Sebastiano Andò

Università della Calabria, Rende, Calabria, Italy

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Publications (201)831.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I-III. Site I is crucial for the formation of an active leptin-leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage-dependent and -independent growth as well as the migration of ERα-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
    Journal of Cellular and Molecular Medicine 02/2015; · 3.70 Impact Factor
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    ABSTRACT: Leydig cell tumors (LCTs) of the testis are steroid-secreting tumors associated with various steroid biosynthetic abnormalities and endocrine dysfunctions. Despite their overall rarity, LCTs are still of substantial interest owing to the paucity of information regarding their exact nature and malignant potential. In the present study we disclose the ability of androgens to inhibit Leydig tumor cell proliferation by opposing to self-sufficient in situ estrogen production. In rat Leydig tumor cells, R2C, androgen treatment significantly decreases the expression and the enzymatic activity of P450 aromatase, responsible for the local conversion of androgens into estrogens. This inhibitory effect relies on androgen receptor activation and involves negative regulation of the CYP19 gene transcriptional activity through the nuclear orphan receptor DAX-1. Ligand-activated androgen receptor up-regulates the expression of DAX-1 and promotes its increased recruitment within the SF-1-containing region of the PII-aromatase proximal promoter in association with the corepressor N-CoR. The biological relevance in LCTs of the newly highlighted functional interplay between androgen receptor, DAX-1 and aromatase is underlined by our in vivo observations revealing a marked down-regulation of AR and DAX-1 expression and a strong increase in aromatase levels in testes tissues from old Fisher rats with spontaneously developed Leydig cell neoplasia, compared to normal testes tissues from younger animals. In elucidating a mechanism by which androgens modulate the growth of Leydig tumor cells, our finding support the hypothesis that maintaining the adequate balance between androgen and estrogens may represent the key for blocking estrogen-secreting Leydigioma development, opening new prospects for therapeutic intervention.
    Endocrinology 01/2015; · 4.72 Impact Factor
  • The FASEB Journal 01/2015; · 5.48 Impact Factor
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    ABSTRACT: Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellular proliferation, invasion, and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. To determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cell lines were grown in vivo versus tissue cultures. The whole body, bone, and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors. Cancer Res; 74(23); 7103-14. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Research 12/2014; 74(23):7103-14. · 9.28 Impact Factor
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    ABSTRACT: Androgen receptor (AR) is an attractive target in breast cancer because of its frequent expression in all the molecular subtypes, especially in estrogen receptor (ER)-positive luminal breast cancers. We have previously shown a role for AR overexpression in tamoxifen resistance. We engineered ER-positive MCF-7 cells to overexpress aromatase and AR (MCF-7 AR Arom cells) to explore the role of AR in aromatase inhibitor (AI) resistance. Androstendione (AD) was used as a substrate for aromatization to estrogen. The nonsteroidal AI anastrazole (Ana) inhibited AD-stimulated growth and ER transcriptional activity in MCF-7 Arom cells, but not in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R and pAKT was found in AR-overexpressing cells, and their inhibitors restored sensitivity to Ana, suggesting that these pathways represent escape survival mechanisms. Sensitivity to Ana was restored with AR antagonists, or the antiestrogen fulvestrant. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR-overexpressing ERα-positive breast cancers. AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, and AR and ERα co-localized in AD + Ana-treated cells, suggesting cooperation between the two receptors. AR-mediated resistance was associated with a failure to block ER transcriptional activity and enhanced up-regulation of AR and ER-responsive gene expression. Clinically, it may be necessary to block both AR and ERα in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways may provide alternative approaches to block escape pathways and restore hormone sensitivity in resistant breast tumors.
    Breast Cancer Research and Treatment 09/2014; · 4.47 Impact Factor
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    ABSTRACT: The tumour suppressor activity of the phosphatase and tensin homologue on chromosome 10 (PTEN) is subject of intense investigative efforts, although limited information on its regulation in breast cancer is available. Herein, we report that, in breast cancer cells, progesterone (OHPg), through its cognate receptor PR-B, positively modulates PTEN expression by inducing its mRNA and protein levels, and increasing PTEN-promoter activity. The OHPg-dependent up-regulation of PTEN gene activity requires binding of the PR-B to an Sp1-rich region within the PTEN gene promoter. Indeed, ChIP and EMSA analyses showed that OHPg treatment induced the occupancy of PTEN promoter by PR and Sp1 together with transcriptional coactivators such as SRC1 and CBP. PR-B isoform knockdown abolished the complex formation indicating its specific involvement. The OHPg/PR-B dependent induction of PTEN causes the down-regulation of PI3K/AKT signal, switching on the autophagy process through an enhanced expression of UVRAG and leading to a reduced cell survival. Altogether these findings highlight a novel functional connection between OHPg/PR-B and tumour suppressor pathways in breast cancer.
