Publications by authors named "Federica Rota"

24 Publications

  • Page 1 of 1

Detection of IgM, IgG and SARS-CoV-2 RNA among the personnel of the University of Milan, March through May 2020: the UNICORN study.

BMJ Open 2021 03 24;11(3):e046800. Epub 2021 Mar 24.

Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy

Objectives: In Italy, the pandemic of COVID-19 resulted in congestion of hospitals and laboratories and probably determined an underestimation of the number of infected subjects, as the molecular diagnosis of SARS-CoV-2 infection was mainly performed on hospitalised patients. Therefore, limited data are available about the number of asymptomatic/paucisymptomatic subjects in the general population across time. To understand SARS-CoV-2 infection in the general population, we have developed a cross-sectional study (the 'UNIversity against CORoNavirus study') to investigate infection trends in asymptomatic/paucisymptomatic subjects in Milan (Italy), between March and June 2020.

Participants: The study population included 2023 subjects asymptomatic at the enrolment.

Primary Outcome Measures: A nasal mid-turbinate swab for the detection of SARS-CoV-2 RNA and blood specimen for testing serum antibodies (immunoglobulin M (IgM) and IgG) were collected.

Results: Subjects showing positivity for the SARS-CoV-2 RNA and/or for anti-SARS-CoV-2 Ig is 237 (11.7%). Only 1.2% (n=25) of the total population had a positive nasal swab for SARS-CoV-2 and the large majority (21/25) of them were observed in March. A total of 226 subjects (11%) had IgM (n=19; 0.9%), IgG (n=155; 7.7%) or both (n=52; 2.6%) against SARS-CoV-2. Subjects with a present or past SARS-CoV-2 infection did not differ from other subjects as regards the number of cohabiting family members, travels, fever and upper and lower respiratory infection episodes.

Conclusions: Results from the present study support the hypothesis that the actual spread of the virus in Lombardy was underestimated in the official records. However, as it is not known how long Ig persist, numbers should be taken cautiously.
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http://dx.doi.org/10.1136/bmjopen-2020-046800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992385PMC
March 2021

Bronchiolitis and SARS-CoV-2.

Arch Dis Child 2021 Mar 11. Epub 2021 Mar 11.

Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardia, Italy.

Background: It has been speculated that the SARS-CoV-2 was already widespread in western countries before February 2020.

Methods: We gauged this hypothesis by analysing the nasal swab of infants with either bronchiolitis or a non-infectious disease admitted to the Ospedale Maggiore, Milan (one of the first epicentres of SARS-CoV-2 outbreak in Europe) from November 2019.

Results: The SARS-CoV-2 RNA was never detected in 218 infants with bronchiolitis (95 females, median age 4.9 months) and 49 infants (22 females, median age 5.6 months) with a non-infectious disease between November 2019 and February 2020. On the contrary, two infants hospitalised for bronchiolitis between March and April 2020 tested positive for SARS-CoV-2.

Conclusions: This study does not support the hypothesis that SARS-CoV-2 was already circulating among infants before the official outbreak of SARS-CoV-2 infection. However, it shows for the first time that SARS-CoV-2 might cause bronchiolitis requiring hospitalisation.
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http://dx.doi.org/10.1136/archdischild-2020-321108DOI Listing
March 2021

INSIDE Project: Individual Air Pollution Exposure, Extracellular Vesicles Signaling and Hypertensive Disorder Development in Pregnancy.

Int J Environ Res Public Health 2020 12 4;17(23). Epub 2020 Dec 4.

EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy.

Hypertensive disorders are common complications during pregnancy (HDP) with substantial public health impact. Acute and chronic particulate matter (PM) exposure during pregnancy increases the risk of HDP, although the underlying molecular mechanisms remain unclear. Extracellular vesicles (EVs) may be the ideal candidates for mediating the effects of PM exposure in pregnancy as they are released in response to environmental stimuli. The INSIDE project aims to investigate this mechanism in pregnancy outcomes. The study population is enrolled at the Fetal Medicine Unit of Fondazione IRCCS Ca'Granda-Ospedale Maggiore Policlinico at 10-14 weeks of gestation. Exposure to PM and PM is assessed using the flexible air quality regional model (FARM) and Bayesian geostatistical models. Each woman provides a blood sample for EV analysis and circulating biomarker assessment. Moreover, a subgroup of recruited women (n = 85) is asked to participate in a cardiovascular screening program including a standard clinical evaluation, a non-invasive assessment of right ventricular function, and pulmonary circulation at rest and during exercise. These subjects are also asked to wear a personal particulate sampler, to measure PM, PM, and PM. The INSIDE study is expected to identify the health impacts of PM exposure on pregnancy outcomes.
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http://dx.doi.org/10.3390/ijerph17239046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731194PMC
December 2020

Blood-derived extracellular vesicles isolated from healthy donors exposed to air pollution modulate in vitro endothelial cells behavior.

