G Corneo

Università degli Studi di Milano-Bicocca, Milano, Lombardy, Italy

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Publications (102)514.79 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We studied monosomy and deletions of chromosome 7 in 170 patients with myeloid disorders and we identified a minimal region of loss in 7q31.1 spanning between the D7S2554 and D7S2460 markers. The closest gene to our most deleted microsatellite, D7S2554, is the human I-mfa domain containing (HIC) gene, alias MyoD family inhibitor domain containing (MDFIC). We investigated the involvement of HIC in myeloid neoplasms by screening for mutations the coding regions and the intron-exon boundaries of this gene in 15 patients who presented chromosome 7 deletions in the region of HIC. No mutations were found in the coding region of this gene.
    Leukemia Research 05/2007; 31(4):477-82. DOI:10.1016/j.leukres.2006.09.007 · 2.35 Impact Factor
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    ABSTRACT: Tumor cell contamination of the apheresis in multiple myeloma is likely to affect disease-free and overall survival after autografting. To purge myeloma aphereses from tumor contaminants with a novel culture-based purging method. We cultured myeloma-positive CD34+ PB samples in conditions that retained multipotency of hematopoietic stem cells, but were unfavourable to survival of plasma cells. Moreover, we exploited the resistance of myeloma plasma cells to retroviral transduction by targeting the hematopoietic CD34+ cell population with a retroviral vector carrying a selectable marker (the truncated form of the human receptor for nerve growth factor, DeltaNGFR). We performed therefore a further myeloma purging step by selecting the transduced cells at the end of the culture. Overall recovery of CD34+ cells after culture was 128.5%; DeltaNGFR transduction rate was 28.8% for CD34+ cells and 0% for CD138-selected primary myeloma cells, respectively. Recovery of CD34+ cells after DeltaNGFR selection was 22.3%. By patient-specific Ig-gene rearrangements, we assessed a decrease of 0.7-1.4 logs in tumor load after the CD34+ cell selection, and up to 2.3 logs after culture and DeltaNGFR selection. We conclude that ex-vivo culture and retroviral-mediated transduction of myeloma leukaphereses provide an efficient tumor cell purging.
    Journal of Translational Medicine 02/2007; 5(1):35. DOI:10.1186/1479-5876-5-35 · 3.93 Impact Factor
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    Nature Medicine 02/2007; 13(1):13-4; author reply 15-6. DOI:10.1038/nm0107-13b · 27.36 Impact Factor

