Vassilis G Gorgoulis

National and Kapodistrian University of Athens, Athínai, Attica, Greece

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Publications (220)1225.62 Total impact

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    ABSTRACT: Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.
    Cellular and Molecular Life Sciences CMLS 09/2014; DOI:10.1007/s00018-014-1717-x · 5.86 Impact Factor
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    ABSTRACT: Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.
    British Journal of Haematology 08/2014; 167(4). DOI:10.1111/bjh.13079 · 4.94 Impact Factor
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    ABSTRACT: Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. Other ARF activities, particularly p53-independent ones, that could help in understanding cancer development and provide potential therapeutic exploitation are underrated. Although ARF is generally not expressed in normal tissues, it is essential for ocular and male germ cells development. The underlying mechanism(s) in these processes, while not clearly defined, point toward a functional link between ARF, DNA damage and angiogenesis. Based on a recent study from our group demonstrating a functional interplay between ataxia-telangiectasia mutated (ATM) and ARF during carcinogenesis, we discuss the role of ARF at the crossroads of cancer and developmental processes.
    Frontiers in Genetics 07/2014; 5:236. DOI:10.3389/fgene.2014.00236
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    Tomer Cooks, Ioannis S Pateras, Vassilis G Gorgoulis
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    ABSTRACT: Mutant p53 functions as a key molecular element in the inflamed colon tissue joining forces with nuclear factor kappa-B (NF-κB) to prolong and intensify the inflammatory response, leading eventually to a higher risk for colitis associated colorectal cancer (CAC). This phenomenon coincides with the fact that mutations in p53 are an initiating factor of CAC unlike sporadic colorectal cancer (CRC) where they are considered a late event contributing to tumor progression. This research highlight attempts to illuminate the consequences of such a reshuffling in the molecular sequence of events from non-cancerous tissue to invasive carcinoma of the colon. Implications of this different role taken by mutant p53 when inflammation is involved might affect tumorigenesis, pathogenesis, and hierarchical morphogenesis and suggest the reevaluation of current animal models used to study CAC. We also discuss the possible role of mutant p53 in stromal and immune compartments, either in an autonomous or non-autonomous manner. Cancer Cell & Microenvironment 2014; 1:66-71. doi: 10.14800/ccm.135; © 2014 by Smart Science & Technology, LLC. The monolayered epithelia of the intestine have to maintain a constant delicate balance, taking into account radical changes at the luminal end. Throughout this continuous battle, which involves exposure to harsh mechanical, chemical and biological conditions, the intestinal epithelium is required to juggle between the absorption of nutrients and metabolites while restricting the penetration of unwelcome infectious agents [1, 2]
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    ABSTRACT: Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents. <>
    Cell Death and Differentiation 06/2014; 24(6):998-1012. DOI:10.1038/cdd.2014.16 · 8.39 Impact Factor
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    ABSTRACT: Sensing, integrating, and processing of stressogenic signals must be followed by accurate differential response(s) for a cell to survive and avoid malignant transformation. The DNA damage response (DDR) pathway is vital in this process, as it deals with genotoxic/oncogenic insults, having p53 as a nodal effector that performs most of the above tasks. Accumulating data reveal that other pathways are also involved in the same or similar processes, conveying also to p53. Emerging questions are if, how, and when these additional pathways communicate with the DDR axis. Two such stress response pathways, involving the MKK7 stress-activated protein kinase (SAPK) and ARF, have been shown to be interlocked with the ATM/ATR-regulated DDR axis in a highly ordered manner. This creates a new landscape in the DDR orchestrated response to genotoxic/oncogenic insults that is currently discussed.
    Cell cycle (Georgetown, Tex.) 03/2014; 13(8). DOI:10.4161/cc.28654 · 5.24 Impact Factor
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    ABSTRACT: Colorectal cancer is frequently associated with chronic inflammation, with the intestinal epithelial barrier playing an important protective role against the infections and injuries that cause colitis. The p38α pathway regulates inflammatory responses but can also suppress tumor initiation in epithelial cells. We have found that p38α signaling has a dual function in colorectal tumorigenesis. On one side, p38α protects intestinal epithelial cells against colitis-associated colon cancer by regulating intestinal epithelial barrier function. Accordingly, p38α downregulation results in enhanced colitis-induced epithelial damage and inflammation, which potentiates colon tumor formation. Surprisingly, inhibition of p38α in transformed colon epithelial cells reduces tumor burden. Thus, p38α suppresses inflammation-associated epithelial damage and tumorigenesis but contributes to the proliferation and survival of tumor cells.
    Cancer cell 03/2014; DOI:10.1016/j.ccr.2014.02.019 · 25.29 Impact Factor
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    ABSTRACT: Ionizing radiation (IR) has been described as a double-edged sword, since it is used for diagnostic and therapeutic medical applications, and at the same time it is a well known human mutagen and carcinogen, causing wide-ranging chromosomal aberrations. It is nowadays accepted that the detrimental effects of IR are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. This review presents the role of oxidative stress in the induction of bystander effects referring to the types of the implicated oxidative DNA lesions, the contributing intercellular and intracellular stress mediators, the way they are transmitted from irradiated to bystander cells and finally, the complex role of the bystander effect in the therapeutic efficacy of radiation treatment of cancer.
    Cancer letters 02/2014; 356(1). DOI:10.1016/j.canlet.2014.01.023 · 5.02 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B73-B73. DOI:10.1158/1535-7163.TARG-13-B73 · 6.11 Impact Factor
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    ABSTRACT: Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention. Stem Cells 2013;31:2813–2826
    Stem Cells 12/2013; 31(12). DOI:10.1002/stem.1488 · 7.70 Impact Factor
  • Thorax 11/2013; 68(Suppl 3):A2-A3. DOI:10.1136/thoraxjnl-2013-204457.5 · 8.56 Impact Factor
  • Free Radical Biology and Medicine 09/2013; 65:S52-S53. DOI:10.1016/j.freeradbiomed.2013.08.089 · 5.71 Impact Factor
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    ABSTRACT: The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.
    Nature Cell Biology 07/2013; DOI:10.1038/ncb2795 · 20.06 Impact Factor
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    ABSTRACT: Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.Cell Death and Differentiation advance online publication, 12 July 2013; doi:10.1038/cdd.2013.76.
