S Daum

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (50)136.37 Total impact

  • Zeitschrift fur Gastroenterologie. 07/2014; 52(7):711-743.
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    ABSTRACT: In some cases the diagnosis of gastric cancer is difficult and the endoscopic presentation may be misleading. Diffuse type gastric carcinoma with peritoneal metastasis may present primarily with abdominal pain, colonic infiltration and/or diarrhea, thus other differential diagnoses like Crohn's disease (CD) may be considered at first. Therefore intensive diagnostic work-up is important. We report two cases of gastric cancer with ascites due to peritoneal carcinomatosis who were first diagnosed as CD. The patients were hospitalized in different institutions for weight loss, abdominal pain and nausea. The first colonoscopy, upper endoscopy with multiple biopsies and ascites puncture were negative for malignant disease, but macroscopic lesions resembling CD were described. Both patients were released on a prednisolone-based treatment for suspected CD. They presented to our hospital for further evaluation due to persistent symptoms. Neither lower nor upper endoscopy were suggestive of CD and endoscopic ultrasound was suspicious of malignancy in one case. Histology was diagnostic and showed gastric infiltration by a poorly differentiated adenocarcinoma. Diffuse type gastric cancer (gastric linitis plastica) with peritoneal metastasis may mimic certain clinical, endoscopic and CT imaging features of CD. Repeated biopsies and endoscopic investigations are often necessary to confirm a malignant process, especially in case of an inconclusive clinical and endoscopic picture. Endoscopic ultrasound may be useful to evaluate the risk of malignancy in patients with macroscopic suspicion of malignancy and negative biopsies.
    Case Reports in Gastroenterology 09/2012; 6(3):695-703.
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    ABSTRACT: PURPOSE: Up to 20 % of colorectal cancer patients develop recurrent disease despite standardized surgical techniques and multimodal treatment strategies. Radical resection is the central component of curative therapy in these cases. The aim of this study was to evaluate treatment results in patients with locoregionally recurrent colorectal cancer. METHODS: From January 1995 to December 2007, surgery was performed for recurrent colorectal cancer in 82 patients who had undergone curative (R0) resection of their primary tumor. Assessment included patient, tumor and treatment characteristics, postoperative complications, and time without re-recurrence; recurrence-free and overall survival rates were calculated according to the Kaplan-Meier method. RESULTS: Resection was performed in 60 of the 82 patients (73 %), repeat R0 resection in 52 % (31/60). Patients had a postoperative morbidity of 39 % (31/82), a relaparotomy rate of 13 % (11/82), and a lethality of 7 % (6/82). Forty-eight percent of all surgically-treated patients received a permanent stoma. Re-recurrence was seen in 52 % (16/31). R0 resection was associated with a 5-year survival rate of 35 % (11/31). CONCLUSIONS: Extensive reinterventions often enable repeat R0 resection. Despite relevant morbidity, the lethality appears to be acceptable. Decisive for the prognosis is re-recurrence.
    Langenbeck s Archives of Surgery 06/2012; · 1.89 Impact Factor
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    ABSTRACT: Pin1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function.
    Molecular cell 04/2011; 42(2):147-59. · 14.61 Impact Factor
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    ABSTRACT: The parvulin family of peptidyl-prolyl cis/trans isomerases (PPIases) catalyzes the cis/trans isomerization of the peptide bonds preceding Pro residues. Eukaryotic parvulin-type PPIases have been shown to be involved in cell proliferation and cell cycle progression. Here we present the biochemical and molecular characterization of a novel multi-domain parvulin-type PPIase from the human pathogenic Trypanosoma cruzi, annotated as TcPar45. Like most other parvulins, Par45 has an N-terminal extension, but, in contrast to human Pin1, it contains a forkhead-associated domain (FHA) instead of a WW domain at the N-terminal end. Par45 shows a strong preference for a substrate with the basic Arg residue preceding Pro (Suc-Ala-Arg-Pro-Phe-NH-Np: k(cat)/K(M)=97.1 /M/s), like that found for human Par14. In contrast to human Pin1, but similarly to Par14, Par45 does not accelerate the cis/trans interconversion of acidic substrates containing Glu-Pro bonds. It is preferentially located in the parasite nucleus. Single RNA interference (RNAi)-mediated knock-down showed that there was a growth inhibition in procyclic Trypanosoma brucei cells. These results identify Par45 as a phosphorylation-independent parvulin required for normal cell proliferation in a unicellular eukaryotic cell.