  • Nature Medicine 02/2007; 13(2). DOI:10.1038/nm0207-224 · 27.36 Impact Factor
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    ABSTRACT: Despite the positive results achieved by Imatinib mesylate (Imatinib) in the treatment of chronic myeloid leukemia (CML), over the past several years, Imatinib does not eradicate the leukemic clone. The long-term duration of response to the drug is not known. Long-term follow-up of CML patients treated with Imatinib will ultimately define the durability of such treatment and the frequency of reemergence of progressive disease. We present the results of a 6-year follow-up of 40 CML patients either in chronic or accelerated phase who obtained a durable (>6 months) complete cytogenetic remission (CCyR) after treatment with Imatinib in a single center. In 34 cases CCyR was obtained at an Imatinib dose of 400-600 mg/day and in 6 cases after a dose increase to 600-800 mg/day. At a median follow-up of 68 months, 6 cytogenetic relapses (15%) were observed. No progressions to more advanced phases of disease have been detected during the follow-up period. Cytogenetic relapse was predicted by either a decrease in the amount of BCR-ABL transcript of less than 2 logs after the achievement of CCyR (p=0.0041) or a time-to-CCyR of more than 12 months (p<0.0001). This 6-year follow-up of the efficacy of Imatinib therapy in CML patients who obtained a durable CCyR indicates that the relapses rate is low over this period of observation and that the rate of relapse does not increase over time.
    Blood Cells Molecules and Diseases 09/2006; 37(2):111-5. DOI:10.1016/j.bcmd.2006.06.002 · 2.65 Impact Factor
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    Leukemia 12/2005; 19(11):1985-7. DOI:10.1038/sj.leu.2403928 · 10.43 Impact Factor
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    ABSTRACT: B-chronic lymphocytic leukemia is a disease characterized by an accumulation of monoclonal B cells that are resistant to apoptosis. In chronic lymphocytic leukemia, the prognosis depends on the stage of the disease, according to the classifications of Rai and Binet. However, in recent years, the number of patients with very early disease (stage 0 of Rai) and without any clinical symptom, has considerably increased because of the extensive use of automatic apparatus for leukocyte counting and immunophenotypic analysis of lymphocytes. It has become, therefore, useful to find new prognostic criteria particularly for these patients. In the present study, 30 patients with B-chronic lymphocytic leukemia were investigated for stage of the disease, survival, immunoglobulin gene rearrangements, presence of nurse like cells in in vitro cultures and spontaneous clinical lymph node regression. We observed that all these criteria are useful prognostic indexes for the disease.
    Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna 01/2004; 19(3):171-4.
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    ABSTRACT: cKit and platelet-derived growth-factor receptor (PDGFR) are receptor tyrosine kinases expressed in the testis, are involved in testosterone production, and are inhibited by imatinib. We measured hormone concentrations in 38 men receiving imatinib for chronic myeloid leukaemia at baseline and during treatment. Mean follow-up was 23.6 months (SD 7.5). We noted seven cases of gynaecomastia (18%, 95% CI 6-30%). A comparison of hormone concentrations in 21 patients before and during treatment showed that patients who developed gynaecomastia had a reduction in free testosterone concentrations of 29.53 pmol/L (95% CI 11.63-47.43), while patients who did not had a decrease of 6.36 pmol/L (-1.02 to 13.74). In most men with chronic myeloid leukaemia studied here, imatinib was associated with a reduction in the production of testicular hormones and in some, with the development of gynaecomastia.
    The Lancet 07/2003; 361(9373):1954-6. DOI:10.1016/S0140-6736(03)13554-4 · 45.22 Impact Factor
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    ABSTRACT: cKit and platelet-derived growth-factor receptor (PDGFR) are receptor tyrosine kinases expressed in the testis, are involved in testosterone production, and are inhibited by imatinib. We measured hormone concentrations in 38 men receiving imatinib for chronic myeloid leukaemia at baseline and during treatment. Mean follow-up was 23·6 months (SD 7·5). We noted seven cases of gynaecomastia (18%, 95% CI 6–30%). A comparison of hormone concentrations in 21 patients before and during treatment showed that patients who developed gynaecomastia had a reduction in free testosterone concentrations of 29·53 pmol/L (95% CI 11·63–47·43), while patients who did not had a decrease of 6·36 pmol/L (–1·02 to 13·74). In most men with chronic myeloid leukaemia studied here, imatinib was associated with a reduction in the production of testicular hormones and in some, with the development of gynaecomastia.
