Peter Valent

Ludwig Boltzmann-Cluster Oncology (LB-CO) | Medical University Vienna, Wien, Vienna, Austria

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Publications (705)3424.63 Total impact

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    ABSTRACT: Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN-blockers, whereas normal cells are FASN-negative and FASN-inhibitor-resistant. Here we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN-inhibitor-sensitive. Upon subculture, non-malignant cells cease growth, express senescence-associated-β-galactosidase, lose FASN and become FASN-inhibitor-resistant. Immortalized ovarian/oviductal epithelial cell lines - although resisting senescence - reveal distinct growth activities, which correlate with FASN-levels and FASN-drug-sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN-levels and lipogenic activities affect cellular lipid composition as demonstrated by thin-layer chromatography. Correlation between proliferation and FASN-levels was finally evaluated in cancer cells such as HOC-7, which contain subclones with variable differentiation/senescence and corresponding FASN-expression/FASN-drug-sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC-7 by differentiating agents. In OC cells, FASN-drugs induce cell cycle-blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle-deceleration without apoptosis. Thus normal cells, although growth-inhibited, may survive and recover from FASN-blockade, whereas malignant cells get extinguished. FASN-expression and FASN-drug-sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2015; 136(9). DOI:10.1002/ijc.29261 · 5.01 Impact Factor
  • AACR 2015, Philadelphia; 04/2015
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    ABSTRACT: More than 10% of the population in Europe and North America suffer from IgE-associated allergy to grass pollen. In this article, we describe the development of a vaccine for grass pollen allergen-specific immunotherapy based on two recombinant hypoallergenic mosaic molecules, designated P and Q, which were constructed out of elements derived from the four major timothy grass pollen allergens: Phl p 1, Phl p 2, Phl p 5, and Phl p 6. Seventeen recombinant mosaic molecules were expressed and purified in Escherichia coli using synthetic genes, characterized regarding biochemical properties, structural fold, and IgE reactivity. We found that depending on the arrangement of allergen fragments, mosaic molecules with strongly varying IgE reactivity were obtained. Based on an extensive screening with sera and basophils from allergic patients, two hypoallergenic mosaic molecules, P and Q, incorporating the primary sequence elements of the four grass pollen allergens were identified. As shown by lymphoproliferation experiments, they contained allergen-specific T cell epitopes required for tolerance induction, and upon immunization of animals induced higher allergen-specific IgG Abs than the wild-type allergens and a registered monophosphoryl lipid A-adjuvanted vaccine based on natural grass pollen allergen extract. Moreover, IgG Abs induced by immunization with P and Q inhibited the binding of patients' IgE to natural allergens from five grasses better than IgG induced with the wild-type allergens or an extract-based vaccine. Our results suggest that vaccines based on the hypoallergenic grass pollen mosaics can be used for immunotherapy of grass pollen allergy. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 03/2015; DOI:10.4049/jimmunol.1400402 · 5.36 Impact Factor
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    ABSTRACT: Mastocytosis is a term referring to a heterogeneous group of disorders characterized by abnormal mast cell (MC) accumulation in the skin and/or internal organs. In children, the disease involves mostly the skin (cutaneous mastocytosis; CM), whereas in adults the disease is usually systemic (systemic mastocytosis; SM). Advanced SM variants with end-organ damage and reduced life expectancy have also been described, but are rare. Clinical signs and symptoms in SM result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. As a consequence, treatment of indolent SM aims primarily at the control of symptoms caused by MC mediator release. By contrast, in advanced SM, such as aggressive SM, MC leukemia and MC sarcoma, intensive (chemo)therapy with or without allogeneic stem cell transplantation has to be considered. In addition, activating mutations in KIT (mostly KIT D816V in adults) are found in most SM patients, so that targeted therapies aimed at blocking mutant KIT variants or/and downstream signaling pathways, are currently being developed. Other targets, such as specific surface-antigens expressed on neoplastic MCs, might be considered for the development of future therapies in advanced SM. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 03/2015; DOI:10.1111/ejh.12544 · 2.41 Impact Factor
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    ABSTRACT: A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the WHO-classification based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS vs. IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS vs. IPSS-R model. Overall both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant information for the implementation of risk-adapted strategies in MDS.Leukemia accepted article preview online, 27 February 2015. doi:10.1038/leu.2015.55.
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2015; DOI:10.1038/leu.2015.49 · 9.38 Impact Factor
