M R Brunetto

Università di Pisa, Pisa, Tuscany, Italy

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Publications (259)1088.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: HBV-DNA integration frequently occurs in HBV-related hepatocellularcarcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here we first characterized HBV antigen expression in HCC metastases occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed, for the first time in HCC, autologous T cells genetically modified to express a HBsAg specific T cell receptor as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not the donor liver) and demonstrated that tumor cells were recognized in vivo by lymphocytes engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR redirected therapy against HCC and advocate the strategy as a novel therapeutic opportunity in Hepatitis B associated malignancies.
    Journal of hepatology. 10/2014;
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    ABSTRACT: Serum hepatitis B surface antigen (HBsAg) levels may predict treatment response in chronic hepatitis B (CHB). We examined the association between changes in HBsAg levels and response to treatment in the BE-LOW study.
    Journal of hepatology. 08/2014;
  • Maurizia Rossana Brunetto, Ferruccio Bonino
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    ABSTRACT: Chronic hepatitis B (CHB) results from the inability of the host's immune system to control viral replication. Interferon-α (IFN-α) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients. In spite of the low response rate, IFN-α therapy has the advantage of having a limited duration and being effective even after therapy, as demonstrated by a much higher incidence of HBsAg clearance in responders to IFN-α than in naturally occurring inactive HBsAg carriers. IFN-α has multiple antiviral, antiproliferative, and immunomodulatory activities and targets: cellular genes (IFN-stimulated genes) activating different pathways of antiviral defense in infected and noninfected cells, HBV replication blocking the RNA-containing core particle formation and accelerating their decay, degrading pregenomic RNA, and modulating the nuclear viral minichromosome (covalently closed circular DNA) activity by targeting its epigenetic regulation and both innate and adaptive immune response. The interference of viral heterogeneity and genetic polymorphisms of the host on IFN-α susceptibility is under investigation. Only a better understanding of the complex interplay between the different activities of IFN-α would warrant the amelioration of current therapeutic strategies and the design of new therapeutic approaches. The study of on-treatment dynamics of HBV infection by means of combined quantitative monitoring of serum HBV DNA and HBsAg warrant tailoring treatment at the single-patient level and can help to make treatment more cost-effective by using the different combinations of currently available antivirals, including IFN, more appropriately. Integrated molecular and clinical knowledge in a systems medicine fashion is mandatory to further improve antiviral therapy in CHB. © 2014 S. Karger AG, Basel.
    Intervirology 01/2014; 57(3-4):163-70. · 1.89 Impact Factor
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    Maurizia Rossana Brunetto
    Journal of Hepatology 12/2013; · 9.86 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-(IFN)/ribavirin-(RBV)] were randomly assigned to vaccine (V:23), Peg-IFNα2a-180-ug/qw and ribavirin 1000-1200-mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2-specific-CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV-RNA levels (P = 0.026) at week 16. HCV E1E2MF59 vaccine in combination with Peg-IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies.
    Journal of Viral Hepatitis 08/2013; · 3.08 Impact Factor
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    ABSTRACT: We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a ± lamivudine in the Phase III trial. All patients (n = 230) who participated in long-term follow-up were included according to the availability of HBsAg levels measurements. Long-term virological response was defined as HBV DNA ⩽10,000 cp/mL (1786 IU/mL) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24 and 72. Baseline HBsAg levels were significantly higher for A than B, C and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12 to 24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71% and 75% for genotypes A (<400 IU/mL), B (<50 IU/mL), C (<75 IU/mL) and D (<1000 IU/mL), respectively. On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.
