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.

Air pollution exposure, SARS-CoV-2 infection, and immune response in a cohort of healthcare workers of a large university hospital in Milan, Italy.

Several studies have examined the possible relationship between air pollutants and the risk of COVID-19 but most returned controversial findings. We tried to assess the association between (short- and long-term) exposure to particulate and gaseous pollutants, SARS-CoV-2 infections, and immune response in a population of healthcare workers (HCWs) with well-characterized individual data. We collected occupational and clinical characteristics of all HCWs who performed a nasopharyngeal swab (NPS) for detecting SARS-CoV-2 at the Policlinico Hospital in Milan (Lombardy, Italy) between February 24, 2020 (day after first documented case of COVID-19 in our hospital) and December 26, 2020 (day before start of the vaccination campaign). Each subject was assigned daily average levels of particulate matter ≤10 µm (PM10), nitrogen dioxide (NO2), and ozone (O3) retrieved from the air quality monitoring station closest to his/her residential address. Air pollution data were treated as time-dependent variables, generating person-days at risk. Multivariate Poisson regression models were fit to evaluate the rate of positive NPS and to assess the association between air pollution and antibody titer among NPS-positive HCWs. Among 3712 included HCWs, 635 (17.1%) had at least one positive NPS. A 10 µg/m3 increase in NO2 average concentration in the four days preceding NPS was associated with a higher risk of testing positive [Incidence Rate Ratio (IRR) = 1.08, 95% confidence interval (CI): 1.01; 1.16)]. When considering a 1 µg/m3 increase in 2019 annual NO2 average, we observed a higher risk of infection (IRR: 1.02, 95%CI: 1.00; 1.03) and an increased antibody titer (+2.4%, 95%CI: 1.1; 3.6%). Findings on PM10 and O3 were less consistent and, differently from NO2, were not confirmed in multipollutant models. Our study increases the body of evidence suggesting an active role of air pollution exposure on SARS-CoV-2 infection and confirms the importance of implementing pollution reduction policies to improve public health.

Air Pollution and Perinatal Mental Health: A Comprehensive Overview.

BACKGROUND: The aim of the present study was to summarise the available data about the link between air pollution exposure and the new-onset and severity of psychiatric disorders in pregnant women during the perinatal period. MATERIALS AND METHODS: We selected articles published until June 2022 on PubMed and the Web of Science. Pollutants included were PM2.5 (particulate matter 2.5 micrometres and smaller), PM10 (particulate matter 10 micrometres and smaller), NO2 (nitrogen dioxide), O3 (ozone), SO2 (sulphur dioxide), CO (carbon monoxide), PBDEs (polybrominated diphenyl ethers), PFAS (per- and polyfluoroalkyl substances), lead, and cadmium. The perinatal period was considered as the time of pregnancy until one year after childbirth. RESULTS: Nine studies were included; most of them evaluated the association between exposure to air pollutants and the onset of Postpartum Depression (PPD). Two studies showed an association between, respectively, only PM2.5 and both PM2.5 and NO2 exposure and PPD onset 12 months after childbirth, while another study found a significant association between NO2 exposure and PPD occurrence 6 months after childbirth. PBDE blood levels were associated with more severe depressive symptoms. Lastly, one study observed a link between stressful symptoms and exposure to PM2.5, PM10 during pregnancy. CONCLUSION: More comprehensive and uniform studies are required to make a roadmap for future interventions, given the growing relevance of issues such pollution and mental health, particularly during the perinatal period.

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.

Understanding the Interplay between Air Pollution, Biological Variables, and Major Depressive Disorder: Rationale and Study Protocol of the DeprAir Study.

Major depressive disorder (MDD) is a serious and disabling condition, whose etiological mechanisms are not fully understood. The aim of the DeprAir study is to verify the hypothesis that air pollution exposure may exacerbate neuroinflammation with consequent alterations in DNA methylation of genes involved in circadian rhythms and hormonal dysregulation, resulting in the worsening of depressive symptoms. The study population consists of 420 depressed patients accessing the psychiatry unit of the Policlinico Hospital (Milan, Italy), from September 2020 to December 2022. Data collection is still ongoing for about 100 subjects. For each participant demographic and lifestyle information, depression history and characteristics, as well as blood samples, were collected. MDD severity was assessed through five rating scales commonly used in clinical practice to assess the severity of affective symptoms. Exposure to particulate and gaseous air pollutants is assigned to each subject using both air pollution monitoring station measurements and estimates derived from a chemical transport model. DeprAir is the first study investigating in a comprehensive picture whether air pollution exposure could be an important modifiable environmental factor associated with MDD severity and which biological mechanisms mediate the negative effect of air pollution on mental health. Its results will represent an opportunity for preventive strategies, thus entailing a tremendous impact on public health.

