A Mantovani

Istituto Superiore di Sanità, Roma, Latium, Italy

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Publications (451)2246.91 Total impact

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    ABSTRACT: In Latium (central Italy), arsenic concentrations exceeding the regulatory limit of 10 μg/L for drinking water are present in groundwater from a large area of volcanic origin. At least in part of the area, high arsenic concentrations have been detected also in soil and phytoavailable geogenic arsenic enters the food chain. As a result, local population may be exposed to inorganic arsenic via water and also through consumption of food with higher than background arsenic concentrations. A cross sectional study was conducted to assess inorganic arsenic exposure and metabolism in 269 residents of 27 municipalities in the provinces of Viterbo, Rome and Latina. Total arsenic in toenails and the sum of inorganic arsenic and methylated metabolites in urine, the latter determined by HPLC-ICP-MS, were used as biomarkers of inorganic arsenic exposure. All the subjects involved in the study provided samples of the water(s) used for drinking and cooking as well as detailed information on water use. To get an insight into dietary intake from locally-processed food, inorganic arsenic in bread samples collected in affected municipalities of the three provinces was determined and compared to background levels of samples from reference areas. 30% of the sample used bottled water or resorted to water treatment in order to lower the arsenic content <10 μg/L (Group 1), 51% of the sample drank bottled water and used tap water with an arsenic content exceeding 10 μg/L for cooking only (Group 2), 19% of the sample used tap water with an arsenic content exceeding 10 μg/L for both drinking and cooking (Group 3). Nail arsenic was higher for Group 2 and 3 compared to Group 1, whereas all groups had higher nail arsenic than the reference group. The sum of inorganic arsenic and related metabolites in urine was higher in Group 3 than in the other two groups, and higher in Group 2 compared to Group 1. White bread from the study area showed significantly higher inorganic arsenic levels compared to samples from reference areas. Use of toenail arsenic as biomarker of long-term exposure allowed to retrospectively reconstruct exposure irrespective of recent modifications due to changes in water use. In Group 3, urinary concentration of inorganic arsenic and metabolites exceeded the upper limit of the reference concentration range for the Italian population. Inter-individual variability of the efficiency of arsenic metabolism in the study population was substantial indicating that a subgroup of the population is more susceptible to the toxic effects of inorganic arsenic owing to a lower methylation capability.
    Annali di igiene: medicina preventiva e di comunità 01/2015; 27(1):39-51.
  • Reproductive Toxicology 09/2014; 48:13–14. DOI:10.1016/j.reprotox.2014.07.005 · 2.77 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):819-819. DOI:10.1136/annrheumdis-2014-eular.3387 · 9.27 Impact Factor
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    ABSTRACT: Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and, like C-reactive protein, is independently associated with the risk of developing vascular events. Aim of this study was to investigate, in two large population-based surveys, the Bruneck Study and the PLIC Study, whether PTX3 plasma levels predict the progression of common carotid artery intima-media thickness (CCA-IMT), a surrogate marker of atherosclerosis, in the general population during 5 or 6 years of follow-up. In the Bruneck Study, PTX3 plasma levels did not predict a faster progression of CCA-IMT either in the carotid artery or in the femoral artery. This finding was confirmed in the PLIC Study where subjects within the highest tertile of PTX3 did not show an increased progression of CCA-IMT. PTX3 plasma levels were also not associated with the fastest maximum IMT progression. In summary, in more than 2400 subjects from the general population, PTX3 plasma level is neither an independent predictor of progression of subclinical atherosclerosis in different arterial territories, including carotid and femoral arteries nor of incident cardiovascular events. These findings support the relevance of investigating the predictive value of PTX3 plasma levels only in specific settings, like overt CVD, heart failure or acute myocardial infarction.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 12/2013; DOI:10.1016/j.numecd.2013.10.030 · 3.88 Impact Factor
  • Reproductive Toxicology 11/2013; 41:16. DOI:10.1016/j.reprotox.2013.06.010 · 2.77 Impact Factor
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    ABSTRACT: Background: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. Methods: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-KrasG12D mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. Results: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1+ and -CL1+. In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. Conclusion: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.
    British Journal of Cancer 10/2013; 109(9). DOI:10.1038/bjc.2013.565 · 4.82 Impact Factor
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    The Journal of Immunology 09/2013; 191(6). · 5.36 Impact Factor
  • Annual Joint Conference of the International-Cytokine-Society and the; 09/2013
  • Annual Joint Conference of the International-Cytokine-Society and the; 09/2013