    Biochimica et Biophysica Acta 09/2010; 1803(9):1028-37. · 4.66 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2010; 48(08). · 1.41 Impact Factor
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    ABSTRACT: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.
    Endoscopy 03/2010; 42(3):197-202. · 5.74 Impact Factor
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    ABSTRACT: Tumors may influence immunologic reactions. Here, we report on a 72-year-old patient who suffered from celiac disease (CD) that had been diagnosed 20 years before. Under a normal diet but without any evidence of enteropathy or CD-associated antibodies, the patient developed a jejunal T-cell lymphoma. It was resected due to perforation and four courses of IMVP-16 were added. The patient started and kept a strict gluten-free diet (GFD). Two years later, he presented with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-beta) expression in intraepithelial lymphocytes. At this time point, he showed high titers of CD-associated antibodies, although he was on a strict GFD. This case report highlights several questions: the missing enteropathy under a gluten-containing diet supports the notion of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. Secondly, the patient developed an early form of a second independent T-cell lymphoma (refractory sprue type II) under a strict GFD, then with CD-associated antibodies, which raises the question whether the clonal intraepithelial lymphocytes were stimulating antibody production. Thus, the single detection of CD-associated antibodies in patients with CD is not itself proof of noncompliance with GFD.
    Digestion 01/2010; 81(4):231-4. · 1.94 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2010; 48(08).
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    ABSTRACT: Cyclophilins belong to the enzyme class of peptidyl prolyl cis-trans isomerases which catalyze the cis-trans isomerization of prolyl bonds in peptides and proteins in different folding states. Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4(+) T cells by the inhibitor provided biological proof of discrimination in vivo.
    Biochemistry 07/2009; 48(26):6268-77. · 3.38 Impact Factor
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    ABSTRACT: The gastrointestinal tract may be of major clinical or diagnostic importance in fever of unknown origin. To the classical diseases in this sense belong very different diseases as Whipple's disease, Familiar Mediterranean Fever, isolated mesenterial vasculitis, and manifestations of immune reconstitution inflammatory disease, but also unusual manifestations of otherwise easily recognized diseases like special forms of celiac disease, or inflammatory bowel disease. Endoscopical techniques to obtain biopsies for diagnostic procedures are frequently crucial to solve the diagnostic puzzle. In some cases the bioptic material may not be sufficient to reach a diagnosis and further surgical intervention is necessary (intestinal lymph-nodes or bowel resections) to acquire enough tissue for a definite diagnosis. Nevertheless using these different approaches in most cases of fever of unknown origin the underlying cause can be identified which for many patients means not more or less than significant improvement or even survival.
    Der Internist 07/2009; 50(6):668-75. · 0.33 Impact Factor
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    ABSTRACT: Der Gastrointestinaltrakt kann bei Patienten mit Fieber unklarer Genese klinisch oder diagnostisch im Vordergrund stehen. Wichtige Erkrankungen umfassen den Morbus Whipple, das Mittelmeerfieber, isoliert auf die mesenterialen Gefäße beschränkte Formen der Vaskulitis und Manifestationen des Immunrekonstitutionssyndroms. Gelegentlich präsentieren sich chronisch entzündliche Darmerkrankungen primär mit Fieber. Die enge interdisziplinäre Zusammenarbeit ist von entscheidender Bedeutung bei der Aufklärung dieser Erkrankungen. Endoskopische Verfahren zur Gewinnung von Probenmaterial sind häufig für die Diagnosestellung entscheidend. In manchen Fällen reicht aber das bioptische Material zur Diagnosesicherung nicht aus, und es müssen durch einen chirurgischen Eingriff größere Gewebeproben (z.B. intestinale Lymphknoten oder Darmresektate) gewonnen werden. Sonst symptomfreie gastrointestinale Malignome (insbesondere Kolon und Pankreas) sind eine wichtige Differenzialdiagnose. Letztendlich kann in den meisten Fällen die für die Prognose des Patienten entscheidende Diagnose gestellt werden. The gastrointestinal tract may be of major clinical or diagnostic importance in fever of unknown origin. To the classical diseases in this sense belong very different diseases as Whipple’s disease, Familiar Mediterranean Fever, isolated mesenterial vasculitis, and manifestations of immune reconstitution inflammatory disease, but also unusual manifestations of otherwise easily recognized diseases like special forms of celiac disease, or inflammatory bowel disease. Endoscopical techniques to obtain biopsies for diagnostic procedures are frequently crucial to solve the diagnostic puzzle. In some cases the bioptic material may not be sufficient to reach a diagnosis and further surgical intervention is necessary (intestinal lymph-nodes or bowel resections) to acquire enough tissue for a definite diagnosis. Nevertheless using these different approaches in most cases of fever of unknown origin the underlying cause can be identified which for many patients means not more or less than significant improvement or even survival.