    Journal of Hepatology 07/2013; · 9.86 Impact Factor
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    ABSTRACT: To detect HBV rtM204V/I lamivudine resistant strains in serum of patients with acute hepatitis B and to assess their biological and clinical significance METHODS: 80 HBV DNA-positive patients with symptomatic acute hepatitis B observed from 1999 to 2010 were enrolled. A plasma sample obtained at the first observation was tested for HBV mutants in the polymerase region by direct sequencing; the antiviral drug-resistant rtM204V/I mutations, the most frequent HBV mutants in Italy, were also sought by the more sensitive allele-specific polymerase chain reaction (PCR). No HBV mutation associated with resistance to nucleos(t)ide analogues was identified by direct sequencing, whereas allele-specific PCR identified HBV strains carrying the substitution rtM204V/I in 11 (13.7%) patients. Compared with those with the HBV wild strain, patients with rtM204V/I more frequently showed severe acute hepatitis B (36.4 % vs 8.7 %; p<0.05) and lower values of serum HBV DNA (1.77x10(6) ± 4.76x10(6) vs. 1.68x10(8) ± 5.46x10(8)). In addition, a multivariate analysis identified the presence of a pre-existing HCV chronic infection as independently associated with severe acute hepatitis B (p<0.05). HBV rtM204V/I lamivudine-resistant strains were detected in serum of 11 (13.7%) patients with acute hepatitis B by allele-specific polymerase chain reaction. The frequent association of rtM204V/I with a more severe acute hepatitis B and with a lower viral load may suggest that greater and/or more prolonged immune pressure might have induced their selection.
    The Journal of infection 06/2013; · 4.13 Impact Factor
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    ABSTRACT: BACKGROUND: HBeAg-negative chronic hepatitis B (CHB) is the most frequent and difficult to treat viral hepatitis worldwide. HBV-DNA and HBsAg serum levels, which help the early identification of non-responders to peg-interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleos(t)ide analogs (NAs). We assessed the cost-effectiveness of week-12 HBV-DNA\HBsAg stopping rule for early interruption and switch to currently most effective NAs treatments (entecavir-ETV or tenofovir-TDF). METHODS: A decision-analytic Markov model was developed in health-related states: CHB, compensated and decompensated cirrhosis, hepatocarcinoma, liver transplant, post-liver transplant, death and virologic response, relapse, HBsAg clearance. Simulated strategies were: 1) ETV/TDF in CHB; 2) ETV/TDF delayed until compensated cirrhosis (CC); 3) first-line-PEG-IFN followed by switch to ETV/TDF for either patients meeting week-12 stopping rule or week-48 null-responders/relapsers ; 4) first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of 8 strategies. A lifetime simulation horizon was applied. RESULTS: Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (about 22-life-years and 15-QALYs). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20-50% higher. First-line-PEG-IFN strategies resulted ranging from dominant (i.e. more effective and less costly) to highly cost-effective, even though differences in QALY were always very narrow. CONCLUSIONS: The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting week-12 HBV-DNA/HBsAg stopping rule or week-48 non responders/relapsers.
    Antiviral therapy 03/2013; · 3.07 Impact Factor
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    ABSTRACT: To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients. HBeAg-negative patients received peginterferon alfa-2a (180 μg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment. HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline. Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.
    Hepatology International 03/2013; 7(1):88-97. · 2.64 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10(-4), FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.Genes and Immunity advance online publication, 7 February 2013; doi:10.1038/gene.2013.1.
    Genes and immunity 02/2013; · 4.22 Impact Factor
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    ABSTRACT: The Gunther's vector-free method (GM), using PCR-amplified full length HBV-DNA (fl-HBV-DNA), is currently the best in-vitro HBV replication system despite the low intracellular HBV-DNA production. The replication efficiency and HBsAg secretion of 12 isolates from HBsAg/HBeAg positive sera by GM, Monomer-Linear-Sticky-Ends-DNA (MLSE) and Monomer-Circular-Closed (MCC) were compared in HuH7 cells. Eight of 12 genomes (67%) were replication competent by GM; however Direct Sequencing (DS) showed that more than 80% of input DNA was undigested in spite of SapI treatment. Replication Intermediates (RI) were detected earlier (24 vs 48hours) and in higher amounts (2.51± 0.32 and 6.43± 0.43 fold) by MCC than GM or MLSE. By MCC 10 of 12 genomes (83%) were replication competent and 7 produced high RI levels. RI and HBsAg kinetics correlated positively in MCC (R=0.696, p=0.017 overall; R=0.928, p=0.008), but not in GM (R=- 0.437, p=0.179 overall; R=-0.395, p=0.439) in genotype D isolates. In conclusion, HBV-DNA circularization prior transfection improves in vitro viral replication and replication competent HBsAg production, mimicking better the in vivo conditions.