Sci Rep 2020 11 18;10(1):20138. Epub 2020 Nov 18.

EPIGET LAB, Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Via San Barnaba, 8, 20122, Milan, Italy.

The release of Extracellular Vesicles (EVs) into the bloodstream is positively associated with Particulate Matter (PM) exposure, which is involved in endothelial dysfunction and related to increased risk of cardiovascular disease. Obesity modifies the effects of PM exposure on heart rate variability and markers of inflammation, oxidative stress, and acute phase response. We isolated and characterized plasmatic EVs from six healthy donors and confirmed a positive association with PM exposure. We stratified for Body Mass Index (BMI) and observed an increased release of CD61+ (platelets) and CD105+ (endothelium) derived-EVs after high PM level exposure in Normal Weight subjects (NW) and no significant variations in Overweight subjects (OW). We then investigated the ability to activate endothelial primary cells by plasmatic EVs after both high and low PM exposure. NW-high-PM EVs showed an increased endothelial activation, measured as CD105+/CD62e+ (activated endothelium) EVs ratio. On the contrary, cells treated with OW-high-PM EVs showed reduced endothelial activation. These results suggest the ability of NW plasmatic EVs to communicate to endothelial cells and promote the crosstalk between activated endothelium and peripheral cells. However, this capacity was lost in OW subjects. Our findings contribute to elucidate the role of EVs in endothelial activation after PM exposure.
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http://dx.doi.org/10.1038/s41598-020-77097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674466PMC
November 2020

Extracellular Vesicles Released by Colorectal Cancer Cell Lines Modulate Innate Immune Response in Zebrafish Model: The Possible Role of Human Endogenous Retroviruses.

Int J Mol Sci 2019 Jul 26;20(15). Epub 2019 Jul 26.

EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy.

Extracellular vesicles (EVs) are important components of the metastatic niche and are crucial in infiltration, metastasis, and immune tolerance processes during tumorigenesis. We hypothesized that human endogenous retroviruses (HERV) positive EVs derived from tumor cellsmay have a role in modulating the innate immune response. The study was conducted in two different colorectal cancer cell lines, representing different stages of cancer development: Caco-2, derived from a non-metastatic colorectal adenocarcinoma, and SK-CO-1, derived from metastatic colorectal adenocarcinoma (ascites). Both cell lines were treated with decitabine to induce global hypomethylation and to reactivate HERV expression. EVs were quantified by nanoparticle tracking analysis, and HERV-positive EV concentrations were measured by flow cytometry. The effect of EVs isolated from both untreated and decitabine-treated cells on the innate immune response was evaluated by injecting them in zebrafish embryos and then assessing Interleukin 1β (), Interleukin 10 (), and the myeloperoxidase () expression levels by real-time qPCR. Interestingly, HERV-K positive EVs concentrations were significantly associated with a reduced expression of and , supporting our hypothesis that HERV-positive EVs may act as immunomodulators in tumor progression. The obtained results open new perspectives about the modulation of the immune response in cancer therapy.
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http://dx.doi.org/10.3390/ijms20153669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695895PMC
July 2019

[The rhythm of life].

Epidemiol Prev 2018 Sep-Dec;42(5-6):378-379

Fondazione IRCCS Ca' Granda Ospedale maggiore policlinico, Clinica del lavoro L. Devoto, Milano.

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http://dx.doi.org/10.19191/EP18.5-6.P378.110DOI Listing
September 2019

[The epigenetic relevance of the first 1,000 days].

Epidemiol Prev 2018 May-Aug;42(3-4):255-256

Fondazione IRCCS Ca' Granda Ospedale maggiore policlinico, Clinica del lavoro L. Devoto, Milano.

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http://dx.doi.org/10.19191/EP18.3-4.P255.075DOI Listing
September 2019

[Caress your DNA, live healthier!]

Epidemiol Prev 2018 Mar-Apr;42(2):180-181

Fondazione IRCCS Ca'Granda Ospedale maggiore policlinico, Clinica del lavoro L. Devoto, Milano.