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    ABSTRACT: Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in cells and various tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly-sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) which is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM, and help to avoid unnecessary referrals.Leukemia accepted article preview online, 04 February 2015. doi:10.1038/leu.2015.24.
    Leukemia 02/2015; DOI:10.1038/leu.2015.24 · 9.38 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB136. DOI:10.1016/j.jaci.2014.12.1377 · 11.25 Impact Factor
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    ABSTRACT: To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V+ indolent systemic mastocytosis (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1 to 4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V positive single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V negative. These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD, (c) KIT D816V is thus a phenotype-modifier towards SM and (d) KIT D816V or other mutations are rare in CFU-GM colonies of ISM/SSM patients which might explain at least in part their better prognosis.Leukemia accepted article preview online, 08 January 2015. doi:10.1038/leu.2015.4.
    Leukemia 01/2015; DOI:10.1038/leu.2015.4 · 9.38 Impact Factor
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    ABSTRACT: Basophilia is an established prognostic variable in Ph-chromosome+ chronic myeloid leukemia (CML). However, in CML, basophils are often immature and thus escape microscopic quantification. We have previously shown that tryptase is produced and secreted by immature CML basophils. In the current study, serum samples of 79 CML patients (chronic phase=CP, n=69; accelerated/blast phase=AP/BP, n=10) treated with BCR/ABL inhibitors, were analyzed for their tryptase content. Serum-tryptase levels at diagnosis were found to correlate with basophil counts and were higher in AP/BP patients (median tryptase: 29.9 ng/mL) compared to patients with CP (11.7 ng/mL; p<0.05). In 20/69 patients with CP, progression occurred. The progression-rate was higher in patients with tryptase >15 ng/mL (31%) compared to those with normal tryptase levels (9%, p<0.05). To validate tryptase as new prognostic variable, we replaced basophils by tryptase levels in the EUTOS score. This modified EUTOS-T score was found to predict progression-free and event-free survival significantly better, with p values of 0.000064 and 0.00369, respectively, compared to the original EUTOS score (progression-free survival: p=0.019; event-free survival: p=0.156). In conclusion, our data show that the serum-tryptase level at diagnosis is a powerful prognostic biomarker in CML. Inclusion of tryptase in prognostic CML scores may improve their predictive value.
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    ABSTRACT: Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro- and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC50: 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0±11.1 ng/ml; post-therapy: 3.4±1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MC-development in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo. However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.
    Oncotarget 12/2014; · 6.63 Impact Factor
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    ABSTRACT: Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving second- or third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease as well as other arterial disorders in patients receiving nilotinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of drug-induced vasculopathy are not well understood. In this spotlight-article, recent data and concepts around VAEs in TKI-treated patients with CML are discussed, with special reference to potential mechanisms, event-management and strategies aimed at avoiding the occurrence of such events in long-term treated patients. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(6). DOI:10.1182/blood-2014-09-594432 · 9.78 Impact Factor
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    ABSTRACT: The concept of leukaemic stem cells (LSCs) has been developed to explain the complex cellular hierarchy and biology of leukaemias and to screen for pivotal targets that can be employed to improve drug therapies through LSC eradication in these patients. Some of the newly discovered LSC markers seem to be expressed in a disease‐specific manner and may thus serve as major research tools and diagnostic parameters. A useful LSC marker in chronic myeloid leukaemia (CML) appears to be CD26, also known as dipeptidylpeptidase IV. Expression of CD26 is largely restricted to CD34+/CD38− LSCs in BCR/ABL1+ CML, but is not found on LSCs in other myeloid or lymphoid neoplasms, with the exception of lymphoid blast crisis of CML, BCR/ABL1p210+ acute lymphoblastic leukaemia, and a very few cases of acute myeloid leukaemia. Moreover, CD26 usually is not expressed on normal bone marrow (BM) stem cells. Functionally, CD26 is a cytokine‐targeting surface enzyme that may facilitate the mobilization of LSCs from the BM niche. In this article, we review our current knowledge about the biology and function of CD26 on CML LSCs and discuss the diagnostic potential of this new LSC marker in clinical haematology.
    European Journal of Clinical Investigation 12/2014; 44(12). DOI:10.1111/eci.12368 · 2.83 Impact Factor
