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Kirstin Reinecke,
Sevgi Eminel,
Franziska Dierck,
Wibke Roessner,
Sabine Kersting, Ansgar Michael Chromik,
Olga Gavrilova,
Ale Laukevicience,
Ivo Leuschner,
Vicki Waetzig,
Philip Rosenstiel,
Thomas Herdegen,
Christian Sina
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ABSTRACT: The c-Jun N-terminal kinase (JNK)-inhibiting peptide D-JNKI-1, syn. XG-102 was tested for its therapeutic potential in acute inflammatory bowel disease (IBD) in mice. Rectal instillation of the chemical irritant trinitrobenzene sulfonic acid (TNBS) provoked a dramatic acute inflammation in the colon of 7-9 weeks old mice. Coincident subcutaneous application of 100 µg/kg XG-102 significantly reduced the loss of body weight, rectal bleeding and diarrhoea. After 72 h, the end of the study, the colon was removed and immuno-histochemically analysed. XG-102 significantly reduced (i) pathological changes such as ulceration or crypt deformation, (ii) immune cell pathology such as infiltration and presence of CD3- and CD68-positive cells, (iii) the production of tumor necrosis factor (TNF)-α in colon tissue cultures from TNBS-treated mice, (iv) expression of Bim, Bax, FasL, p53, and activation of caspase 3, (v) complexation of JNK2 and Bim, and (vi) expression and activation of the JNK substrate and transcription factor c-Jun. A single application of subcutaneous XG-102 was at least as effective or even better depending on the outcome parameter as the daily oral application of sulfasalazine used for treatment of IBD.The successful and substantial reduction of the severe, TNBS-evoked intestinal damages and clinical symptoms render the JNK-inhibiting peptide XG-102 a powerful therapeutic principle of IBD.
PLoS ONE 01/2012; 7(3):e30985. · 4.09 Impact Factor
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ABSTRACT: Redo procedures of the pancreas are complex operations associated with significant morbidity and mortality rates. The operative risk may be minimised when indications for redo procedure are well reflected and operation is performed by an experienced surgeon. The aim of this study was to confirm this hypothesis evaluating our experiences with redo procedures.
We reviewed 28 patients (mean age of 54 years; range 11-75 years) undergoing a redo procedure of the pancreas from January 2004 to June 2008 at our hospital. The term redo procedure was defined as a pancreatic reoperation that was carried out after preceding pancreatic surgery. Relaparotomies following acute complications after pancreatic surgery were not taken into consideration.
The following parameters were evaluated: median operative time 332 min (range 160-730 min), median intraoperative blood loss 625 ml (range 300-2,800 ml), median postoperative stay on Intensive Care Unit 20 h (range 0-112 h), median postoperative hospital stay 15 days (range 7-98), morbidity (14%), and mortality (3.6%).
Redo procedures of the pancreas can be performed with low complication rates. In order to achieve a satisfactory outcome, the indication of redo procedures has to be well reflected, and operation may be performed by specialised and experienced surgeons.
Journal of Gastrointestinal Surgery 11/2010; 15(1):191-8. · 2.83 Impact Factor
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ABSTRACT: New chemopreventive strategies for ulcerative colitis (UC)-associated dysplasia and cancer have to be evaluated. Taurolidine (TRD) has anti-inflammatory, anti-proliferative and anti-neoplastic properties with almost absent toxicity. The aim of the study was to determine whether TRD decreases dysplasia in the well-characterized Dextran Sulfate Sodium - Azoxymethane (DSS-AOM) animal model for UC-associated carcinogenesis.
The DSS-AOM model of carcinogenesis was induced in female inbred C57BL/6 mice. Half of the mice were treated with TRD, the other served as control. After 100 days macroscopic, histological and immunhistochemical (beta-Catenin, E-Cadherin, SOX9, Ki-67, Cyclin-D1) examination of the colon was performed.
Incidence, multiplicity, grading and growth pattern of adenomas did not differ significantly between TRD and control group. In all animals, inflammatory changes were absent. Immunhistochemistry revealed increased expression of Ki-67, beta-catenin, SOX9 and Cyclin-D1 in adenomas compared to normal mucosa - without significant difference between TRD and control treatment.
Oral administration of TRD has no impact on DSS-induced colitis-associated carcinogenesis. However, SOX9 and Cyclin-D1 representing key members of the Wnt pathway have not yet been described in the DSS-AOM model of carcinogenesis - underlining the importance of this oncogenic pathway in this setting.
Journal of Carcinogenesis 01/2010; 9:5.