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http://dx.doi.org/10.19191/EP18.2.P180.049DOI Listing
March 2019

Epigenetic and Transcriptional Modifications in Repetitive Elements in Petrol Station Workers Exposed to Benzene and MTBE.

Int J Environ Res Public Health 2018 04 12;15(4). Epub 2018 Apr 12.

EPIGET, Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, via San Barnaba 8, 20122 Milan, Italy.

Benzene, a known human carcinogen, and methyl -butyl ether (MTBE), not classifiable as to its carcinogenicity, are fuel-related pollutants. This study investigated the effect of these chemicals on epigenetic and transcriptional alterations in DNA repetitive elements. In 89 petrol station workers and 90 non-occupationally exposed subjects the transcriptional activity of retrotransposons (LINE-1, Alu), the methylation on repeated-element DNA, and of H3K9 histone, were investigated in peripheral blood lymphocytes. Median work shift exposure to benzene and MTBE was 59 and 408 µg/m³ in petrol station workers, and 4 and 3.5 µg/m³, in controls. Urinary benzene (BEN-U), -phenylmercapturic acid, and MTBE were significantly higher in workers than in controls, while -muconic acid (-MA) was comparable between the two groups. Increased BEN-U was associated with increased and expression; moreover, increased -MA was associated with increased and and LINE-1 (L1)-5'UTR expression. Among repetitive element methylation, only L1-Pa5 was hypomethylated in petrol station workers compared to controls. While L1-Ta and Alu-YD6 methylation was not associated with benzene exposure, a negative association with urinary MTBE was observed. The methylation status of histone H3K9 was not associated with either benzene or MTBE exposure. Overall, these findings only partially support previous observations linking benzene exposure with global DNA hypomethylation.
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http://dx.doi.org/10.3390/ijerph15040735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923777PMC
April 2018

[Epigenetics and air pollution: a "hot" topic].

Epidemiol Prev 2018 Jan-Feb;42(1):94-95

EPIGET (epidemiologia, epigenetica e tossicologia) Lab, Dipartimento di scienze cliniche e di comunità, Università degli Studi di Milano, Clinica del lavoro L. Devoto, Milano.

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http://dx.doi.org/10.19191/EP18.1.P094.026DOI Listing
March 2019

[Homo faber fortunae suae?]

Epidemiol Prev 2017 Sep-Dec;41(5-6):316-317

Dipartimento di Scienze Cliniche e di Comunità, "Clinica del Lavoro Luigi Devoto", Università degli Studi di Milano.

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http://dx.doi.org/10.19191/EP17.5-6.P316.098DOI Listing
February 2019

Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation.

Part Fibre Toxicol 2017 08 24;14(1):32. Epub 2017 Aug 24.

EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122, Milan, Italy.

Background: Exposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter ≤ 10 μm (PM) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study.

Results: Short-term exposure to PM (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio™ 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM exposure and fibrinogen levels.

Conclusions: Research on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development.
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http://dx.doi.org/10.1186/s12989-017-0214-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594543PMC
August 2017

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Nature 2017 01 21;541(7635):81-86. Epub 2016 Dec 21.

German Center for Diabetes Research (DZD), München-Neuherberg, Germany.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10, range P = 9.2 × 10 to 6.0 × 10; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10, range P = 5.5 × 10 to 6.1 × 10, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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http://dx.doi.org/10.1038/nature20784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570525PMC
January 2017

Hydroquinone induces DNA hypomethylation-independent overexpression of retroelements in human leukemia and hematopoietic stem cells.

Biochem Biophys Res Commun 2016 06 3;474(4):691-695. Epub 2016 May 3.

Department of Life Sciences, University of Parma, Parma, Italy. Electronic address:

Hydroquinone (HQ) is an important benzene-derived metabolite associated with acute myelogenous leukemia risk. Although altered DNA methylation has been reported in both benzene-exposed human subjects and HQ-exposed cultured cells, the inventory of benzene metabolite effects on the epigenome is only starting to be established. In this study, we used a monocytic leukemia cell line (THP-1) and hematopoietic stem cells (HSCs) from cord blood to investigate the effects of HQ treatment on the expression of the three most important families of retrotransposons in the human genome: LINE-1, Alu and Endogenous retroviruses (HERVs), that are normally subjected to tight epigenetic silencing. We found a clear tendency towards increased retrotransposon expression in response to HQ exposure, more pronounced in the case of LINE-1 and HERV. Such a partial loss of silencing, however, was generally not associated with HQ-induced DNA hypomethylation. On the other hand, retroelement derepression was also observed in the same cells in response to the hypomethylating agent decitabine. These observations suggest the existence of different types of epigenetic switches operating at human retroelements, and point to retroelement activation in response to benzene-derived metabolites as a novel factor deserving attention in benzene carcinogenesis studies.
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http://dx.doi.org/10.1016/j.bbrc.2016.05.010DOI Listing
June 2016

Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.

