Matthias Schwab

Universität Ulm, Ulm, Baden-Württemberg, Germany

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Publications (407)2319.47 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Since over 50 years, 5-fluorouracil (5-FU) is in use as backbone of chemotherapy treatment regimens for a wide range of cancers including colon, breast, and head and neck carcinomas. However, drug resistance and severe toxicities such as mucositis, diarrhea, neutropenia, and vomiting in up to 40% of treated patients often lead to dose limitation or treatment discontinuation. Because the oral bioavailability of 5-FU is unpredictable and highly variable, 5-FU is commonly administered intravenously. To overcome medical complications and inconvenience associated with intravenous administration, the oral prodrugs capecitabine and tegafur have been developed. Both fluoropyrimidines are metabolically converted intracellularly to 5-FU, which then needs metabolic activation to exert its damaging activity on RNA and DNA. The low response rates of 10-15% of 5-FU monotherapy can be improved by combination regimens of infusional 5-FU and leucovorin together with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), thereby increasing response rates to 30-40%. The impact of metabolizing enzymes in the development of fluoropyrimidine toxicity and resistance has been studied in great detail. In addition, membrane drug transporters, which are critical determinants of intracellular drug concentrations, may play a role in occurrence of toxicity and development of resistance against fluoropyrimidine-based therapy as well. This review therefore summarizes current knowledge on the role of drug transporters with particular focus on ATP-binding cassette transporters in fluoropyrimidine-based chemotherapy response. © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Risk classification and prediction of prognosis in GIST is still a matter of debate. Data on the impact of age and gender as potential confounding factors are limited. Therefore we comprehensively investigated age and gender as independent risk factors for GIST. Two independent patient cohorts (cohort I, n = 87 [<50 years]; cohort II, n = 125 [≥50 years]) were extracted from the multicentre Ulmer GIST registry including a total of 659 GIST patients retrospectively collected in 18 collaborative German oncological centers. Based on demographic and clinicopathological parameters and a median follow-up time of 4.3 years (range 0.56; 21.33) disease-specific-survival (DSS), disease-free-survival (DFS) and overall survival (OS) were calculated. GIST patients older than fifty years showed significantly worse DSS compared to younger patients (p = 0.021; HR = 0.307, 95% CI [0.113; 0.834]). DSS was significantly more favorable in younger female GIST patients compared with elderly females (p = 0.008). Female gender resulted again in better prognosis in younger patients (p = 0.033). Patient age (<50 years) and female gender were significantly associated with a more favourable prognosis in GIST. Extended studies are warranted to confirm our clinical results and to elucidate underlying pathophysiological mechanisms.
    BMC Cancer 12/2015; 15(1):1054. DOI:10.1186/s12885-015-1054-y · 3.32 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555216 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555307 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555178 · 1.67 Impact Factor
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    ABSTRACT: There is evidence that molecular features support subclassification of tumours, thereby improving prediction of patient outcome. Currently, two gene expression signatures (ccA/ccB and ClearCode34) have been established to classify clear cell renal cell carcinoma (ccRCC). Because RCC arises from nephron cell types, we aimed to explore its heterogeneity on a molecular level by comparing gene expression between tumour tissue and nephron regions. Based on genes that differ in expression between nephron regions, expression data of 479 ccRCCs and 212 papillary and 66 chromophobe RCCs from The Cancer Genome Atlas were correlated to those of nephron cell types. Cancer-specific survival (CSS) of ccRCC patients was significantly associated with gene expression similarity to the proximal tubules. Subsequently, a ccRCC risk score (S3-score) was established. Survival analyses indicated that the S3-score was significantly associated