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    ABSTRACT: The Austrian myelodysplastic syndromes (MDS) Platform was founded as a national working group in 2003 to initiate and coordinate common projects in the field. The incidence of MDS in Austria is approximately 400-500 new MDS cases per year. The overall low number of MDS patients underlines the importance of a national initiative to concentrate knowledge at certain specialized centres, where treatment of these patients mainly takes place. Clinical trials as well as basic research are facilitated by the cooperation of university and non-university hospitals. Other objectives are the generation of therapeutic standards, organization of meetings to spread this information to physicians and patients as well as promoting patient-support groups. Cooperation with international working groups is another important aim of the Platform. The 10th anniversary of the Austrian MDS Platform was organized as a meeting for all interested physicians throughout Austria providing an update on the disease and ongoing projects.
    Wiener klinische Wochenschrift 11/2014; DOI:10.1007/s00508-014-0627-0 · 0.79 Impact Factor
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    ABSTRACT: Grass pollen is one of the most important sources of respiratory allergies worldwide. This study describes the development of a grass pollen allergy vaccine based on recombinant hypoallergenic derivatives of the major timothy grass pollen allergens Phl p 1, Phl p 2, Phl p 5, and Phl p 6 by using a peptide-carrier approach. Fusion proteins consisting of nonallergenic peptides from the 4 major timothy grass pollen allergens and the PreS protein from hepatitis B virus as a carrier were expressed in Escherichia coli and purified by means of chromatography. Recombinant PreS fusion proteins were tested for allergenic activity and T-cell activation by means of IgE serology, basophil activation testing, T-cell proliferation assays, and xMAP Luminex technology in patients with grass pollen allergy. Rabbits were immunized with PreS fusion proteins to characterize their immunogenicity. Ten hypoallergenic PreS fusion proteins were constructed, expressed, and purified. According to immunogenicity and induction of allergen-specific blocking IgG antibodies, 4 hypoallergenic fusion proteins (BM321, BM322, BM325, and BM326) representing Phl p 1, Phl p 2, Phl p 5, and Phl p 6 were included as components in the vaccine termed BM32. BM321, BM322, BM325, and BM326 showed almost completely abolished allergenic activity and induced significantly reduced T-cell proliferation and release of proinflammatory cytokines in patients' PBMCs compared with grass pollen allergens. On immunization, they induced allergen-specific IgG antibodies, which inhibited patients' IgE binding to all 4 major allergens of grass pollen, as well as allergen-induced basophil activation. A recombinant hypoallergenic grass pollen allergy vaccine (BM32) consisting of 4 recombinant PreS-fused grass pollen allergen peptides was developed for safe immunotherapy of grass pollen allergy. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 11/2014; 130. DOI:10.1016/j.jaci.2014.09.012 · 11.25 Impact Factor
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    ABSTRACT: International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on Fluorescence-in-situ-hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34+) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes: For cytogenetic risk classification by Fluorescence-in-situ-hybridization analyses of CD34+ peripheral blood cells the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of Fluorescence-in-situ-hybridization analyses of peripheral CD34+ blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel. This trial was registered at www.clinicaltrials.gov as #NCT01355913.
    Haematologica 10/2014; DOI:10.3324/haematol.2014.110452 · 5.87 Impact Factor
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    ABSTRACT: Eosinophil-associated diseases often present with life-threatening manifestations and/or chronic organ damage. Currently available therapeutic options are limited to a few drugs that often have to be prescribed on a lifelong basis to keep eosinophil counts under control. In the past 10 years, treatment options and outcomes in patients with clonal eosinophilic and other eosinophilic disorders have improved substantially. Several new targeted therapies have emerged, addressing different aspects of eosinophil expansion and inflammation. In this review, we discuss available and currently tested agents as well as new strategies and drug targets relevant to both primary and secondary eosinophilic diseases, including allergic disorders. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 55 is January 06, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual Review of Pharmacology 10/2014; 55(1). DOI:10.1146/annurev-pharmtox-010814-124407 · 18.52 Impact Factor
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    ABSTRACT: The two transcription factors STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases and they fulfill all criteria of drug targets. STAT5A and STAT5B display unique nuclear shuttling mechanisms and they have a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). Moreover, STAT5A and STAT5B promote survival of leukemic stem cells. We here discuss the possibility of targeting up-stream kinases with TKI, direct STAT5 inhibition via SH2 domain obstruction and blocking nuclear translocation of STAT5. All discussed options will result in a stop of STAT5 transport to the nucleus to block STAT5-mediated transcriptional activity. In summary, recently described shuttling functions of STAT5 are discussed as potentially druggable pathways in leukemias.
    Oncotarget 10/2014; · 6.63 Impact Factor

