.6 (mean ± SD). Overall, the findings of the linear univariate and multiple linear regression showed an inverse association between long-term PM10 exposure and adduct levels; this unexpected result might be since the population consists of subjects with an unhealthy BMI, which might show an atypical reaction to airborne urban pollutants; a hermetic response which happens when small amounts of pollutants are present. Pollutants can linger for a long time in the adipose tissue of obese persons, contributing to an increase in oxidative DNA damage, inflammation, and thrombosis when exposure is sustained.

Asbestos Exposure in Patients with Malignant Pleural Mesothelioma included in the PRIMATE Study, Lombardy, Italy.

The PRIMATE study is an Italian translational research project, which aims to identify personalized biomarkers associated with clinical characteristics of malignant pleural mesothelioma (MPM). For this purpose, characteristics of MPM patients with different degrees of asbestos exposure will be compared to identify somatic mutations, germline polymorphism, and blood inflammatory biomarkers. In this framework, we assessed exposure to asbestos for 562 cases of MPM extracted from the Lombardy region Mesothelioma Registry (RML), for which a complete interview based on a standardized national questionnaire and histopathological specimens were available. Exposure assessment was performed: (1) through experts' evaluation (considered as the gold standard for the purpose of this study), according to the guidelines of the Italian National Mesothelioma Registry (ReNaM) and (2) using a job-exposure matrix (SYN-JEM) to obtain qualitative (ever/never) and quantitative estimates of occupational asbestos exposure (cumulative exposure expressed in fibers per mL (f/mL)). The performance of SYN-JEM was evaluated against the experts' evaluation. According to experts' evaluation, occupational asbestos exposure was recognized in 73.6% of men and 23.6% of women; furthermore, 29 men (7.8%) and 70 women (36.9%) had non-occupational exposure to asbestos. When applying SYN-JEM, 225 men (60.5%) and 25 women (13.2%) were classified as occupationally exposed, with a median cumulative exposure higher for men (1.7 f/mL-years) than for women (1.2 f/mL-years). The concordance between the two methods (Cohen's kappa) for occupational exposure assessment was 0.46 overall (0.41 in men, and 0.07 in women). Sensitivity was higher in men (0.73) than in women (0.18), while specificity was higher in women (0.88) than in men (0.74). Overall, both methods can be used to reconstruct past occupational exposure to asbestos, each with its own advantages and limitations.

Development of a Crosswalk to Translate Italian Occupation Codes to ISCO-68 Codes.

In occupational epidemiology, job coding is an important-but time-consuming-step in assigning exposure. We implemented a tool (i.e. a crosswalk) to translate occupation codes from the Italian (ISTAT-CIP-91, n = 6319 five-digit job codes) to the International Standard Classification of Occupations (ISCO-68, n = 1881 five-digit job codes). The former is currently used in Italy for various purposes (e.g. in the National Mesothelioma Registry). The latter has been used in several studies on occupational cancers because it facilitates communication of results to the scientific community and, most importantly, because some job exposure matrices (JEMs) are based on international codes. Three authors created a table containing the crosswalk structure, providing an interpretation for each of the ISTAT-CIP-91 codes job descriptions and then manually recoding them according to ISCO-68. Two other authors independently revised it. The performance of the final version was assessed by comparison with results obtained by manual ISCO-68 coding performed in two previous case-control studies on asbestos and mesothelioma. More specifically, the automatically obtained ISCO-68 codes were merged with a JEM (DOM-JEM). The resulting individual asbestos exposure estimates (ever versus never exposed) were compared to those originally obtained (using the same DOM-JEM) from manual translation of ISTAT-CIP-91 to ISCO-68 (considered as the 'gold standard'). In the first study, among 159 peritoneal mesothelioma cases (400 job codes), Cohen's kappa was 0.91, sensitivity 0.95, and specificity 0.96. In the second study, among 716 pleural mesothelioma cases and controls (4400 job codes) kappa was 0.86, sensitivity 0.94, and specificity 0.91. Performance was better among in women. For men, performance was lower among cases than among controls (kappa 0.70, sensitivity 0.95, specificity 0.72 versus kappa 0.87, sensitivity 0.97, and specificity 0.92). In conclusion, the proposed tool allowed a rapid translation of thousands of job codes with good to excellent accuracy. The table containing ISTAT-CIP-91 codes and job descriptions and the corresponding ISCO-68 codes and job descriptions is made publicly available and can be freely used for epidemiological analyses in Italy and international collaborations.

Association between night shift work and methylation of a subset of immune-related genes.