    Journal of virological methods 02/2013; · 2.13 Impact Factor
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    ABSTRACT: Autoimmune Hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. Diagnosis requires the exclusion of other conditions and the presence of characteristic features such as specific autoantibodies. Presently, these autoantibodies have relatively low sensitivity and specificity and are identified by immunostaining of cells or tissues, therefore there is a diagnostic need for better and easy to assess markers. To identify new AIH-specific autoantigens, we developed a protein microarray comprising 1626 human recombinant proteins, selected in silico for being secreted or membrane-associated. We screened sera from AIH patients on this microarray and compared their reactivity with sera from healthy donors and patients with chronic viral hepatitis C. We identified six human proteins that are specifically recognized by AIH sera. Serum reactivity to combination of these six autoantigens allows identification of AIH patients with high sensitivity (77%+/-4) and specificity (91%+/-8). Of the six autoantigens, the IL4 Receptor (CD124), which is expressed on the surface of both lymphocytes and hepatocytes, showed the highest individual sensitivity and specificity for AIH. Remarkably, sera of patients inhibited STAT6 phosphorylation induced by IL4 binding to CD124, demonstrating these autoantibodies are functional and suggesting IL4 neutralisation has a pathogenetic role in AIH.
    Molecular &amp Cellular Proteomics 09/2012; · 7.25 Impact Factor
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    ABSTRACT: A regulatory subset of B cells has been found to modulate immune responses in autoimmunity, infection, and cancer, but it has not been investigated in the setting of human persistent viral infection. IL-10 is elevated in patients with chronic hepatitis B virus infection (CHB), but its cellular sources and impact on antiviral T cells have not been addressed. We investigated the role of IL-10 and regulatory B cells in the pathogenesis of CHB. Serum IL-10 levels were studied longitudinally in patients with CHB undergoing spontaneous disease flares. There was a close temporal correlation between IL-10 levels and fluctuations in viral load or liver inflammation. Blockade of IL-10 in vitro rescued polyfunctional virus-specific CD8 T cell responses. To investigate the potential contribution of regulatory B cells, their frequency was measured directly ex vivo and after exposure to stimuli relevant to hepatitis B virus (HBV) (CpG or HBV Ags). IL-10-producing B cells were enriched in patients, and their frequency correlated temporally with hepatic flares, both after stimulation and directly ex vivo. Phenotypically, these cells were predominantly immature (CD19(+)CD24(hi)CD38(hi)) ex vivo; sorted CD19(+)CD24(hi)CD38(hi) cells suppressed HBV-specific CD8 T cell responses in an IL-10-dependent manner. In summary, these data reveal a novel IL-10-producing subset of B cells able to regulate T cell immunity in CHB.
    The Journal of Immunology 09/2012; 189(8):3925-35. · 5.52 Impact Factor
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    ABSTRACT: Background / Purpose: This study was conducted to assess the long-term effectiveness and safety of entecavir (ETV) in a large cohort of NUC-naive patients with chronic hepatitis B. Main conclusion: ETV monotherapy was safe and effective for up to four years in clinical practice, providing high rates of virological suppression and increasing rates of HBeAg and HBsAg seroconversion.
    47th Annual International Liver Congress 2012; 06/2012
  • Digestive and Liver Disease 03/2012; 44:S4–S5. · 3.16 Impact Factor
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    ABSTRACT: In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed. In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.
    Journal of Hepatology 02/2012; 56(6):1254-8. · 9.86 Impact Factor
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    ABSTRACT: It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy.