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    ABSTRACT: Fish represents source of nutrients and major dietary vehicle of lipophilic persistent contaminants. The study compared the effects of two legacy and two emerging fish pollutants (hexabromocyclododecane HBCD; 2,2',4,4'-Tetrabromodiphenyl ether BDE-47; 2,2',4,4',5,5'-Hexachlorobiphenyl PCB-153; 2,3,7,8-Tetrachlorodibenzo-p-doxin TCDD) in juvenile female mice exposed through a salmon based rodent diet for 28 days (dietary doses: HBCD 199 mg/kg bw/day; BDE-47 450 μg/kg bw/day; PCB-153 195 μg/kg bw/day; TCDD 90 ng/kg bw/day). Dose levels were comparable to previously reported developmental Lowest Observed Adverse Effect Levels. None of the treatments elicited signs of overt toxicity, but HBCD increased relative liver weight. All compounds caused changes in liver, thymus and thyroid; spleen was affected by BDE-47 and PCB-153; no effects were seen in uterus and adrenals. Strongest effects in thyroid follicles were elicited by PCB-153, in thymus and liver by BDE-47. HBCD and BDE-47 induced liver fatty changes, but appeared to be less potent in the other tissues. HBCD, BDE-47 and TCDD increased serum testosterone levels and the testosterone/estradiol ratio, suggesting a potential involvement of pathways related to sex steroid biosynthesis and/or metabolism. The results support the role of toxicological studies on juvenile rodents in the hazard characterization of chemicals, due to endocrine and/or immune effects.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 03/2013; 56. DOI:10.1016/j.fct.2013.02.056 · 2.61 Impact Factor
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    ABSTRACT: Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and, like C-reactive protein, is independently associated with the risk of developing vascular events. Aim of this study was to investigate, in two large population-based surveys, the Bruneck Study and the PLIC Study, whether PTX3 plasma levels predict the progression of common carotid artery intima-media thickness (CCA-IMT), a surrogate marker of atherosclerosis, in the general population during 5 or 6 years of follow-up. In the Bruneck Study, PTX3 plasma levels did not predict a faster progression of CCA-IMT either in the carotid artery or in the femoral artery. This finding was confirmed in the PLIC study where subjects within the highest tertile of PTX3 did not show an increased progression of CCA-IMT. PTX3 plasma levels were also not associated with the fastest maximum IMT progression. In summary, in more than 2400 subjects from the general population, PTX3 plasma level is neither are independent predictor of progression of subclinical atherosclerosis in different arterial territories, including carotid and femoral arteries nor of incident cardiovascular events. These findings support the relevance of investigating the predictive value of PTX3 plasma levels only in specific settings, like overt CVD, heart failure or acute myocardial infarction.
  • Blood 09/2012; 120(13):2773-2773. DOI:10.1182/blood-2012-08-447797 · 10.43 Impact Factor
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    ABSTRACT: The long pentraxin PTX3 is a soluble Pattern Recognition Molecule (sPRM) with non-redundant roles in resistance to selected pathogens, such as the opportunistic fungus Aspergillus fumigatus. PTX3 facilitates recognition and phagocytosis of fungal conidia mainly by polymorphonuclear neutrophils (PMNs) via Fcγ receptors (FcγRs) and alternative complement pathway (ACP) mechanisms. The human PTX3 protein contains a single N-glycosylation site with complex type sialylated oligosaccharides that has been involved in a number of PTX3 functions [1]. The present study was designed to characterize the role of this post translational modification in the PTX3-depedent recognition and phagocytosis of A. fumigatus. This microorganism has developed several strategies to evade the immune response, such as attracting onto the conidial wall inhibitors of the ACP, like factor H (FH, a ligand of PTX3). Here we present preliminary evidences on the effect of PTX3 on FH engagement by A. fumigatus.Methods Recombinant as well as natural human PTX3 (i.e., from PMNs) was purified by immunoaffinity chromatography and the attached oligosaccharides were analyzed using glycosidases, lectin blotting and mass spectrometry. A range of PTX3 glycoforms were made in vitro by enzymatic hydrolysis of terminal monosaccharides of the recombinant protein. The opsonic and pro-phagocytic activities of these variants were characterized in buffer solutions and whole human peripheral blood, respectively, by flow cytometry. The influence of PTX3 on FH binding to conidia was studied in competition assays using microtiter plates.ResultsComplex-type sugars were found on PTX3 of both natural and recombinant origins. These showed heterogeneity with regard to the relative content of terminal sialic acid (SA) and bi-, tri- and tetrantennary glycans, depending on the cellular source. Enzymatic removal of SA caused ∼50% reduction of PTX3 binding to A. fumigatus conidia, with no further change due to additional deglycosylation. Conversely, saccharide hydrolysis had no effect on PTX3 binding to PMNs, where FcγRs have been proposed as putative receptors of this pentraxin [1]. However, consistent with binding data from conidia, desialylated PTX3 showed reduced potentiation of conidia phagocytosis by PMNs as compared to the unmodified protein. Also, we observed that PTX3 inhibits the binding of FH to A. fumigatus conidia, even when these were pre-opsonised with the long pentraxin and FH was applied at physiologically relevant concentrations.Conclusion Different pathogens express neuraminidases on their surface during infection and natural immunity cells, such as PMNs, mobilize intracellular neuraminidases to the plasma membrane upon inflammation. Here, we report that the glycosylation status of the sPRM PTX3 changes, with respect to SA, depending on cellular source and perhaps inducing stimuli. We describe that SA modulates the PTX3-dependent recognition and phagocytosis of A. fumigatus, which points to glycosylation as a strategy to tune PTX3 functions in innate immunity. Furthermore, we provided evidences that PTX3 impairs the interaction of FH with A. fumigatus, where this might link to a new mechanism to counterbalance the complement evasion strategy exploited by this pathogen.
    Cytokine 09/2012; 59(3):566. DOI:10.1016/j.cyto.2012.06.244 · 2.87 Impact Factor