    The Lancet 06/2003; 361(9373):1954. · 45.22 Impact Factor
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    ABSTRACT: Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.
    Clinical Cancer Research 03/2003; 9(2):625-32. · 8.72 Impact Factor
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    ABSTRACT: Imatinib mesylate (imatinib) inhibits Bcr/Abl, an oncogenic fusion protein. The in vitro effects of imatinib on BCR/ABL+ leukemic cells include inhibition of Bcr/Abl tyrosine phosphorylation, block of proliferation, and induction of apoptosis. The in vivo effects of imatinib were evaluated in 12 CML (chronic myeloid leukemia) patients in blast crisis or accelerated phase who were treated with imatinib. Treatment caused a decrease in spontaneous proliferation of leukemic cells in 10 of 12 evaluable patients and the development of apoptosis in 9 of 11 cases. Imatinib also caused an inhibition of Bcr/Abl autophosphorylation; however, the degree of inhibition obtained in vivo was substantially lower than that achieved in vitro with similar concentrations of imatinib. In seven patients cells could be evaluated at relapse: spontaneous proliferation was no longer inhibited and Bcr/Abl phosphorylation was comparable or superior to that present at the beginning of treatment, before imatinib administration. Plasma imatinib concentrations were not reduced. Leukemic cells obtained at relapse maintained in vitro sensitivity (Bcr/Abl autophosphorylation and proliferation inhibition) to imatinib concentration measured in vivo (3 microM or higher), although a partial resistance to the antiproliferative effects of imatinib was present at low (0.01-0.3 microM) concentrations. In four patients, addition of erythromycin to blood samples obtained at relapse restored imatinib sensitivity in terms of phosphorylation inhibition, indicating that the majority of plasma imatinib was not available to cells and probably bound to alpha1 acid glycoprotein. These data suggest that measurements of Bcr/Abl kinase activity in peripheral blood samples may represent a more reliable indicator of active concentrations than the measurement of imatinib plasma levels.
    Blood Cells Molecules and Diseases 05/2002; 28(3):361-72. DOI:10.1006/bcmd.2002.0526 · 2.65 Impact Factor
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    ABSTRACT: Between 1991 and 1993 we conducted a collaborative trial in adult acute lymphoblastic leukaemia, introducing an idarubicin (IDA)-containing regimen for induction and early consolidation, and increasing consolidation intensity with an autologous bone marrow transplantation phase (ABMT, patients aged <51 years) followed by further chemotherapy for 12 weeks and low-dose maintenance for 6 months (ABMT patients) or 18 months. 96 patients were evaluable for antileukaemic response after induction with vincristine–prednisone–l-asparaginase plus cumulative IDA 36 or 20 mg/m2 (IVAP-1 and IVAP-2), and for disease-free survival (DFS) after a minimum follow-up >3.5 years with an off-therapy interval >1.5 years. The response rate was 44% (7/16) with IVAP-1 and 90% (72/80) with IVAP-2 (P = 0.0001), due to regimen-related toxicities. Post-remission therapy was administered as planned to most cases but protocol violation was registered in some patients eligible to ABMT and post-graft chemotherapy. The 5-year disease-free survival (DFS) rate was 31%. Multivariate analysis indicated that DFS was improved in patients receiving a transplant (11 allogeneic, DFS 70%; 32 ABMT, 36%; 37 neither, 17%; P < 0.001) and was negatively affected by high-risk features such as blast cell count >25 × 109/l, T-cell or mature B-cell immunophenotype, and t(9;22)/t(4;11) (all P values <0.05). The 5-year DFS rate was 54% for 26 patients with no high-risk factor, 26% for 35 patients with any one, and 6% for 18 patients with any two (P < 0.005). IVAP-2 brought about a high complete response rate and post-remission treatment including ABMT was feasible and modestly toxic. In spite of the short post-graft chemotherapy phase, the long-term DFS rate was good in cases with no high-risk feature. However, because autografting may be redundant in the standard-risk category, its role requires further investigation for high-risk cases.
    British Journal of Haematology 12/2001; 104(4):755 - 762. DOI:10.1046/j.1365-2141.1999.01258.x · 4.71 Impact Factor
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    ABSTRACT: We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions.
    Leukemia Research 10/2001; 25(9):735-9. DOI:10.1016/S0145-2126(01)00012-1 · 2.35 Impact Factor