with CSS considering all cases of ccRCC, as well as metastatic and nonmetastatic ccRCC. Results could be validated in an independent cohort. The S3-score significantly improved the predictive ability of the ccA/ccB and ClearCode34 signatures, and the clinicopathologic-based stage, size, grade, and necrosis score (p [chi-square] = 1.56E-04). Intratumour heterogeneity of the S3-score was observed in 6 of 10 ccRCCs. In summary, the nephron-based S3-score enables prognostic risk stratification for ccRCC. Further studies are needed to evaluate its clinical utility. We developed a novel risk score for clear cell renal cell carcinoma to identify patients at risk of worse outcome that may improve patient care in the future. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 06/2015; DOI:10.1016/j.eururo.2015.05.045 · 12.48 Impact Factor
  • Blood 05/2015; 125(21):3355-7. DOI:10.1182/blood-2015-02-628339 · 10.43 Impact Factor
  • Nature Biotechnology 05/2015; 33(6). DOI:10.1038/nbt.3241 · 39.08 Impact Factor
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    ABSTRACT: Background Platelet secretion is critical to development of acute thrombotic occlusion. Platelet dense granules contain a variety of important hemostatically active substances. Nevertheless, biogenesis of platelet granules is poorly understood.ObjectivesSGK1 has been shown to be highly expressed in platelets and megakaryocytes, but its role in the regulation of platelet granule biogenesis and its impact on thrombosis has not been investigated so far.Methods and ResultsElectron microscopy analysis of platelet ultrastructure revealed significant reduction in number and packing of dense granules in platelets lacking SGK1 (sgk1-/-). In sgk1-/- platelets serotonin content was significantly reduced and activation-dependent secretion of ATP, serotonin and CD63 significantly impaired. In vivo adhesion after carotis ligation was significantly decreased in platelets lacking SGK1 and occlusive thrombus formation after FeCl3-induced vascular injury was significantly diminished in sgk1-/- mice. Transcript levels and protein abundance of dense granule biogenesis regulating GTPase Rab27b were significantly reduced in sgk1-/- platelets without affecting Rab27b mRNA stability. In MEG-01 cells transfection with constitutively active S422DSGK1 but not with inactive K127NSGK1 significantly enhanced Rab27b mRNA levels. Sgk1-/- megakaryocytes show significantly reduced expression of Rab27b and serotonin/CD63 levels compared to sgk1+/+ megakaryocytes. Proteome analysis identified 9 further vesicular transport proteins regulated by SGK1 which may have an impact on impaired platelet granules biogenesis in sgk1-/- platelets independent of Rab27b.Conclusions The present observations unravel SGK1 as a novel powerful regulator of platelet dense granule biogenesis, platelet secretion and thrombus formation. SGK1 is at least partially effective by regulating transcription of Rab27b in megakaryocytes.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 05/2015; DOI:10.1111/jth.12998 · 5.55 Impact Factor
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    ABSTRACT: ScopeHesperetin-7-O-rutinoside (hesperidin) reduces blood pressure in healthy volunteers but its intestinal absorption and metabolism are not fully understood. Therefore, we aimed to determine sites of absorption and metabolism of dietary flavanone glycosides in humans.Methods and resultsUsing a single blind, randomized crossover design, we perfused equimolar amounts of hesperetin-7-O-rutinoside and hesperetin-7-O-glucoside directly into the proximal jejunum of healthy volunteers. We assessed the appearance of metabolites in the perfusate, blood and urine, to determine the sites of metabolism and excretion, and compared this to oral administration. Theglucoside was rapidly hydrolysed by brush border enzymes without any contribution from pancreatic, stomach or other secreted enzymes, or from bacterial enzymes. Only ∼3% of the dose was recovered intact in the perfusate, indicating high absorption. A proportion was effluxed directly back into the perfused segment mainly in the form of hesperetin-3’-O-sulfate. In contrast, very little hydrolysis or absorption of hesperetin-7-O-rutinoside was observed with ∼80% recovered in the perfusate, no hesperetin metabolites were detected in blood and only traces were excreted in urine.Conclusions The data elucidate the pathways of metabolism of dietary hesperidin in vivo and will facilitate better design of mechanistic studies both in vivo and in vitro.The trial was registered at Medical Faculty of the University of Tübingen. Eudra-CT number 2006-006008-12This article is protected by copyright. All rights reserved