    Der Internist 06/2009; 50(6):668-675. · 0.33 Impact Factor
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    ABSTRACT: The alpha(2)-gliadin-33mer has been shown to be important in the pathogenesis of coeliac disease. We aimed to study mechanisms of its epithelial translocation and processing in respect to transcytotic and paracellular pathways. Transepithelial passage of a fluorescence-labelled alpha(2)-gliadin-33mer was studied in Caco-2 cells by using reverse-phase high-performance liquid chromatography, mass spectrometry, confocal laser scanning microscopy (LSM) and fluorescence activated cell sorting (FACS). Endocytosis mechanisms were characterised with rab-GFP constructs transiently transfected into Caco-2 cells and in human duodenal biopsy specimens. The alpha(2)-gliadin-33mer dose-dependently crossed the epithelial barrier in the apical-to-basal direction. Degradation analysis revealed translocation of the 33mer polypeptide in the uncleaved as well as in the degraded form. Transcellular passage was identified by confocal LSM, inhibitor experiments and FACS. Rab5 but not rab4 or rab7 vesicles were shown to be part of the transcytotic pathway. After pre-incubation with interferon-gamma, translocation of the 33mer was increased by 40%. In mucosal biopsies of the duodenum, epithelial 33mer uptake was significantly higher in untreated coeliac disease patients than in healthy controls or coeliac disease patients on a gluten-free diet. Epithelial translocation of the alpha(2)-gliadin-33mer occurs by transcytosis after partial degradation through a rab5 endocytosis compartment and is regulated by interferon-gamma. Uptake of the 33mer is higher in untreated coeliac disease than in controls and coeliac disease patients on a gluten-free diet.
    Gut 07/2008; 57(6):747-54. · 10.73 Impact Factor
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    ABSTRACT: An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/microl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/microl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25(+)CD4(+) cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.
    Zeitschrift für Rheumatologie 07/2008; 67(4):277-8, 280-3. · 0.45 Impact Factor
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    ABSTRACT: Eine überschießende Immunreaktion mit granulomatöser Entzündung nach Infektionen mit opportunistischen Pathogenen wird als inflammatorisches Immunrekonstitutionssyndrom (IRIS) bezeichnet. Es wird in der Literatur im Wesentlichen bei HIV-infizierten Patienten unter hochaktiver antiretroviraler Therapie (HAART) mit signifikantem Anstieg primär niedriger (<50/µl) CD4-T-Zellen beschrieben. IRIS kann zu Organschädigungen führen, und die Differenzialdiagnose ist häufig schwierig. Hier wird der Fall einer 38-jährigen Patientin mit einem systemischen Lupus erythematodes (SLE) beschrieben, die nach verschiedenen immunsuppressiven Therapien eine Mycobacterium-genavense-Infektion der Leber und des Dünndarms entwickelte. Bei sehr niedrigen CD4-T-Zell-Zahlen wurde die Immunsuppression beendet und eine antimykobakterielle Therapie konsequent durchgeführt. Trotz ansteigender CD4-Zellen persistierten Zeichen einer schweren Malabsorption. Die Duodenoskopie zeigte eine kontinuierliche Entzündung mit Pseudopolypen, histologisch mit granulomatöser Inflammation. Nach Ausschluss einer persistierenden mykobakteriellen Infektion wurde die Diagnose eines Immunrekonstitutionssyndroms gestellt und eine Prednisolon-Therapie begonnen. Das klinische und histologische Bild besserte sich signifikant, einhergehend mit einem Abfall CD4+CD25+-Zellen in der Lamina propria des Duodenums und einer Akkumulation von Foxp3+-regulatorischer T-Zellen (Treg) in der Umgebung der Granulome. Dieser Fall zeigt, dass IRIS auch bei nicht-HIV-positiven immunsupprimierten Patienten an ungewöhnlichen Lokalisationen auftreten kann. Aufgrund der völlig unterschiedlichen Therapiestrategien ist die richtige Diagnose bei diesem Krankheitsbild essenziell. An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/μl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/μl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25+CD4+ cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.