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Langenbeck s Archives of Surgery 06/2009; 394(3):589. · 1.81 Impact Factor
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Adrien Daigeler,
Daigeler Adrien,
Ludger Klein-Hitpass,
Klein-Hitpass Ludger,
Ingo Stricker,
Stricker Ingo,
Oliver Müller,
Müller Oliver,
Cornelius Kuhnen,
Kuhnen Cornelius, Ansgar Michael Chromik,
Chromik Ansgar Michael,
Lars Steinstraesser,
Steinstraesser Lars,
Ole Goertz,
Goertz Ole,
Hans-Ulrich Steinau,
Steinau Hans-Ulrich,
Marcus Lehnhardt,
Lehnhardt Marcus
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ABSTRACT: The new classification of malignant fibrous histiocytoma leaves only a small group of tumors without further line of differentiation, so-called pleomorphic sarcomas, not otherwise specified (NOS) as a pseudo-entity. This study focused on these tumors and analyzed the association of gene expression profiles to clinical outcome.
Ten fresh samples of pleomorphic NOS sarcomas were evaluated histopathologically and by means of microarray analysis. Analysis of expression profiles was performed by clustering methods as well as by statistical analysis of primary vs recurrent tumors, irradiated vs nonirradiated tumors, tumors of patients above and below 60 years of age, male and female, and of tumors that developed metastatic or recurrent disease during the clinical course and those that did not.
Tumor clustering did not correlate to any histopathological or clinical finding. Detailed gene expression analysis showed a variety of genes whose upregulation (platelet-derived growth factor receptor alpha polypeptide, solute carrier family 39 member 14, solute carrier family 2 member 3, pleiotrophin, trophinin, pleckstrin and Sec7 domain containing 3, enolase 2, biglycan, SH3 and cysteine-rich domain, matrix metalloproteinases 16) and whose downregulation (tissue inhibitor of metalloproteinase 4, hairy/enhancer of split related with YRPW motif 2, protein tyrosine phosphatase receptor-type Z polypeptide 1, SH3 domain GRB2-like 2, microtubule-associated protein 7, potassium voltage-gated channel shaker-related subfamily member 1, RUN and FYVE domain containing 3, Sin3A-associated protein 18 kDa, proline-rich 4, calcium/calmodulin-dependent protein kinase ID, myeloid/lymphoid or mixed-lineage leukemia translocated to 3, insulin-like growth factor binding protein 5, nucleoside diphosphate-linked moiety X-type motif 9, NudC domain containing 3, imprinted in Prader-Willi syndrome, TAF6-like RNA polymerase II p300/CBP-associated factor 65 kDa, WD repeat and SOCS box-containing 2, adenosine diphosphate ribosylation factor 3, KRR1, proliferation-associated 2G4; CD36, complement component (3b/4b) receptor 1, solute carrier family 4 sodium bicarbonate cotransporter member 4, lipoprotein lipase (LPL), GATA binding protein 3, LPL, glutathione peroxidase 3, D: -aspartate oxidase, apolipoprotein E, sphingomyelin phosphodiesterase acid-like 3A) were associated with poor clinical outcome in terms of development of metastatic or recurrent disease.
The classification of these tumors may undergo further changes in the future. Gene expression profiling can provide additional information to categorize pleomorphic sarcoma (NOS) and reveal potential prognostic factors in this "entity."
Langenbeck s Archives of Surgery 02/2009; 395(3):261-75. · 1.81 Impact Factor
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ABSTRACT: The treatment of choice for esophageal cancer is considered surgical resection, but a median survival of around 20 months after treatment is still discouraging. The value of adjuvant or neoadjuvant radiation or chemotherapy is limited and to date, benefits have only been described for certain tumor stages. Therefore, new therapeutic options are required. As alternative chemotherapeutics, we tested the antibiotic taurolidine (TRD) on KYSE 270 human esophageal carcinoma cells alone and in combination with rhTRAIL (TNF related apoptosis-inducing ligand). Viability, apoptosis and necrosis were visualized by TUNEL assay and quantitated by FACS analysis. Gene expression was analysed by RNA microarray. The most effective concentration of TRD as single substance (250 micromol/l) induced apoptosis to a maximum of 40% after 12-h dose dependently, leaving 4% viable cells after 48 h; by comparison, rhTRAIL did not have a significant effect. The combination of both substances doubled the effect of TRD alone. Gene expression profiling revealed that TRD downregulated endogenous TRAIL, TNFRSF1A, TRADD, TNFRSF1B, TNFRSF21, FADD, as well as MAP2K4, JAK2 and Bcl2, Bcl2l1, APAF1 and caspase-3. TNFRSF25, cytochrome-c, caspase-1, -8, -9, JUN, GADD45A and NFKBIA were upregulated. TRAIL reduced endogenous TRAIL, Bcl2l1 and caspase-1 expression. BIRC2, BIRC3, TNFAIP3, and NFKBIA were upregulated. The combined substances upregulated endogenous TRAIL, NFKBIA and JUN, whereas DFFA and TRAF3 were downregulated compared to TRD as single substance. We conclude that TRD overcomes TRAIL resistance in KYSE 270 cells. Synergistic effects are dependent on the same and on distinct apoptotic pathways which, jointly triggered, result in an amplified response. Several apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway, were differentially regulated by the substances on gene expression level. Additionally transcription factors seem to be influenced, NFKB in particular. Endogenous TRAIL expression is increased by the combination of substances, whereas it is reduced by each single substance. Taking into consideration that the non-toxic TRD was able to reduce rhTRAIL toxicity and dose, combined therapy with TRD and rhTRAIL may offer new options for treatment in esophageal cancer.