Publication Stats

21k Citations
3,424.63 Total Impact Points

Institutions

  • 2007–2015
    • Ludwig Boltzmann-Cluster Oncology (LB-CO) | Medical University Vienna
      Wien, Vienna, Austria
    • Stockholm University
      Tukholma, Stockholm, Sweden
    • University of Rochester
      Rochester, New York, United States
    • Evangelisches Krankenhaus Hamm
      Hamm, North Rhine-Westphalia, Germany
    • Bristol-Myers Squibb
      New York, New York, United States
  • 1989–2015
    • Medical University of Vienna
      • • Institute for Social Medicine
      • • Clinical Division of Hematology and Hemastaseology
      • • Department of Vascular Biology and Thrombosis Research
      Wien, Vienna, Austria
  • 2007–2014
    • Hanusch Krankenhaus
      Wien, Vienna, Austria
  • 2013
    • Stanford Medicine
      Stanford, California, United States
  • 1995–2013
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
  • 1988–2013
    • University of Vienna
      • • Clinic for Internal Medicine I
      • • Center for Pathophysiology, Infectology and Immunology
      • • Institute of Social Medicine
      Wien, Vienna, Austria
  • 2012
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2008–2012
    • Austrian Academy of Sciences
      • Forschungszentrum für Molekulare Medizin (CeMM)
      Vienna, Vienna, Austria
  • 1999–2012
    • Vienna General Hospital
      Wien, Vienna, Austria
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany
    • ORTON Foundation, Helsinki, Finland
      Helsinki, Southern Finland Province, Finland
  • 2011
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
  • 2010
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2006–2009
    • University of Veterinary Medicine in Vienna
      • Department for Companion Animals and Horses
      Vienna, Vienna, Austria
    • Technische Universität München
      München, Bavaria, Germany
    • Novartis
      Bâle, Basel-City, Switzerland
    • Universitätsklinikum Schleswig - Holstein
      • Institut für Pathologie (Kiel)
      Kiel, Schleswig-Holstein, Germany
    • Semmelweis University
      • Department of Genetics, Cell and Immunobiology
      Budapeŝto, Budapest, Hungary
  • 1997–2008
    • University of Tuebingen
      • Institute of Pathology and Neuropathology
      Tübingen, Baden-Wuerttemberg, Germany
  • 2002–2006
    • Universität zu Lübeck
      • Institut für Pathologie
      Lübeck Hansestadt, Schleswig-Holstein, Germany
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 2005
    • Harvard University
      Cambridge, Massachusetts, United States
    • Oregon Health and Science University
      Portland, Oregon, United States
    • Çanakkale Onsekiz Mart Üniversitesi
      • Department of Chemistry
      Kale-Sultanie, Çanakkale, Turkey
  • 2004
    • St Anna's Kinderspital
      Wien, Vienna, Austria
  • 2003
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2001
    • Florida State University
      • Department of Biological Science
      Tallahassee, Florida, United States
  • 2000
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 1998
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany
  • 1996
    • University of Salzburg
      Salzburg, Salzburg, Austria
  • 1993
    • Allgemeines Krankenhaus Linz
      Linz, Upper Austria, Austria