    Journal of Cellular and Molecular Medicine 09/2014; · 3.70 Impact Factor
  • ChemInform 06/2014; 45(24).
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    ABSTRACT: Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Aromatase inhibitors are effective in women who progressed or recurred on tamoxifen, suggesting a role of local estrogen production by aromatase in driving tamoxifen-resistant phenotype. However, the link between aromatase activity and tamoxifen resistance has not yet been reported. We investigated whether long-term tamoxifen exposure may affect aromatase activity and/or expression, which may then sustain tamoxifen-resistant breast cancer cell growth. We employed MCF-7 breast cancer cells, tamoxifen-resistant MCF-7 cells (MCF-7 TR1 and TR2), SKBR-3 breast cancer cells, cancer-associated fibroblasts (CAFs1 and CAFs2). We used tritiated-water release assay, realtime-RT-PCR, and immunoblotting analysis for evaluating aromatase activity and expression; anchorage-independent assays for growth; reporter-gene, electrophoretic-mobility-shift, and chromatin-immunoprecipitation assays for promoter activity studies. We demonstrated an increased aromatase activity and expression, which supports proliferation in tamoxifen-resistant breast cancer cells. This is mediated by the G-protein-coupled receptor GPR30/GPER, since knocking-down GPER expression or treatment with a GPER antagonist reversed the enhanced aromatase levels induced by long-term tamoxifen exposure. The molecular mechanism was investigated in ER-negative, GPER/aromatase-positive SKBR3 cells, in which tamoxifen acts as a GPER agonist. Tamoxifen treatment increased aromatase promoter activity through an enhanced recruitment of c-fos/c-jun complex to AP-1 responsive elements located within the promoter region. As tamoxifen via GPER induced aromatase expression also in CAFs, this pathway may be involved in promoting aggressive behavior of breast tumors in response to tamoxifen treatment. Blocking estrogen production and/or GPER signaling activation may represent a valid option to overcome tamoxifen-resistance in breast cancers.
    Breast Cancer Research and Treatment 06/2014; · 4.47 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P5-04-04-P5-04-04. · 9.28 Impact Factor
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    ABSTRACT: Leptin, a pleiotropic molecule mainly produced by adipose tissue, was first discovered as a hormone controlling body weight and energy expenditure. In addition, leptin can modulate several processes in peripheral tissues such as immune response, fertility, hematopoiesis and carcinogenesis. The development of molecules that block or stimulate leptin receptor may therefore serve as a potent tool for studying the role of leptin in mammalian physiology and pathology, but it also may open new possibilities for therapy. This article presents an overview of current knowledge on leptin receptor modulators focusing on leptin mutein, leptin peptide modulators as well as small molecules with heterocyclic structure.
    European Journal of Medicinal Chemistry 03/2014; 78C:97-105. · 3.43 Impact Factor
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    ABSTRACT: The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. Emerging data have reported that androgen receptor (AR) activation inhibits ER-positive breast cancer progression mainly by antagonizing ER-alpha signaling. However, to date no studies have specifically evaluated a potential involvement of ER-beta in the inhibitory effects of androgens. ER-beta expression was examined in human breast cancer cell lines using real-time PCR, Western blotting and small interfering RNA (siRNA) assays. Mutagenesis studies, electromobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis were performed to assess the effects of mibolerone/AR on ER-beta promoter activity and binding. In this study, we demonstrate that mibolerone, a synthetic androgen ligand, up-regulates ER-beta mRNA and protein levels in ER-positive breast cancer cells. Transient transfection experiments, using a vector containing the human ER-beta promoter region, show that mibolerone increases basal ER-beta promoter activity. Site-directed mutagenesis and deletion analysis reveal that an androgen response element (ARE), TGTTCT motif located at positions -383 and -377, is critical for mibolerone-induced ER-beta up-regulation in breast cancer cells. This occurs through an increased recruitment of AR to the ARE site within the ER-beta promoter region, along with an enhanced occupancy of RNA polymerase II. Finally, silencing of ER-beta gene expression by RNA interference is able to partially reverse the effects of mibolerone on cell proliferation, p21 and cyclin D1 expression. Collectively, these data provide evidence for a novel mechanism by which activated AR, through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.