International Journal of Oncology 07/2008; 32(6):1205-20. · 2.40 Impact Factor
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ABSTRACT: Procalcitonin (PCT) is regarded as a specific indicator of bacterial infection. Infectious complications in patients after colorectal surgery are a common cause of morbidity and mortality. The aim of this study was to investigate (a) whether PCT could serve as a negative predictive marker for postoperative complications and (b) whether, in patients with elevated PCT levels, a pre-emptive treatment with the third-generation cephalosporin ceftriaxone is superior to an antibiotic treatment starting later on the appearance of clinical signs and symptoms of infection.
By screening 250 patients with colorectal surgery, we identified 20 patients with PCT serum levels more than 1.5 ng/ml on at least 2 of the first 3 postoperative days. The remaining 230 patients were followed-up for the occurrence of infectious complications. The 20 patients with elevated PCT were included in a prospective randomised pilot study comparing pre-emptive antibiotic treatment with ceftriaxone vs standard treatment.
The negative predictive value of PCT for systemic infectious complications was 98.3%. In patients receiving pre-emptive antibiotic treatment (ceftriaxone), both the incidence and the severity of postoperative systemic infections were significantly lower compared to those in a control group (Pearson's chi(2) test; p=0.001 and p=0.007, respectively). Major differences were also observed with respect to duration of antibiotic treatment and length of hospital stay.
PCT is an early marker for systemic infectious complications after colorectal surgery with a high negative predictive value. A significant reduction in the rate of postoperative infections in patients with elevated PCT serum concentrations was achieved by means of pre-emptive antibiotic treatment.
Langenbeck s Archives of Surgery 07/2006; 391(3):187-94. · 1.81 Impact Factor
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ABSTRACT: Taurolidine (TRD) has antimicrobial and anti-inflammatory properties. However, the anti-inflammatory effects of TRD in inflammatory bowel diseases (IBD) have not been investigated. Here, we have analyzed the toxicity of TRD after oral long-term application in mice and examined the impact of oral TRD in a dextran sulfate sodium (DSS) model of experimental colitis. Female C57/BL6 mice received TRD in various concentrations (0.1% to 0.4%) for 60 days. Toxicity was evaluated by use of a disease activity index (DAI) and histological examination of major metabolic organs. Furthermore, the impact of 0.2% TRD on a chronic DSS colitis was examined by daily DAI, histological crypt damage score (CDS), bacterial translocation into mesenteric lymph nodes (MLN), and colonic expression of tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, interleukin (IL)-1beta, IL-6, cytochrome oxidase (COX)-2, and monocyte chemotactic protein (MCP)-1 by real-time polymerase chain reaction (PCR). Oral TRD administration for 60 days was well tolerated by the animals and did not show any toxic effects in terms of DAI and histological changes. TRD treatment of DSS colitis led to increased survival of 100%, compared to 33% in the untreated colitis group (p < or = .005). Clinical amelioration was mirrored by significantly reduced DAI and CDS in the TRD treated colitis. Colonic cytokine expression and bacterial translocation into MLN showed no differences between both groups. We thus report for the first time that oral application of TRD results in amelioration of an experimental IBD model. We hypothesize direct intraluminal antimicrobial effects of TRD as well as anti-inflammatory effects during the acute phase of DSS colitis.
Journal of Investigative Surgery 20(5):273-82. · 1.09 Impact Factor
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BMC Cancer, v.8, 1-17 (2008).
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Ansgar Michael. Chromik