    Journal of Hepatology 01/2012; 56(5):1006-11. · 9.86 Impact Factor
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    ABSTRACT: Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC). TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC. 323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥9.5 and ≥7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change -16%, -10% and -2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement. LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage.
    PLoS ONE 01/2012; 7(10):e47715. · 3.53 Impact Factor
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    ABSTRACT: Hepatitis B virus (HBV) produces high quantities of subviral surface antigen particles (HBsAg) which circulate in the blood outnumbering virions of about 1\10(3-6) times. In individuals coinfected with the defective hepatitis Delta virus (HDV) the small HDV-RNA-genome and Delta antigen circulate as ribonucleoprotein complexes within HBsAg subviral particles. We addressed the question whether subviral HBsAg particles may carry in the same way cellular microRNAs (miRNAs) which are released into the bloodstream within different subcellular forms such as exosomes and microvescicles. Circulating HBsAg particles were isolated from sera of 11 HBsAg carriers by selective immunoprecipitation with monoclonal anti-HBs-IgG, total RNA was extracted and human miRNAs were screened by TaqMan real-time quantitative PCR Arrays. Thirty-nine human miRNAs were found to be significantly associated with the immunoprecipitated HBsAg, as determined by both comparative DDCT analysis and non-parametric tests (Mann-Whitney, p<0.05) with respect to controls. Moreover immunoprecipitated HBsAg particles contained Ago2 protein that could be revealed in ELISA only after 0.5% NP40. HBsAg associated miRNAs were liver-specific (most frequent = miR-27a, miR-30b, miR-122, miR-126 and miR-145) as well as immune regulatory (most frequent = miR-106b and miR-223). Computationally predicted target genes of HBsAg-associated miRNAs highlighted molecular pathways dealing with host-pathogen. The finding that HBsAg particles carry selective pools of hepatocellular miRNAs opens new avenues of research to disentangle the complex interactions between host and HBV and provides a non invasive tool to study the physiopathology of liver epigenetics.
    PLoS ONE 01/2012; 7(3):e31952. · 3.53 Impact Factor
  • Harry L A Janssen, Milan J Sonneveld, Maurizia R Brunetto
    Gut 12/2011; 61(5):641-5. · 10.73 Impact Factor

Publication Stats

5k Citations
1,088.65 Total Impact Points

Institutions

  • 2001–2014
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • IMS Health
      Parsippany, New Jersey, United Kingdom
  • 2001–2013
    • Azienda Ospedaliero-Universitaria Pisana
      Pisa, Tuscany, Italy
  • 2011
    • Victorian Infectious Diseases Reference Laboratory
      Melbourne, Victoria, Australia
    • Hannover Medical School
      • Department of Gastroenterology, Hepatology and Endocrinology
      Hannover, Lower Saxony, Germany
    • Erasmus MC
      • Department of Gastroenterology and Hepatology
      Rotterdam, South Holland, Netherlands
  • 2006–2007
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      Milano, Lombardy, Italy
    • Santa Chiara Hospital
      Trient, Trentino-Alto Adige, Italy
  • 1989–2005
    • Università degli Studi di Torino
      • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 1988–2005
    • Ospedale San Giovanni Battista, ACISMOM
      Torino, Piedmont, Italy
  • 2003
    • Ain Shams University
      • Department of Pediatrics
      Cairo, Muhafazat al Qahirah, Egypt
  • 2000
    • Second University of Naples
      • Faculty of Medicine and Surgery
      Caserta, Campania, Italy
  • 1998
    • Ospedale Amedeo di Savoia
      Torino, Piedmont, Italy
  • 1997
    • Università degli Studi di Bari Aldo Moro
      Bari, Apulia, Italy
  • 1993–1996
    • Azienda Ospedaliera Bolognini Seriate
      Seriate, Lombardy, Italy
  • 1991–1993
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 1988–1993
    • University of Bologna
      • Department of Experimental, Diagnostic and Specialty Medicine DIMES
      Bolonia, Emilia-Romagna, Italy