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.

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.

Immunogenicity and effectiveness of BNT162b2 COVID-19 vaccine in a cohort of healthcare workers in Milan (Lombardy Region, Northern Italy).

OBJECTIVES: to evaluate immunogenicity and effectiveness of BNT162b2 COVID-19 vaccine in a cohort of healthcare workers (HCWs). DESIGN: cohort study. SETTING AND PARTICIPANTS: in a hospital in Milan (Lombardy Region, Northern Italy) HCWs without ("negative cohort") and with ("positive cohort") history of SARS-CoV-2 infection or elevated serum antibody before the vaccination campaign (27.12.2020) were included. Data collection and follow-up covered the period 27.12.2020-13.05.2022. MAIN OUTCOMES MEASURES: 1. serum anti-spike-1 (anti-S1) antibody levels after vaccination; 2. vaccine effectiveness (VE) against SARS-CoV-2 infections (either symptomatic or not) in the negative cohort. Data on infections were extracted from multiple sources (laboratory, accident reports, questionnaires). Vaccination was treated as a time-dependent variable. Using unvaccinated person-time as reference, hazard ratios (HR) of infections and 95% confidence intervals (95%CI) were calculated with a Cox regression model adjusted for gender, age, and occupation. VE was calculated as (1 - HR)×100. RESULTS: 5,596 HCWs were included, 4,771 in the negative and 825 in the positive cohort. In both cohorts, serum anti-S1 antibodies were high one months after the second dose, halved after six months, and returned to high levels after the third dose. In the negative cohort, 1,401 SARS-CoV-2 infections were identified. VE was 70% (95%CI 54-80; 46 infected) in the first four months after the second dose and later declined to 16% (95%CI 0-43; 97 infected). After the third dose, VE increased to 57% (95%CI 35-71; 61 infected) in the first month but rapidly declined over time, particularly after three months (24% in the fourth month and 1% afterwards). The number of infections avoided by vaccination was estimated to be 643 (95%CI 236-1,237). CONCLUSIONS: in spite of rapidly declining effectiveness, vaccination helped to avoid several hundred infections in the considered hospital.

Body Mass Index Modulates the Impact of Short-Term Exposure to Air Particulate Matter on High-Density Lipoprotein Function.

Air particulate matter (PM) exposure has been associated with increased cardiovascular risk, especially in obesity. By triggering inflammation and oxidative stress, PM could impact atheroprotection by high-density lipoproteins (HDL). The aim of the study was to assess the relationship between short-term exposure to PM and HDL function, and the modifying effect of body mass index (BMI). Daily exposures to PM10 and PM2.5 of 50 subjects with overweight/obesity and 41 healthy volunteers with BMI < 30 kg/m2 were obtained from fixed monitoring stations. HDL function was assessed as promotion of nitric oxide (NO) release by endothelial cells and reduction in cholesterol in macrophages. HDL-induced NO release progressively declined with the increase in BMI. No association was found between HDL function and PM exposure, but a modifying effect of BMI was observed. The positive association between PM10 exposure at day −1 and NO production found at normal BMI values was lost in participants with higher BMI. Similar results were obtained for the reduction in macrophage cholesterol. The loss of the compensatory response of HDL function to PM exposure at increasing BMI levels could contribute to the endothelial dysfunction induced by PM and help to explain the susceptibility of subjects with obesity to air pollution.

Brain-Derived Neurotrophic Factor and Extracellular Vesicle-Derived miRNAs in an Italian Cohort of Individuals With Obesity: A Key to Explain the Link Between Depression and Atherothrombosis.

Background: Obesity and depression are intertwined diseases often associated with an increased risk of cardiovascular (CV) complications. Brain-Derived Neurotrophic Factor (BDNF), altered in the brain both of subjects with depression and obesity, provides a potential link between depression and thrombosis. Since the relationship among peripheral BDNF, depression and obesity is not well-defined, the aim of the present report has been to address this issue taking advantage of the contribution played by extracellular vesicle (EV)-derived miRNAs. Research Process: Associations among circulating BDNF, depression and EV-derived miRNAs related to atherothrombosis have been evaluated in a large Italian cohort of obese individuals (n = 743), characterized by the Beck Depression Inventory (BDI-II) score. Results: BDI-II was negatively associated with BDNF levels without a significant impact of the rs6265 BDNF polymorphism; this association was modified by raised levels of IFN-γ. BDNF levels were linked to an increase of 80 EV-derived miRNAs and a decrease of 59 miRNAs related to atherosclerosis and thrombosis. Network analysis identified at least 18 genes targeted by these miRNAs, 7 of which involved in depression and CV risk. The observation of a possible link among BDNF, depression, and miRNAs related to atherothrombosis and depression in obesity is novel and may lead to a wider use of BDNF as a CV risk biomarker in this specific subject group.