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    ABSTRACT: Chemokine receptors include a set of molecules referred to as “atypical” chemokine receptors (ACR) because unable to induce directional cell migration and elicit conventional GPCR signalling. As no signaling activity has been observed after ACR engagement by their ligands, they are presently considered “silent” receptors. D6 is an ACR with scavenger activity on inflammatory CC chemokines with a non-redundant role for appropriate regulation of innate immunity and inflammation.MethodsD6 expression was evaluated by FACS and confocal microscopy. Chemokine degradation was measured by ELISA test. Protein phosphorylation levels were detected by western blot.ResultsOur previous data showed that, differently from CCR5, ligand induces D6 up-regulation on plasma membrane through a rapid mobilization of receptor from recycling endosomes, thus improving its scavenging performance. Here we report that in cells expressing D6 or CCR5, ligand engagement causes a massive actin cytoskeleton reorganization and changes receptors colocalization with actin filaments in a completely opposite fashion. Both receptors signal to actin cytoskeleton by phosphorylating cofilinA through the Rac1-PAK1-LIMK1-dependent pathway. However, opposite to CCR5, D6 activates this pathway via a beta-arrestin-dependent, G protein-independent mechanism. Inhibition of each component of this signaling cascade completely abrogates D6 adaptive upregulation and scavenging activity.ConclusionD6, and possibly ACR in general, are signaling receptors exerting their regulatory functions on inflammation and immunity via the activation of a distinct signaling pathway.
    Cytokine 09/2012; 59(3):532. DOI:10.1016/j.cyto.2012.06.125 · 2.87 Impact Factor
  • G J Graham, M Locati, A Mantovani, A Rot, M Thelen
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    ABSTRACT: A subset of chemokine receptors, initially called "silent" on the basis of their apparent failure to activate conventional signalling events, has recently attracted growing interest due to their ability to internalize, degrade, or transport ligands and thus modify gradients and create functional chemokine patterns in tissues. These receptors recognize distinct and complementary sets of ligands with high affinity, are strategically expressed in different cellular contexts, and lack structural determinants supporting Gα(i) activation, a key signalling event in cell migration. This is in keeping with the hypothesis that they have evolved to fulfil fundamentally different functions to the classical signalling chemokine receptors. Based on these considerations, these receptors (D6, Duffy antigen receptor for chemokines (DARC), CCX-CKR1 and CXCR7) are now collectively considered as an emerging class of 'atypical' chemokine receptors. In this article, we review the biochemistry and biology of this emerging chemokine receptor subfamily.
    Immunology letters 07/2012; 145(1-2):30-8. DOI:10.1016/j.imlet.2012.04.004 · 2.37 Impact Factor
  • Digestive and Liver Disease 03/2012; 44:S55. DOI:10.1016/S1590-8658(12)00142-9 · 2.89 Impact Factor
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    P Allavena, A Mantovani
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    ABSTRACT: Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2(+) monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti-cancer treatments.
    Clinical & Experimental Immunology 02/2012; 167(2):195-205. DOI:10.1111/j.1365-2249.2011.04515.x · 3.28 Impact Factor
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    ABSTRACT: Many heavy metals are essential nutrients for a healthy life. However, significant evidence supports prolonged prenatal exposure as a risk factor for several adverse health effects. The aim of this study is to evaluate the presence of heavy metals in human amniotic fluid (AF) to demonstrate that there is an early fetal in utero exposure. The concentrations of a variety of heavy metals, including Be, Ag, Ba, Pb, U, Hg, Sr, Cu, Mn, V, Pd, Sn, Sb, Te, Pt, Sc, Tl, Ni, As, Co, Zn and Se, were measured in 25 AF samples obtained from amniocentesis between 15 and 18 weeks of gestational, after informed consent. Be, Ag, Ba, Pb, U, Cu, Sr, Mn, V, Sn, Te, Pt, As, Tl, Sb, Co, Se and Zn concentrations were detected in measurable amounts in second trimester AF. Mg levels are elevated in all samples. Pd, Ni, Sc and Hg concentrations are below the detection limits in all samples. This study demonstrates that heavy metals pass into and accumulate in AF from a very early stage of gestation. Other studies are needed to evaluate the long-term health effects of this early exposure.
    Prenatal Diagnosis 08/2011; 31(8):792-6. DOI:10.1002/pd.2768 · 3.27 Impact Factor
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    ABSTRACT: There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health. Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health.
    Human Reproduction Update 04/2011; 17(3):418-33. DOI:10.1093/humupd/dmq061 · 8.66 Impact Factor
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    ABSTRACT: Innate immunity represents the first line of defence against pathogens and plays key roles in the activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules that recognize pathogen-associated molecular patterns and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. Pentraxins are essential constituents of the humoral arm of innate immunity and represent a superfamily of highly conserved acute phase proteins, traditionally classified into short and long pentraxins. Pentraxin 3 (PTX3) is the prototypic member of the long pentraxins subfamily. As opposed to C-reactive protein, whose sequence and regulation have not been conserved during evolution from mouse to man, the evolutionary conservation of sequence, gene organization and regulation of PTX3 has allowed addressing its pathophysiological roles in genetically modified mice, in diverse conditions, ranging from infections to sterile inflammation, angiogenesis and female fertility. Despite this conservation, a number of predominantly non-coding polymorphisms have been identified in the PTX3 gene which, when associated in particular haplotypes, have been shown to be relevant in clinical conditions including infection and fertility. Here we review the studies on PTX3, with emphasis on pathogen recognition, tissue remodelling and crosstalk with other components of the innate immune system.
    Tissue Antigens 04/2011; 77(4):271-82. DOI:10.1111/j.1399-0039.2011.01645.x · 2.35 Impact Factor