    Molecular Nutrition & Food Research 05/2015; DOI:10.1002/mnfr.201500202 · 4.91 Impact Factor
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    ABSTRACT: Multidrug resistance protein 8 (ABCC11) is an efflux transporter for anionic lipophilic compounds, conferring resistance to antiviral and anticancer agents like 5-fluorouracil (5-FU). ABCC11 missense variants may contribute to variability in drug response but functional consequences, except for the 'earwax variant' c.538G>A, are unknown. Using the 'Screen and Insert' technology, we generated human embryonic kidney 293 cells stably expressing ABCC11 missense variants frequently occurring in different ethnic populations: c.57G>A, c.538G>A, c.950C>A, c.1637C>T, c.1942G>A, c.4032A>G. A series of in silico prediction analyses and in vitro plasma membrane vesicle uptake, immunoblotting and immunolocalization experiments were undertaken to investigate functional consequences. We identified c.1637C>T (T546M), previously associated with 5-FU-related toxicity, as a novel functionally damaging ABCC11 variant exhibiting markedly reduced transport function of 5-FdUMP, the active cytotoxic metabolite of 5-FU. Detailed analysis of 14 subpopulations revealed highest allele frequencies of c.1637C>T in Europeans and Americans (up to 11%) compared with Africans and Asians (up to 3%).The Pharmacogenomics Journal advance online publication, 21 April 2015; doi:10.1038/tpj.2015.27.
    The Pharmacogenomics Journal 04/2015; DOI:10.1038/tpj.2015.27 · 5.51 Impact Factor
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    ABSTRACT: ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.
    Clinical Pharmacokinetics 04/2015; DOI:10.1007/s40262-015-0267-1 · 5.49 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-436-S-437. DOI:10.1016/S0016-5085(15)31475-X · 13.93 Impact Factor
  • European Urology Supplements 04/2015; 193(4):e722. DOI:10.1016/j.juro.2015.02.2142 · 3.37 Impact Factor
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    ABSTRACT: Objectives This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI). Methods 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort. Results Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort. Conclusions Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients.
    PLoS ONE 03/2015; 10(3-3):e0121620. DOI:10.1371/journal.pone.0121620 · 3.53 Impact Factor
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    ABSTRACT: Expression of genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs is collectively impaired during pathophysiological conditions such as cholestasis and inflammation. The mechanism of coordinated ADME gene downregulation remains unclear. In our previous study strongly elevated levels of microRNAs (miRNA) miR-21, miR-34a, and miR-130b in cholestatic liver and of miR-21 and miR-130b during inflammation were observed. Using HepaRG cells, which retain many functional characteristics of human hepatocytes, we investigated the potential of these miRNAs to downregulate ADME genes. Cells were transfected with the corresponding miRNA mimics, chemically modified double-stranded RNAs that mimic endogenous miRNAs, followed by mRNA profiling by quantitative RT-PCR. Enzyme activities of six cytochromes P450 (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4) were determined with a liquid chromatography-tandem mass spectrometric cocktail assay. While miR-21 and miR-34a showed little effects, transfection of miR-130b lead to significantly lower expression of nuclear receptors CAR and FXRa, the CYPs 1A1, 1A2, 2A6, 2C8, 2C9, and 2C19, as well as GSTA2. Furthermore, miR-130b negatively affected activity levels of all measured P450s by more than 40%. Reporter gene assays employing the CYP2C9 3'UTR confirmed direct regulation by miR-130b. These data support miR-130b as a potential negative regulator of drug metabolism by directly and/or indirectly affecting the expression of several ADME genes. This may be of relevance in pathophysiological conditions such as cholestasis and inflammation, which are associated with increased miR-130b expression. The American Society for Pharmacology and Experimental Therapeutics.