Lancet Diabetes Endocrinol 2015 Jul 18;3(7):526-534. Epub 2015 Jun 18.

​ (J C Chambers PhD, M Loh PhD, B Lehne PhD, W R Scott MRCP, W Zhang PhD, G Campanella MSc, M Chadeau-Hyam PhD, U Afzal MRCP, Prof P Froguel PhD, Prof P Vineis MD, Prof M-R Jarvelin PhD, Prof P Elliott PhD) (J C Chambers, Prof M-R Jarvelin, Prof P Elliott, Prof J S Kooner FRCP) (W R Scott, S-T Tan MRCP, Prof J Scott PhD, Prof J S Kooner) (J Abbott PhD) (J C Chambers, W Zhang, S-T Tan, U Afzal, Prof J S Kooner) (J C Chambers, P Punjabi FRCS, Prof J S Kooner) (M Loh) (C Blancher PhD) (A Drong PhD, Prof M I McCarthy MD) (Prof M I McCarthy) (J Kriebel PhD, S Wahl MSc, C Gieger PhD, H Grallert PhD) (C Gieger) (J Kriebel, S Wahl, C Gieger, B Thorand PhD, H Grallert) (H Prokisch PhD) (J Kriebel, S Wahl, B Thorand, H Grallert) (V Motta PhD, F Rota PhD, L Tarantini PhD, B Albetti PhD, Prof P A Bertazzi MD, V Bollati PhD) (Prof M Ala-Korpela PhD) (H R Elliott Dip Biol, R C Richmond BA, R Caiazzo PhD, T R Gaunt FRCP, Prof C L Relton PhD) (L Yengo PhD, Prof F Pattou PhD, R Caiazzo, S Cauchi PhD, Prof P Froguel) (L Yengo, S Cauchi, Prof P Froguel) (L Yengo, Prof F Pattou, S Cauchi, Prof P Froguel) (M Adamowicz-Brice PhD, Prof T J Aitman PhD) (K Bozaoglu PhD, R Caiazzo, J Jowett PhD) (Z Y Mok BSc, H K Ng BSc, M A Rozario BSc, R Soong PhD) (E-S Tai PhD) (E-S Tai) (Prof F Pattou) (H Prokisch) (Prof M Ala-Korpela, A J Kangas MSc, P Soininen PhD) (M Loh, Prof M-R Jarvelin) (Prof M-R Jarvelin) (Prof M Ala-Korpela, P Soininen) (Prof M-R Jarvelin) (Prof M Ala-Korpela) (Prof O Ammerpohl PhD) (Prof C Schafmayer MD) (Prof J Danesh FRCP) (Prof S de Lusignan PhD, Prof S Jones PhD) (Prof T Illig PhD) (S Jha MRCP) (A Kasturiratne MD, Prof A R Wickremasinghe PhD) (N Kato PhD) (N Kotea PhD) (S Kowlessur Dip Pub Health Admin) (J Pitkäniemi PhD) (Prof J Tuomilehto PhD) (J Pitkäniemi) (D Saleheen PhD) (D Saleheen) (D Saleheen) (E-S Tai) (Prof S A Kyrtopoulos PhD) (C Herder PhD) (C Herder) (Prof J Hampe MD) (R Soong) (Prof P Vineis) (Prof M I McCarthy).

Background: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes.

Methods: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians.

Findings: 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)).

Interpretation: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians.

Funding: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.
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http://dx.doi.org/10.1016/S2213-8587(15)00127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724884PMC
July 2015

Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study.

BMC Public Health 2014 Nov 4;14:1137. Epub 2014 Nov 4.

Molecular Epidemiology and Environmental Epigenetics Laboratory, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.

Background: Despite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE ("Susceptibility to Particle Health Effects, miRNAs and Exosomes") project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes.

Methods/design: The study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs.

Discussion: SPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.
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http://dx.doi.org/10.1186/1471-2458-14-1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242553PMC
November 2014

Microvesicle-associated microRNA expression is altered upon particulate matter exposure in healthy workers and in A549 cells.