Introduction: Night shift (NS) work has been associated with an increased risk of different conditions characterized by altered inflammatory and immune responses, such as cardio-metabolic and infectious diseases, cancer, and obesity. Epigenetic modifications, such as DNA methylation, might mirror alterations in biological processes that are influenced by NS work. Methods: The present study was conducted on 94 healthy female workers with different working schedules and aimed at identifying whether NS was associated with plasmatic concentrations of the inflammatory proteins NLRP3 and TNF-alpha, as well as with DNA methylation levels of ten human endogenous retroviral (HERV) sequences, and nine genes selected for their role in immune and inflammatory processes. We also explored the possible role of the body mass index (BMI) as an additional susceptibility factor that might influence the effects of NS work on the tested epigenetic modifications. Results and discussion: We observed a positive association between NS and NLRP3 levels (p-value 0.0379). Moreover, NS workers retained different methylation levels for ERVFRD-1 (p-value = 0.0274), HERV-L (p-value = 0.0377), and HERV-P (p-value = 0.0140) elements, and for BIRC2 (p-value = 0.0460), FLRT3 (p-value = 0.0422), MIG6 (p-value = 0.0085), and SIRT1 (p-value = 0.0497) genes. We also observed that the BMI modified the relationship between NS and the methylation of ERVE, HERV-L, and ERVW-1 elements. Overall, our results suggest that HERV methylation could pose as a promising biomolecular sensor to monitor not only the effect of NS work but also the cumulative effect of multiple stressors.

Clinical Implications of Inter- and Intratumor Heterogeneity of Immune Cell Markers in Lung Cancer.

BACKGROUND: Immune cell transcriptome signatures have been widely used to study the lung tumor microenvironment (TME). However, it is unclear to what extent the immune cell composition in the lung TME varies across histological and molecular subtypes (intertumor heterogeneity [inter-TH]) and within tumors (intratumor heterogeneity [ITH]) and whether ITH has any prognostic relevance. METHODS: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients, we quantified the inter-TH of immune gene expression and immune cell abundance and evaluated the association of median immune cell abundance with clinical and pathological features and overall survival. In 39 tumors with 132 multiregion samples, we also analyzed the ITH of immune cell abundance in relation to overall survival using a variance-weighted multivariate Cox model not biased by the number of samples per tumor. RESULTS: Substantial inter-TH of 14 immune cell types was observed even within the same histological and molecular subtypes, but early stage tumors had higher lymphocyte infiltration across all tumor types. In multiregion samples, an unbiased estimate of low ITH of overall immune cell composition (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002), and macrophages (HR = 0.50, 95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The ITH of 3 markers, including CD163 and CD68 (macrophages) and CCL13 (dendritic cells), was enough to characterize the ITH of the corresponding immune cell abundances and its association with overall survival. CONCLUSION: This study suggests that lack of immune cell diversity may facilitate tumor evasion and progression. ITH inferred from CCL13, CD163, and CD68 could be used as a prognostic tool in clinical practice.

Side effects among healthcare workers from a large Milan university hospital after second dose of BNT162b2 mRNA COVID-19 vaccine.

BACKGROUND: In Italy, healthcare workers (HCWs) were among the first to receive COVID-19 vaccination. Aim of the present study is to evaluate frequency and severity of adverse events (AEs) following the second dose of BNT162b2 vaccine among HCWs of a large university hospital in Milan, Italy. METHODS: One month after having received the second dose of vaccine, HCWs filled-in a form about type, severity, and duration of post-vaccination local and systemic symptoms. We calculated the overall frequency of AEs and used multivariable Poisson regression models (adjusted for sex, age, BMI, smoking, allergy history, previous SARS-CoV-2 infection, anti-hypertensive therapy, and occupation) to calculate risk ratios (RR) and 95% confidence intervals (CI) of AEs according to selected variables. RESULTS: We included 3659 HCWs. Overall, 2801 (76.6%) experienced at least one local event, with pain at injection site being the most frequent (2788, 76.2%). Systemic events were reported by 2080 (56.8%) HCWs, with fatigue (52.3%), muscle pain (42.2%), headache (37.7%), joint pain (31.9%), and fever (26.2%) being the most frequent. Risks of systemic events were associated with female gender (RR=1.14, CI: 1.06-1.23), age (strong decrease with increasing age, p-trend<0.001), allergy history (RR=1.13, CI: 1.05-1.20), and current smoking (RR=0.90, CI: 0.84-0.97). HCWs with previous SARS-CoV-2 infection (even if symptomatic) were not at increased risk. CONCLUSIONS: Both local and systemic acute effects after second dose of BNT162b2 vaccine were frequently reported. However, symptoms were mostly light/mild and of short duration. Thus, our findings support the safety of COVID-19 vaccination in adults in relatively good health.