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.

Clinical characteristics of healthcare workers with SARS-CoV-2 infection after vaccination with BNT162b2 vaccine.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had a significant impact worldwide. Vaccines against COVID-19 appear as a tool able to curb out mortality and reduce the circulation of the virus. Little is known so far about the clinical characteristics of individuals who developed SARS-CoV-2 infection after having received the vaccination, as well as the temporal relationship between vaccine administration and symptoms onset. METHODS: Retrospective cohort study among the 3219 healthcare workers (HCWs) of the Fondazione IRCCS Ospedale Maggiore Policlinico of Milano who received a full immunization with the BNT162b2 vaccine and who developed SARS-CoV-2 infection (documented through positive RT-PCR on nasopharyngeal swab) in March-April 2021. RESULTS: Overall, we have identified 15 HCWs with SARS-CoV-2 infection after vaccination, 7 (46.7%) of them were male and the mean age was 38.4 years (SD 14). In 4 of them, the presence of SARS-CoV-2 anti-nucleocapsid (anti-N) antibodies was assessed before vaccination and resulted positive in 1 case. In all HCWs the presence of SARS-CoV-2 anti-spike (anti-S1) antibodies was assessed, on average 42.2 days after the completion of vaccination, with a mean value of 2055 U/mL (SD 1927.3). SARS-CoV-2 infection was ascertained on average 56.2 days after vaccination. The mean cycle threshold (Ct) of SARS-CoV-2 PCR was 26.4, the lineage was characterized in 9 HCWs. None of the HCWs reported a primary or secondary immunodeficiency. Regarding symptoms, they were reported only by 7 (46.7%) HCWs and appeared on average 55 days after the second dose of vaccination. Of those who reported symptoms, one (14.3%) had fever, 7 (100%) rhinitis/conjunctivitis, 4 (57.1%) taste and smell alterations, none had respiratory symptoms, 4 headache/arthralgia (57.1%) and 1 gastrointestinal symptom (14.3%). All symptoms disappeared in a few days and no other unclassified symptoms were reported. CONCLUSIONS: Infections occurring after vaccination with the BNT162b2 vaccine are mostly asymptomatic and are not associated with the serum titre of anti-S1 antibodies. We did not find a predominance of specific viral variants, with several lineages represented.

Air pollution exposure and depression: A comprehensive updated systematic review and meta-analysis.

We provide a comprehensive and updated systematic review and meta-analysis of the association between air pollution exposure and depression, searching PubMed, Embase, and Web of Sciences for relevant articles published up to May 2021, and eventually including 39 studies. Meta-analyses were performed separately according to pollutant type [particulate matter with diameter ≤10 µm (PM10) and ≤2.5 µm (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)] and exposure duration [short- (<30 days) and long-term (≥30 days)]. Test for homogeneity based on Cochran's Q and I2 statistics were calculated and the restricted maximum likelihood (REML) random effect model was applied. We assessed overall quality of pooled estimates, influence of single studies on the meta-analytic estimates, sources of between-study heterogeneity, and publication bias. We observed an increased risk of depression associated with long-term exposure to PM2.5 (relative risk: 1.074, 95% confidence interval: 1.021-1.129) and NO2 (1.037, 1.011-1.064), and with short-term exposure to PM10 (1.009, 1.006-1.012), PM2.5 (1.009, 1.007-1.011), NO2 (1.022, 1.012-1.033), SO2 (1.024, 1.010-1.037), O3 (1.011, 0.997-1.026), and CO (1.062, 1.020-1.105). The publication bias affecting half of the investigated associations and the high heterogeneity characterizing most of the meta-analytic estimates partly prevent to draw very firm conclusions. On the other hand, the coherence of all the estimates after excluding single studies in the sensitivity analysis supports the soundness of our results. This especially applies to the association between PM2.5 and depression, strengthened by the absence of heterogeneity and of relevant publication bias in both long- and short-term exposure studies. Should further investigations be designed, they should involve large sample sizes, well-defined diagnostic criteria for depression, and thorough control of potential confounding factors. Finally, studies dedicated to the comprehension of the mechanisms underlying the association between air pollution and depression remain necessary.

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.

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.

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.