    Breast cancer research: BCR 02/2014; 16(1):R21. · 5.88 Impact Factor
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    M Lanzino, S Andò
    Cell Death & Disease 01/2014; 5:e978. · 5.18 Impact Factor
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    ABSTRACT: Adipokines represent likely candidates to mediate the increased breast cancer risk and the enhanced progression associated with obesity. Other contributors to obesity-related cancer progression are insulin/IGF-1 pathways and hormones. Among these, the adipokine leptin is the most intensively studied in both metabolism in general and in cancer due to the fact that leptin levels increase in proportion of fat mass. Leptin is primarily synthesized from adipocytes but it is also produced by other cells including fibroblasts. In this latter case, it has been well demonstrated how cancer-associated fibroblasts express leptin receptor and secrete leptin, which sustains a short autocrine loop and is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness. In addition, it has been reported that leptin may induce breast cancer to undergo a transition from epithelial to spindle-like mesenchymal morphology, activating the signaling pathways devoted to the EMT. Thus, it emerges how leptin may play a crucial role in mediating malignant cell and tumor microenvironment interactions. Here, we present an overview of the role of leptin in breast cancer, covering the following topics: (1) leptin as an amplifier of estrogen signaling in tumor epithelial cells contributing to the promotion of carcinogenesis; (2) leptin as a crucial player in mediating tumor-stroma interaction and influencing EMT-linked mechanisms, that may sustain breast cancer growth and progression; (3) leptin and leptin receptor targeting as novel therapeutic strategies for breast cancer treatment.
    Frontiers in oncology. 01/2014; 4:340.
  • Stefania Catalano, Ines Barone, Sebastiano Andò
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    ABSTRACT: Local estrogen production by aromatase plays a more important role than circulating estradiol in breast tumor promotion. Recently, it has been reported that the activity of the aromatase enzyme is tightly regulated by posttranscriptional modifications, such as phosphorylation. Estrogen stimulation of hormone-dependent breast cancer cells rapidly enhances aromatase enzymatic activity through an increase of tyrosine protein phosphorylation. Here, we describe a novel assay protocol to detect changes in the phosphorylation status of the purified six tandem histidine-tagged form of human aromatase transiently expressed in breast cancer cells. This method overcomes the limitations of current immunoprecipitation techniques performed using commercial available aromatase antibodies.
    Methods in Molecular Biology 01/2014; 1204:155-63. · 1.29 Impact Factor
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    ABSTRACT: Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, anti-inflammatory, antiatherogenic, and antiproliferative properties. In addition, it appears to play an important role also in the development and progression of several obesity-related malignancies, including breast cancer. Here, we demonstrated that adiponectin induces a dichotomic effect on breast cancer growth. Indeed, it stimulates growth in ERα+ MCF-7 cells while inhibiting proliferation of ERα- MDA-MB-231 cells. Notably, only in MCF-7 cells adiponectin exposure exerts a rapid activation of MAPK phosphorylation, which is markedly reduced when knockdown of the ERα gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ERα siRNA prevents this effect. Moreover, MAPK activation induced by adiponectin was reversed by IGF-IR siRNA. Coimmunoprecipitation studies show the existence of a multiprotein complex involving AdipoR1, APPL1, ERα, IGF-IR, and c-Src that is responsible for MAPK signaling activation in ER- positive breast cancer cells. It is well known that in addition to the rapid effects through non-genomic mechanisms, ERα also mediates nuclear genomic actions. In this concern, we demonstrated that adiponectin is able to transactivate ERα in MCF-7 cells. We showed the classical features of ERα transactivation: nuclear localization, downregulation of mRNA and protein levels, and upregulation of estrogen-dependent genes. Thus, our study clarifies the molecular mechanism through which adiponectin modulates breast cancer cell growth, providing evidences on the cell-type dependency of adiponectin action in relationship to ERα status.