    Zeitschrift für Rheumatologie 06/2008; 67(4):277-283. · 0.45 Impact Factor
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    ABSTRACT: The human peptidyl prolyl cis/trans isomerase (PPIase) Pin1 has a key role in developmental processes and cell proliferation. Pin1 consists of an N-terminal WW domain and a C-terminal catalytic PPIase domain both targeted specifically to Ser(PO(3)H(2))/Thr(PO(3)H(2))-Pro sequences. Here, we report the enhanced affinity originating from bivalent binding of ligands toward Pin1 compared to monovalent binding. We developed composite peptides where an N-terminal segment represents a catalytic site-directed motif and a C-terminal segment exhibits a predominant affinity to the WW domain of Pin1 tethered by polyproline linkers of different chain length. We used NMR shift perturbation experiments to obtain information on the specific interaction of a bivalent ligand to both targeted sites of Pin1. The bivalent ligands allowed a considerable range of thermodynamic investigations using isothermal titration calorimetry and PPIase activity assays. They expressed up to 350-fold improved affinity toward Pin1 in the nanomolar range in comparison to the monovalent peptides. The distance between the two binding motifs was highly relevant for affinity. The optimum in affinity manifested by a linker length of five prolyl residues between active site- and WW domain-directed peptide fragments suggests that the corresponding domains in Pin1 are allowed to adopt preferred spatial arrangement upon ligand binding.
    Journal of Molecular Biology 12/2007; 374(1):147-61. · 3.91 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2007; 45(08). · 1.41 Impact Factor
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    ABSTRACT: Parvulins are a conserved group of peptidyl-prolyl cis/trans isomerases (PPIases) that catalyze the cis/trans isomerization of proline-preceding peptide bonds. Parvulin-class PPIases are structurally unrelated to cyclophilins and FK506-binding proteins that are defined as receptors for immunosuppressive drugs. In Trypanosoma cruzi we identified parvulin TcPIN1 as a homolog of the human hPin1 PPIase. The 117 amino acids of the TcPIN1 display 40% identity with the catalytic core of hPin1 and exhibit prolyl cis/trans isomerase activity. TcPIN1 lacks the WW domain at the N-terminus, and is able to rescue the temperature-sensitive phenotype on a mutation in the Saccharomyces cerevisiae hPin1 homolog, ESS1/PTF1. Western blot analysis revealed that the enzyme was present both in dividing and non-dividing forms of T. cruzi. In epimastigote cells neither cell growth kinetics nor cell morphology was affected by the overexpression of the small parvulin TcPIN1. These results suggest the occurrence of a supplementary conserved level of post-translational control in trypanosomatids.
    Molecular and Biochemical Parasitology 07/2007; 153(2):186-93. · 2.73 Impact Factor

Publication Stats

494 Citations
136.37 Total Impact Points

Institutions

  • 2004–2014
    • Charité Universitätsmedizin Berlin
      • • Department of Gastroenterology, Infectiology and Rheumatology
      • • Institute of Health Sciences Education and Nursing Science
      Berlín, Berlin, Germany
  • 2012
    • Catholic University of Louvain
      Walloon Region, Belgium
  • 2006–2011
    • Max-Planck-Forschungsstelle für Enzymologie der Proteinfaltung
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 1997–2002
    • Freie Universität Berlin
      • Institute of Social and Cultural Anthropology
      Berlin, Land Berlin, Germany