Can Night Shift Work Affect Biological Age? Hints from a Cross-Sectional Study on Hospital Female Nurses.

Disruption of age-related processes seems to play a relevant role in health effects related to night shift (NS) work. We aim to verify whether NS work can influence biological age (BA), estimated through Zbiec-Piekarska's epigenetic signature, based on methylation of five CpG sites in ELOVL2, C1orf132/MIR29B2C, TRIM59, KLF14, and FHL2. Forty-six female nurses working in NS were matched by age and length of employment with 51 female colleagues not working in NS. Each subject filled in a questionnaire (including the Effort Reward Imbalance (ERI) index to assess job stress) and gave a blood sample. Age acceleration (AA) was estimated by regressing BA on chronological age and taking the residuals. Multivariate linear regression models were applied. BA was not associated with NS. However, we did observe an increase in AA per each year in NS in subjects with overweight/obesity (ß = 0.46, 95% CI: 0.05; 0.87, p = 0.03), experiencing work-related stress (ß = 0.58, 95% CI: 0.10; 1.06, p = 0.018), or both (ß = 0.66, 95% CI: 0.03; 1.29, p = 0.041). Although based on a small sample size, our findings suggest an increased BA only among hypersusceptible subjects and is worth further investigation, also in light of recent results suggesting a higher breast cancer risk in women with increased AA.

Pleural mesothelioma in a circus worker.

OBJECTIVES: To describe an unusual occupational asbestos exposure in a patient with mesothelioma. METHODS: Since 2000, the Lombardy Mesothelioma Registry (LMR) collects cases of malignant mesothelioma (MM) occurring among people residing in the Lombardy Region, North-West Italy, with a population of 10 million inhabitants. For each case, clinical records and asbestos exposure are collected. Each case is then classified in agreement with the guidelines of the National Mesothelioma Registry. RESULTS: We identified a male (86 years old), former smoker, who had been working for 53 years as a circus truck driver and tamer of lions and tigers. The first circumstance of exposure was the use of an asbestos tape that wrapped around the hoop in the feline jumping show with a flaming hoop. The second one was the presence of insulating panels protecting the engine placed inside the trucks. CONCLUSION: A new MM case with an occupational etiology has been found in the public entertainment, an occupational sector not usually considered at risk for the presence of asbestos.

Impact of Histology and Tumor Grade on Clinical Outcomes Beyond 5 Years of Follow-Up in a Large Cohort of Renal Cell Carcinomas.

INTRODUCTION: The optimal length for clinical follow-up of renal cell carcinoma (RCC) patients is unclear. We evaluated the impact of ISUP/WHO tumor grade and histological subtype on short- and long-term survival and risk of recurrence/metastasis in a large cohort of RCC patients. PATIENTS AND METHODS: We studied 1679 RCC patients from a single referral center in Italy. Adjusted hazard ratios for overall survival were estimated using Cox regression models. Adjusted absolute risk of developing recurrence or metastasis was computed considering competing risks of mortality. RESULTS: During up to 13 years of follow-up, 175 (10.4%) RCC patients died, of whom 92% beyond 5 years. Hazard ratio of grade IV clear cell carcinomas (ccRCC) was 3.82 compared to grade II. Notably, 33% of recurrences and 56% of distant metastases occurred beyond 5 years of follow-up. The estimated probabilities of recurrence/metastasis were 15% and 45% within and beyond 5 years of follow-up, respectively. After 5 years, the absolute risk of recurrences increased also for papillary renal cell carcinoma type I (35.2%) and grade I ccRCC (17%). CONCLUSION: After 5 years of follow-up, both risk of mortality and recurrences or metastases were high and were modified by histological types and tumor grade. These data strongly support histology- and grade-tailored surveillance strategies and long-term follow-up for RCC patients.

An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls.

BACKGROUND: Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis. METHODS: We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database. RESULTS: miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways. CONCLUSIONS: Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.

Plasma Metabolomic Profiling in 1391 Subjects with Overweight and Obesity from the SPHERE Study.