J Appl Toxicol 2015 Jan 7;35(1):59-67. Epub 2014 Feb 7.

Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy; Epidemiology Unit, Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy.

Cardiovascular disease risk has been consistently linked with particulate matter (PM) exposure. Cell-derived microvesicles (MVs) are released into plasma and transfer microRNAs (miRNAs) between tissues. MVs can be produced by the respiratory system in response to proinflammatory triggers, enter the circulatory system and remotely modify gene expression in cardiovascular tissues. However, whether PM affects MV signaling has never been investigated. In this study, we evaluated expression of microRNAs contained within plasma MVs upon PM exposure both in vivo and in vitro. In the in vivo study, we isolated plasma MVs from healthy steel plant workers before and after workplace PM exposure. We measured the expression of 88 MV-associated miRNAs by real-time polymerase chain reaction. To assess a possible source of the MV miRNAs identified in vivo, we measured their miRNA expression in PM-treated A549 pulmonary cell lines in vitro. MiRNA profiling of plasma MVs showed 5.62- and 13.95-fold increased expression of miR-128 and miR-302c, respectively, after 3 days of workplace PM exposure (P < 0.001). According to Ingenuity Pathway Analysis, miR-128 is part of coronary artery disease pathways, and miR-302c is part of coronary artery disease, cardiac hypertrophy and heart failure pathways. In vitro experiments confirmed a dose-dependent expression of miR-128 in MVs released from A549 cells after 6 h of PM treatment (P = 0.030). MiR-302c was expressed neither from A549 cells nor in reference lung RNA. These results suggest novel PM-activated molecular mechanisms that may mediate the effects of air pollution and could lead to the identification of new diagnostic and therapeutic interventions.
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http://dx.doi.org/10.1002/jat.2987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125569PMC
January 2015

Role of CYP1A2 polymorphisms on lung cancer risk in a prospective study.

Cancer Genet 2012 Jun;205(6):278-84

Occupational Health Section, Department of Cardiological, Thoracic and Vascular Sciences, Università di Padova, Italy.

Cytochrome P4501A2 (CYP1A2) is a key enzyme for lung carcinogen activation and lung inflammation. We studied the interactions of the CYP1A2 functional variants -3860G/A(rs2069514),-2467T/delT(rs3569413),-163C/A(rs762551)] with occupational/environmental carcinogenic exposures in the development of lung cancer in a case-control study nested in the Danish prospective cohort "Diet, Cancer and Health." At enrollment (1993-1997), blood samples for genotype analyses and information on lifestyle were collected 5 (mean value) years before the onset of the disease. The study population included 425 lung cancer cases and 786 subcohort members, who were gender- and age-matched. We found that -163A carriers were at increased risk of lung cancer (P=0.035) in a multivariate COX regression model, which was adjusted for personal habits (i.e., cumulative smoking, passive smoke at home, alcohol intake, and fruit intake) and occupational exposure. Additionally, the interaction between -2467delT and smoking increases lung cancer risk in males, especially light smokers (<21.5 pack-years, P=0.004). The increased lung cancer risk found in -163C carriers, independent of smoking status, and in -2467delT male smokers, suggests that these variants could influence lung cancer development through different mechanisms (i.e. lung carcinogen activation and lung inflammation).
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http://dx.doi.org/10.1016/j.cancergen.2012.02.004DOI Listing
June 2012

Epigenetic effects of shiftwork on blood DNA methylation.

Chronobiol Int 2010 Jul;27(5):1093-104

Dipartimento di Medicina del Lavoro, Università degli Studi di Milano, Milan, Italy.