    Cell cycle (Georgetown, Tex.) 12/2013; 13(4). · 5.24 Impact Factor
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    ABSTRACT: Aim: The aim of the present study was to prepare a hydrogel, based on ellagic acid and glycine, embedded with folic acid, as a subcutaneous implant for the treatment of breast cancer. The function of folic acid is to selectively and actively target tumor cells which are well-known to overexpress folic acid receptors on their surface. A pro-drug based on L-glycine and ellagic acid, was functionalized with a polymerizable group and loaded with folic acid to make it more natural, non-toxic, compatible and specific for the site of action. Cytotoxicity against MCF-7 cells was also evaluated. Release studies of folic acid were conducted on aliquots of hydrogel at different pH (6.2 and 7.4) and time-points (1, 6, 12 and 24 h) using a shaking water bath at 37°C (body temperature). Our results show that folic acid release by the hydrogel is characterized by a slow kinetic release, especially at pH 6.2. Moreover, it was evidenced that the exposure of human breast cancer cells to ellagic acid-based hydrogel containing folic acid significantly reduced cell viability.
    Anticancer research 11/2013; 33(11):4847-54. · 1.87 Impact Factor
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    ABSTRACT: Several studies have demonstrated that thyroid hormone T3 promotes cancer cell growth, even though the molecular mechanism involved in such processes still needs to be elucidated. In this study we demonstrated that T3 induced proliferation in papillary thyroid carcinoma cell lines concomitantly with an up-regulation of cyclin D1 expression, that is a critical mitogen-regulated cell-cycle control element. Our data revealed that T3 enhanced the recruitment of the TRβ1/Oct-1 complex on Octamer-transcription factor-1 site within cyclin D1 promoter, leading to its transactivation. In addition, silencing of TRβ1 or Oct-1 expression by RNA interference reversed both increased cell proliferation and up-regulation of cyclin D1, underlying the important role of both transcriptional factors in mediating these effects. Finally, T3-induced increase in cell growth was abrogated after knocking down cyclin D1 expression. All these findings highlight a new molecular mechanism by which T3 promotes thyroid cancer cell growth.
    Molecular and Cellular Endocrinology 10/2013; · 4.24 Impact Factor
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    ABSTRACT: The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα-) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position -305/-299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα- invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα-) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα- breast tumors.
    Cell cycle (Georgetown, Tex.) 09/2013; 12(21). · 5.24 Impact Factor
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    ABSTRACT: An efficient tumor targeted-niosomal delivery system for the vehiculation of doxorubicin hydrochloride as an anticancer agent was designed. Niosomes were prepared from a mixture of an opportunely modified Pluronic L64 surfactant and cholesterol as membrane additive and characterized in terms of dimension, distribution size, morphology and doxorubicin entrapment efficiency. After the preparation, Transferrin was conjugated to niosomes in order to produce Tf-niosomes and citotoxicity of the final formulation was studied. The specific uptake of Tf-niosomes into cells was evaluated incubating MCF-7 and MDA-MB-231 cells with fluorescently Rhodamine loaded Tf-niosomes for various times and concentration intervals and further investigated by fluorescence microscopy. Results showed that doxorubicin can be easily encapsulated into niosomes, that are regular and spherical in shape. Moreover, Tf-conjugate niosomes demonstrated far greater extent of cellular uptake to MCF-7 and MDA-MB-231 cells, suggesting that they were mainly taken up by Tf-R mediated endocytosis. Doxorubicin-loaded niosomes anticancer activity was also achieved against MCF-7 and MDA-MB-231 tumoral cell lines and a significant reduction of viability in a dose- and time-related manner was observed. Finally our formulation could be potentially useful as target doxorubicin delivery system in anticancer therapy.
    Langmuir 09/2013; · 4.38 Impact Factor
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    ABSTRACT: We have previously shown that estrogens binding to estrogen receptor (ER) α increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients.
    Cell Death & Disease 08/2013; 4:e747. · 5.18 Impact Factor

Publication Stats

5k Citations
831.54 Total Impact Points

Institutions

  • 1989–2013
    • Università della Calabria
      • • Department of Pharmaco-Biology
      • • Department of Cell Biology
      Rende, Calabria, Italy
  • 2012
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1999–2012
    • Thomas Jefferson University
      • Kimmel Cancer Center
      Philadelphia, Pennsylvania, United States
  • 2009–2011
    • Baylor College of Medicine
      • Lester and Sue Smith Breast Center
      Houston, TX, United States
  • 2007
    • Temple University
      • College of Science and Technology
      Philadelphia, Pennsylvania, United States
  • 2003
    • Faculty of Pharmacy, Sofia
      Ulpia Serdica, Sofia-Capital, Bulgaria
  • 2000
    • University of Oulu
      Uleoborg, Oulu, Finland
  • 1988–1999
    • Università degli Studi della Basilicata
      Potenza, Basilicate, Italy