    Drug metabolism and disposition: the biological fate of chemicals 03/2015; 43(6). DOI:10.1124/dmd.114.062844 · 3.33 Impact Factor
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    ABSTRACT: Surface expression of stromal cell-derived factor-1 (SDF-1, CXCL12) on platelets is enhanced during ischaemic events and plays an important role in peripheral homing of stem cells and myocardial repair mechanisms. SDF-1 effects are mediated through CXCR4 and CXCR7. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in patients with coronary artery disease (CAD) when compared with healthy controls. In this study, we investigated the prognostic role of platelet CXCR4- and CXCR7 surface expression in patients with symptomatic CAD. In a cohort study, platelet surface expression of CXCR4 and CXCR7 was measured by flow cytometry in 284 patients with symptomatic CAD at the time of percutaneous coronary intervention (PCI). The primary combined endpoint was defined as all-cause death and/or MI during 12 month follow-up. Secondary endpoints were defined as the single events of all-cause death and myocardial infarction (MI). We found significant differences of CXCR4 values in patients who developed a combined endpoint compared to event-free patients (mean MFI 3.17 vs. 3.44, 95% CI 0.09 - 0.45) and in patients who subsequently died (mean MFI 3.10 vs. 3.42, 95% CI 0.09 - 0.56). In multivariate Cox regression analysis lower platelet CXCR4 levels were independently and significantly associated with all cause mortality (HR 0.24, 95% CI 0.07 - 0.87) and the primary combined endpoint of all-cause death and/or MI (HR 0.30, 95% CI 0.13 - 0.72). These findings highlight a potential prognostic value of platelet expression CXCR4 on clinical outcomes in patients with CAD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 02/2015; 13(5). DOI:10.1111/jth.12870 · 5.55 Impact Factor
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    ABSTRACT: Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (n = 267) was 62.8% compared to 83.4% in patients without other tumors (n = 569) (P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted. Copyright © 2014. Published by Elsevier Inc.
    Neoplasia (New York, N.Y.) 01/2015; 17(1):134-40. DOI:10.1016/j.neo.2014.12.001 · 5.40 Impact Factor
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    ABSTRACT: BACKGROUND/AIMS: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. METHODS: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. RESULTS: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. CONCLUSION: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.
    Cellular Physiology and Biochemistry 01/2015; 35(2):803-815. DOI:10.1159/000369739 · 3.55 Impact Factor
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    ABSTRACT: Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.
    Emerging infectious diseases 01/2015; 21(1). DOI:10.3201/eid2101.140861 · 7.33 Impact Factor

Publication Stats

14k Citations
2,319.47 Total Impact Points

Institutions

  • 2015
    • Universität Ulm
      • Institute of Pathology
      Ulm, Baden-Württemberg, Germany
  • 2007–2015
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2003–2015
    • Universitätsklinikum Tübingen
      • • Division of Clinical Pharmacology
      • • Division of Neurogastroenterology
      Tübingen, Baden-Württemberg, Germany
    • Klinikum Stuttgart
      Stuttgart, Baden-Württemberg, Germany
  • 2004–2014
    • Universität Stuttgart
      Stuttgart, Baden-Württemberg, Germany
    • Dr. Falk Pharma GmbH
      Freiburg, Baden-Württemberg, Germany
  • 1997–2014
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2013
    • University of Greifswald
      Griefswald, Mecklenburg-Vorpommern, Germany
    • McGill University
      Montréal, Quebec, Canada
  • 2012
    • Binghamton University
      • Department of Biological Sciences
      Binghamton, New York, United States
  • 2011
    • Children's National Medical Center
      Washington, Washington, D.C., United States
  • 2009
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2002–2007
    • Humboldt-Universität zu Berlin
      • Department of Biology
      Berlín, Berlin, Germany
    • Universität Heidelberg
      • Department of Urology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2006
    • University of California, Davis
      • Department of Medical Microbiology and Immunology
      Davis, California, United States
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2005
    • Hannover Medical School
      • Department of Paediatric Haematology and Oncology
      Hannover, Lower Saxony, Germany
    • Medical University of Vienna
      • Klinische Abteilung für Gastroenterologie und Hepatologie
      Vienna, Vienna, Austria
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 2001–2004
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
    • Bundesärztekammer
      Berlín, Berlin, Germany
  • 1999–2004
    • Philipps University of Marburg
      Marburg, Hesse, Germany