  • Science 10/2001; 293(5538):2163. · 33.61 Impact Factor

  • Science 09/2001; 293(5538):U3-U3. · 33.61 Impact Factor
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    ABSTRACT: Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon. From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate. Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass. The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.
    The Hematology Journal 02/2001; 2(2):117-26. DOI:10.1038/sj/thj/6200091 · 1.86 Impact Factor
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    ABSTRACT: Even though the risk of pneumonia is higher in patients with advanced disease, the potential risk of death is particularly relevant during induction therapy, when patients can be potentially cured of their hematologic disease: our study was aimed at evaluating the risk and outcome of pneumonia in these patients. We retrospectively studied all 458 patients affected by acute leukemia receiving an anthracycline-containing induction regimen in the years 1984-1989. Of the 458 patients, 109 (23.8%) developed pneumonia: 91 had acute myelogenous leukemia (AML) and 18 had acute lymphoblastic leukemia (ALL). At univariate analysis, advanced age, AML and total blast count significantly correlated with the risk of pneumonia. At multivariate analysis, only age (p< 0.0001) and total blast count (p=0.002) retained their prognostic significance. Pneumonia responded to treatment in 67 (61.5%) patients, while 42 (38.5%) patients died. Among patients with pneumonia, 51 (46.8%) patients achieved a complete remission: 9/18 ALL and 42/91 AML. At univariate analysis, the most significant determinant of a positive outcome was the achievement of complete remission; a higher absolute neutrophil count at the onset of pneumonia, the absence of rales, a single infiltrate and the absence of microbiological demonstration of infection were also related to a positive outcome. At multivariate analysis, the achievement of complete remission and, with borderline significance, a single infiltrate maintained their prognostic value. Pneumonia remains one of the most relevant risks of morbidity and mortality during induction therapy for acute leukemia. A fatal outcome is associated, in most cases, with a failure to achieve remission of leukemia.
    Haematologica 12/2000; 85(12):1255-60. · 5.81 Impact Factor
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    ABSTRACT: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment. AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.
    JNCI Journal of the National Cancer Institute 11/2000; 92(20):1641-50. DOI:10.1093/jnci/92.20.1641 · 12.58 Impact Factor
  • E M Pogliani · P Perseghin · M Parma · P Pioltelli · G Corneo ·
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    ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is a common illness characterized by platelet thrombi within the microvascularization. In its natural course, this disease has had a mortality rate of 90%. Plasma infusion or exchange achieved a survival rate of 70% to 90%. However, 10% to 30% of patients surviving the initial TTP episode relapse at regular intervals. The treatment of recurrent forms of the disease remains a challenge; several approaches have been shown to induce medium to long term remissions. We describe a patient with recurrent TTP whose disease remitted after administration of defibrotide.
    Clinical and Applied Thrombosis/Hemostasis 05/2000; 6(2):69-70. DOI:10.1177/107602960000600203 · 2.39 Impact Factor
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    ABSTRACT: In a prior study, primary resistant acute lymphoblastic leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of resistant disease, fractionated cyclophosphamide (f-CY) was then added to the IVAP regimen. Study 08-96 was a prospective, collaborative phase II trial carried out at eight general hospital centers specialized in the care of hematologic malignancies. Historical IVAP-treated patients served as a retrospective control group. All consecutive, untreated patients (>15 years) with a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible. RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40 days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and 2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4 consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in mg/m(2)). Eighty-eight patients were evaluable (age range 15-74 years, blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first 39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and the last 27 patients were not given any f-CY. These changes were dictated by the results of interim analyses of the f-CY groups (RES-ALL rate not reduced, myelotoxicity increased). Altogether, compared with the historical IVAP and no f-CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY 1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count. However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5 of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21 (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small sample size, this difference was not statistically significant. This preliminary experience suggests that T-ALL may be more sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis could be tested in a larger clinical trial.
    Haematologica 12/1999; 84(12):1088-93. · 5.81 Impact Factor

Publication Stats

2k Citations
514.79 Total Impact Points


  • 2002-2007
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
  • 1992-2007
    • Azienda Ospedaliera San Gerardo
      Monza, Lombardy, Italy
  • 1967-1996
    • University of Milan
      • • Department of Biology and Genetics for Medical Sciences
      • • Istituto di Scienze Dermatologiche
      • • Istituto di Patologia Generale
      Milano, Lombardy, Italy
  • 1989
    • Università degli Studi di Messina
      Messina, Sicily, Italy
  • 1980
    • University of California, Davis
      Davis, California, United States
  • 1974
    • The University of Edinburgh
      • Division of Genetics and Genomics
      Edinburgh, Scotland, United Kingdom