    Cell death and differentiation 07/2013; 20(11). DOI:10.1038/cdd.2013.76 · 8.24 Impact Factor
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    ABSTRACT: The ubiquitin-proteasome system is central to the regulation of cellular proteostasis. Nevertheless, the impact of in vivo proteasome dysfunction on the proteostasis networks and the aging processes remains poorly understood. We found that RNAi-mediated knockdown of 20S proteasome subunits in Drosophila melanogaster resulted in larval lethality. We therefore studied the molecular effects of proteasome dysfunction in adult flies by developing a model of dose-dependent pharmacological proteasome inhibition. Impaired proteasome function promoted several "old-age" phenotypes and markedly reduced flies' lifespan. In young somatic tissues and in gonads of all ages, loss of proteasome activity induced higher expression levels and assembly rates of proteasome subunits. Proteasome dysfunction was signaled to the proteostasis network by reactive oxygen species that originated from malfunctioning mitochondria and triggered an Nrf2-dependent upregulation of the proteasome subunits. RNAi-mediated Nrf2 knockdown reduced proteasome activities, flies resistance to stress, as well as longevity. Conversely, inducible activation of Nrf2 in transgenic flies, upregulated basal proteasome expression and activity independently of age, and conferred resistance to proteotoxic stress. Interestingly, prolonged Nrf2 over-expression reduced longevity, indicating that excessive activation of the proteostasis pathways can be detrimental. Our in vivo studies add new knowledge on the proteotoxic stress-related regulation of the proteostasis networks in higher metazoans. Proteasome dysfunction triggers the activation of an Nrf2-dependent tissue- and age-specific regulatory circuit aiming to adjust the cellular proteasome activity according to temporal and/or spatial proteolytic demands. Prolonged deregulation of this proteostasis circuit accelerates aging. This article is protected by copyright. All rights reserved.
    Aging cell 06/2013; DOI:10.1111/acel.12111 · 7.55 Impact Factor
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    ABSTRACT: The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.
    Cancer cell 05/2013; 23(5):634-46. DOI:10.1016/j.ccr.2013.03.022 · 25.29 Impact Factor
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    ABSTRACT: Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.
    Proceedings of the National Academy of Sciences 03/2013; 110(16). DOI:10.1073/pnas.1215938110 · 9.81 Impact Factor
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    ABSTRACT: Organisms are constantly challenged by stressors and thus the maintenance of biomolecules functionality is essential for the assurance of cellular homeostasis. Proteins carry out the vast majority of cellular functions by mostly participating in multimeric protein assemblies that operate as protein machines. Cells have evolved a complex proteome quality control network for the rescue, when possible, or the degradation of damaged polypeptides. Nevertheless, despite these proteostasis ensuring mechanisms, new protein synthesis, and the replication-mediated dilution of proteome damage in mitotic cells, the gradual accumulation of stressors during ageing (or due to lifestyle) results in increasingly damaged proteome. Non-enzymatic post-translational protein modifications mostly arise by unbalanced redox homeostasis and/or high glucose levels and may cause disruption of proteostasis as they can alter protein function. This outcome may then increase genomic instability due to reduced fidelity in processes like DNA replication or repair. Herein, we present a synopsis of the major non-enzymatic post-translation protein modifications and of the proteostasis network deregulation in carcinogenesis. We propose that activation of the proteostasis ensuring mechanisms in premalignant cells has tumor-preventive effects, whereas considering that over-activation of these mechanisms represents a hallmark of advanced tumors, their inhibition provides a strategy for the development of anti-tumor therapies. This article is part of a Special Issue entitled: Protein Modifications.
    Journal of proteomics 03/2013; DOI:10.1016/j.jprot.2013.02.024 · 5.07 Impact Factor
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    ABSTRACT: Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ∼50% reduction of proteasome expression and catalytic activities. In contrast, gonads of aging flies were relatively free of proteome oxidative damage and maintained substantial proteasome expression levels and highly active proteasomes. Moreover, gonads of young flies were found to possess more abundant and more active proteasomes than somatic tissues. Exposure of flies to oxidants induced higher proteasome activities specifically in the gonads, which were, independently of age, more resistant than soma to oxidative challenge and, as analyses in reporter transgenic flies showed, retained functional antioxidant responses. Finally, inducible Nrf2 activation in transgenic flies promoted youthful proteasome expression levels in the aged soma, suggesting that age-dependent Nrf2 dysfunction is causative of decreasing somatic proteasome expression during aging. The higher investment in proteostasis maintenance in the gonads plausibly facilitates proteome stability across generations; it also provides evidence in support of the trade-off theories of aging.-Tsakiri, E. N., Sykiotis, G. P., Papassideri, I. S., Gorgoulis, V. G., Bohmann, D., Trougakos, I. P. Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress.
    The FASEB Journal 03/2013; 27(6). DOI:10.1096/fj.12-221408 · 5.48 Impact Factor
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    ABSTRACT: There is shortage of extensive clinicopathologic studies of cellular senescence because the most reliable senescence biomarker, the detection of Senescence-Associated-beta-galactosidase activity (SA-β-gal), is inapplicable in archival material and requires snap-frozen tissues. We validated the histochemical Sudan-Black-B (SBB) specific stain of lipofuscin, an aggregate of oxidized proteins, lipids and metals, known to accumulate in aged tissues, as an additional reliable approach to detect senescent cells independently of sample preparation. We analyzed cellular systems in which senescence was triggered by replicative exhaustion or stressful stimuli, conditional knock-in mice producing precancerous lesions exhibiting senescence, and human preneoplastic lesions known to contain senescent cells. In the above settings we demonstrated co-localization of lipofuscin and SA-β-gal in senescent cells in vitro and in vivo (cryo-preserved tissue), strongly supporting the candidacy of lipofuscin for a biomarker of cellular senescence. Furthermore, cryo-preserved tissues positive for SA-β-gal were formalin-fixed, paraffin-embedded, and stained with SBB. The corresponding SA-β-gal positive tissue areas stained specifically for lipofuscin by SBB, whereas tissues negative for SA-β-gal were lipofuscin negative, validating the sensitivity and specificity of the SBB staining to visualize senescent cells in archival material. The latter unique property of SBB could be exploited in research on widely available retrospective tissue material.
    Aging 02/2013; 5(1). · 4.89 Impact Factor
    This article is viewable in ResearchGate's enriched format