In the present study, the authors investigated the effects of shiftwork exposure on DNA methylation using peripheral blood DNA from subjects working in two chemical plants in Northern Italy. The investigation was designed to evaluate (a) DNA methylation changes in Alu and long interspersed nuclear element-1 (LINE-1) repetitive elements as a surrogate of global methylation and (b) promoter methylation of glucocorticoid receptor (GCR), tumor necrosis factor alpha (TNF-alpha), and interferon-gamma (IFN-gamma). One hundred and fifty white male workers (mean +/- SD: 41.0 +/- 9 yrs of age) were examined: 100 3 x 8 rotating shiftworkers (40.4 +/- 8.7 yrs of age) and 50 day workers (42.2 +/- 9.4 yrs of age). The authors used bisulfite-pyrosequencing to estimate repetitive elements and gene-specific methylation. Multiple regression analysis, adjusted for age, body mass index (BMI), and job seniority, did not show any significant association between the five DNA methylation markers and shiftwork. However, job seniority, in all subjects, was significantly associated with Alu (beta = -0.019, p = .033) and IFN-gamma (beta = -0.224, p < .001) methylation, whereas TNF-alpha methylation was inversely correlated with age (beta = -0.093, p < .001). Considering only shiftworkers, multiple regression analysis, adjusted for age, BMI, and job seniority, showed a significant difference between morning and evening types in TNF-alpha methylation (mean morning type [MT] 11.425 %5mC versus evening type [ET] 12.975 %5mC; beta = 1.33, p = .022). No difference was observed between good and poor tolerance to shiftwork. Increasing job seniority (<5, 5-15, >15 yrs) was associated with significantly lower Alu (beta = -0.86, p = .006) and IFN-gamma methylation (beta = -6.50, p = .007) after adjustment for age, BMI, and morningness/eveningness. In addition, GCR significantly increased with length of shiftwork (beta = 3.33, p = .05). The data showed alterations in blood DNA methylation in a group of shiftworkers, including changes in Alu repetitive elements methylation and gene-specific methylation of IFN-gamma and TNF-alpha promoters. Further studies are required to determine the role of such alterations in mediating the effects of shiftwork on human health.
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http://dx.doi.org/10.3109/07420528.2010.490065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647609PMC
July 2010

TMS-adaptation reveals abstract letter selectivity in the left posterior parietal cortex.

Cereb Cortex 2009 Oct 15;19(10):2321-5. Epub 2009 Jan 15.

Department of Psychology, University of Pavia, Pavia, Italy.

Activation of the left posterior parietal cortex (PPC) has been associated with the encoding of letters independent of visual form. Here we used transcranial magnetic stimulation (TMS)-adaptation to investigate whether this abstract letter selectivity plays a causal role in letter processing. Visual adaptation was used to manipulate the initial activation state of neurons tuned to different letters prior to the application of TMS, after which subjects performed a detection task on letters that were presented in a different case from the adapting letter. After adaptation, TMS applied over the left PPC facilitated the detection of the adapted letter, whereas it had no impact on the detection of nonadapted letters. TMS applied over the right PPC had no significant effect on either type of letter. This interaction between adaptation and the effects of left PPC TMS demonstrates that adaptation modulated neural activity in the left PPC and thus demonstrates abstract letter selectivity in this region. Importantly, as the adapted letter and the target letters were presented in different cases, this finding demonstrates that the left PPC plays a causal role in letter processing independent of visual form.
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http://dx.doi.org/10.1093/cercor/bhn249DOI Listing
October 2009

Using state-dependency of transcranial magnetic stimulation (TMS) to investigate letter selectivity in the left posterior parietal cortex: a comparison of TMS-priming and TMS-adaptation paradigms.

Eur J Neurosci 2008 Nov;28(9):1924-9

Department of Psychology, University of Pavia, Pavia, Italy.

The state-dependency of transcranial magnetic stimulation (TMS) can be used to investigate the neural properties of subregions of the stimulated region. The objective of the present study was to determine whether state-dependency can reveal letter selectivity in the left posterior parietal cortex (PPC), a region known to contain letter-selective neurons. In two experiments, we used visual priming and adaptation to modulate the initial activation state of the left PPC prior to application of TMS. In the priming experiment, TMS was applied over the left PPC during the delay between the prime and the target stimulus on each experimental trial. Left PPC TMS reversed the effects of priming by facilitating the detection of non-primed letters, whereas detection of primed letters was unaffected. As neurons tuned to non-primed letters were less active at the time of TMS application than neurons tuned to the primed letters, this finding demonstrates that TMS preferentially facilitates the detection of attributes encoded by the less active neural populations. A similar facilitation of the less active neural populations was observed when adaptation was used to suppress letter-selective neurons prior to application of TMS. Our study demonstrates that TMS-priming and TMS-adaptation paradigms can reveal letter selectivity in the left PPC and thus be useful in the study of language processes. Our results also show that the state-dependent TMS effects obtained with visual priming are similar to those found with TMS adaptation: in both cases, attributes encoded by the less active neural populations are preferentially facilitated.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06466.xDOI Listing
November 2008

Sterile abscesses complicating monoclonal gammopathy of undetermined significance.

Eur J Haematol 2008 Sep 28;81(3):246. Epub 2008 Jun 28.

Department of Clinical Immunology, S. Camillo-Forlanini Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/j.1600-0609.2008.01084.xDOI Listing
September 2008