Overweight and obesity have high prevalence worldwide and assessing the metabolomic profile is a useful approach to study their related metabolic processes. In this study, we assessed the metabolomic profile of 1391 subjects affected by overweight and obesity, enrolled in the frame of the SPHERE study, using a validated LC-MS/MS targeted metabolomic approach determining a total of 188 endogenous metabolites. Multivariable censored linear regression Tobit models, correcting for age, sex, and smoking habits, showed that 83 metabolites were significantly influenced by body mass index (BMI). Among compounds with the highest association, aromatic and branched chain amino acids (in particular tyrosine, valine, isoleucine, and phenylalanine) increased with the increment of BMI, while some glycerophospholipids decreased, in particular some lysophosphatidylcholines (as lysoPC a C18:2) and several acylalkylphosphatidylcholines (as PC ae C36:2, PC ae C34:3, PC ae C34:2, and PC ae C40:6). The results of this investigation show that several endogenous metabolites are influenced by BMI, confirming the evidence with the strength of a large number of subjects, highlighting differences among subjects with different classes of obesity and showing unreported associations between BMI and different phosphatidylcholines.

Seroprevalence of anti-SARS-CoV-2 IgG among healthcare workers of a large university hospital in Milan, Lombardy, Italy: a cross-sectional study.

OBJECTIVES: To assess the seroprevalence of anti-SARS-CoV-2 IgG among health careworkers (HCWs) in our university hospital and verify the risk of acquiring the infection according to work area. DESIGN: Cross-sectional study. SETTING: Monocentric, Italian, third-level university hospital. PARTICIPANTS: All the employees of the hospital on a voluntary base, for a total of 4055 participants among 4572 HCWs (88.7%). PRIMARY AND SECONDARY OUTCOME MEASURES: Number of anti-SARS-CoV-2 positive serology according to working area. Association of anti-SARS-CoV-2 positive serology to selected variables (age, gender, country of origin, body mass index, smoking, symptoms and contact with confirmed cases). RESULTS: From 27 April 2020 to 12 June 2020, 4055 HCWs were tested and 309 (7.6%) had a serological positive test. No relevant difference was found between men and women (8.3% vs 7.3%, p=0.3), whereas a higher prevalence was observed among foreign-born workers (27/186, 14.5%, p<0.001), employees younger than 30 (64/668, 9.6%, p=0.02) or older than 60 years (38/383, 9.9%, p=0.02) and among healthcare assistants (40/320, 12.5%, p=0.06). Working as frontline HCWs was not associated with an increased frequency of positive serology (p=0.42). A positive association was found with presence and number of symptoms (p<0.001). The symptoms most frequently associated with a positive serology were taste and smell alterations (OR 4.62, 95% CI: 2.99 to 7.15) and fever (OR 4.37, 95% CI: 3.11 to 6.13). No symptoms were reported in 84/309 (27.2%) HCWs with positive IgG levels. Declared exposure to a suspected/confirmed case was more frequently associated (p<0.001) with positive serology when the contact was a family member (19/94, 20.2%) than a patient or colleague (78/888, 8.8%). CONCLUSIONS: SARS-CoV-2 infection occurred undetected in a large fraction of HCWs and it was not associated with working in COVID-19 frontline areas. Beyond the hospital setting, exposure within the community represents an additional source of infection for HCWs.

Mesothelioma in Agriculture in Lombardy, Italy: An Unrecognized Risk.

Cohort studies showed consistently low risks for malignant mesothelioma (MM) among agricultural workers, however the investigated exposures did not include asbestos. Our aim is to describe sources of asbestos exposure of MM in agriculture. Twenty-six MM cases in agricultural or seed trades workers were identified through the MM registry of the Lombardy region, Italy in 2000-2016. Asbestos exposures were investigated through a standardized questionnaire. The most frequent exposure circumstances were recycled jute bags previously containing asbestos (11 cases) and maintenance and repair of asbestos roofs (12 subjects). Three subjects performed maintenance and repair of tractor asbestos brakes and two used asbestos filters for wine production. Our data suggest asbestos exposure opportunities in the agricultural setting, underlining the need to look for this exposure in subjects affected with mesothelioma.

Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, which originates from the mesothelial cells of the pleura and is associated with asbestos exposure. In light of its aggressive nature, late diagnosis and dismal prognosis, there is an urgent need for identification of biomarkers in easily accessible samples (such as blood) for early diagnosis of MPM. In the last 10 years, epigenetic markers, such as DNA methylation and microRNAs (miRNAs), have gained popularity as possible early diagnostic and prognostic biomarkers in cancer research. The aim of this review is to provide a critical analysis of the current evidences on circulating epigenetic biomarkers for MPM and on their translational potential to the clinical practice for early diagnosis and for prognosis.