Publication Stats

7k Citations
1,225.62 Total Impact Points


  • 2002–2014
    • National and Kapodistrian University of Athens
      • • Department of Cell Biology and Biophysics
      • • Faculty of Medicine
      • • Division of Histology - Embryology
      Athínai, Attica, Greece
    • Harvard University
      • Department of Oral Health Policy and Epidemiology
      Cambridge, Massachusetts, United States
  • 1996–2014
    • Athens State University
      Athens, Alabama, United States
  • 2013
    • Academy of Athens
      Athínai, Attica, Greece
  • 2012
    • Hospital Universitario Madrid Sanchinarro
      Madrid, Madrid, Spain
  • 2002–2011
    • Harokopion University of Athens
      Athínai, Attica, Greece
  • 2002–2007
    • University of Patras
      • • Department of General Biology
      • • School of Medicine
      Rhion, West Greece, Greece
  • 2006
    • Danish Cancer Society
      København, Capital Region, Denmark
  • 2005–2006
    • Agricultural University of Athens
      • Department of Anatomy and Physiology of Farm Animals
      Athínai, Attica, Greece
    • Leiden University
      Leyden, South Holland, Netherlands
    • Onassis Cardiac Surgery Center
      Kallithea, Attica, Greece
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2004
    • Saint Savvas Hospital
      Athínai, Attica, Greece
  • 1998–2004
    • Wistar Institute
      Filadelfia, Pennsylvania, United States
  • 1995–2004
    • Laiko Hospital
      Athínai, Attica, Greece
  • 1994–1995
    • University of Crete
      Retimo, Crete, Greece
  • 1992–1995
    • Red Cross Hospital, Athens
      Athínai, Attica, Greece
  • 1993
    • University Hospital of Heraklion
      Irákleio, Attica, Greece