Publication Stats

23k Citations
2,246.91 Total Impact Points

Institutions

  • 1988–2015
    • Istituto Superiore di Sanità
      • • Department of Food Safety and Veterinary Public Health
      • • Department of Environment and Primary Prevention
      Roma, Latium, Italy
  • 1983–2013
    • University of Milan
      • • Department of Medical Biotechnology and Translational Medicine
      • • Istituto di Patologia Generale
      Milano, Lombardy, Italy
  • 2007–2012
    • Istituto Clinico Humanitas IRCCS
      • Department of Immunology and Inflammation
      Italy
  • 2008
    • Kagawa University
      Takamatu, Kagawa, Japan
  • 1975–2007
    • Mario Negri Institute for Pharmacological Research
      • • Department of Molecular Medicine
      • • Department of Cardiovascular Research
      • • Department of Oncology
      Milano, Lombardy, Italy
  • 1998–2003
    • Sapienza University of Rome
      • • Department of Public Health and Infectious Diseases
      • • Department of Experimental Medicine
      Roma, Latium, Italy
    • Università degli Studi di Trieste
      Trst, Friuli Venezia Giulia, Italy
  • 1998–2001
    • Università degli Studi di Brescia
      • • Department of Clinical and Experimental Sciences
      • • "Istituto Angelo Nocivelli” Centre for Research into Molecular Medicine
      Brescia, Lombardy, Italy
  • 2000
    • University of Udine
      Udine, Friuli Venezia Giulia, Italy
  • 1998–1999
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
  • 1997
    • University of Leuven
      • Department of Microbiology and Immunology
      Louvain, Flemish, Belgium
    • Research Center Borstel
      Borstel, Lower Saxony, Germany
  • 1996
    • University of Verona
      • Section of General Pathology
      Verona, Veneto, Italy
    • National Research Council
      • Institute of Biomedical Technologies ITB
      Roma, Latium, Italy
  • 1991
    • It-Robotics
      Vicenza, Veneto, Italy
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 1990
    • National Cancer Institute (USA)
      • Laboratory of Molecular Immunoregulation
      Maryland, United States
    • Università degli studi di Parma
      • Department of Clinical and Experimental Medicine
      Parma, Emilia-Romagna, Italy
  • 1986
    • Ospedali Riuniti di Bergamo
      • Department of Hematology
      Bérgamo, Lombardy, Italy
  • 1985
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1984–1985
    • Università degli Studi di Bari Aldo Moro
      Bari, Apulia, Italy
  • 1979
    • National Institutes of Health
      • Laboratory of Tumor Immunology and Biology
      Maryland, United States