A Roessner

Otto-von-Guericke-Universität Magdeburg, Magdeburg, Saxony-Anhalt, Germany

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Publications (565)1416.19 Total impact

  • Norbert Nass, Albert Roessner, Thomas Kalinski
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    ABSTRACT: Objective Interleukin (IL)-1 signalling plays an important role in inflammatory and also malignant processes. IL-1 signals essentially via nuclear factor (NF)-κB, which controls the expression of genes involved in cell proliferation, invasion, angiogenesis and metastasis, among them vascular endothelial growth factor A (VEGF-A). As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumours, such as chondrosarcomas, we investigated whether the anti-inflammatory compound curcumin is able to interfere with IL-1-induced VEGF-a secretion. Methods Cell cultures of chondrosarcoma cell lines C3842 and SW1353 were treated with IL-1ß and curcumin and VEGF-A secretion was analysed by Western blotting. Gene expression was determined by qRT-PCR. The angiogenenic potential of cell culture supernatants was investigated by a 2-dimensional angiogenesis assay using human umbilical chord endothelial cells (HUVECs). Activation of the nuclear factor NF-κB was analysed by determination of IκBα phosphorylation on Western blots and immunofluorescence. Results IL-1 signalling and VEGF-A expression are blocked by curcumin in chondrosarcoma cells. We further show that curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. Conclusions We propose that IL-1 blockade is an additionally treatment option in chondrosarcoma, either by curcumin, its derivatives or other IL-1 blocking agents.
    26th European Congress of Pathology, London, UK; 09/2014
  • Norbert Nass, Albert Roessner, Thomas Kalinski
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    ABSTRACT: Aims. The alpha-oxo-aldehydes glyoxal and methylglyoxal are byproducts of fatty acid oxidation and glycolysis. Due to the high glycolytic activity caused by the Warburg effect, cancer cells produce significantly more aldehydes than other cells. These substances are highly reactive and modify amino groups on proteins, often resulting in loss of function. These modifications also result in stable accumulating products, the so called advanced glycation end products (AGEs). In this study we analysed the responses of the estrogen receptor positive mamma carcinoma cell line MCF-7 to glyoxal and methylglyoxal to evaluate if dialdehyde defence might be a target for breast cancer treatment. Methods. Cell vitality was determined by the resazurin assay. Activation of MAP-kinases and NF-κB was determined by Western blotting, using specific antibodies against the phosphorylated proteins. Oxidative stress was measured by loading the cells with the oxidation-sensitive fluorochrome dihydrofluorescein-diacetate. Mode of cell death was analysed by caspase activity assay and annexin-V flow cytometry. Results. Dialdehydes resulted in cell death in low millimolar concentrations. Cells exposed to the aldehydes responded by a rapid activation of MAP-kinase signalling especially p38-MAPK and production of reactive oxygen species as well as activation of caspase 3/7 activity, finally leading to cell death. Interestingly, a tamoxifen resistant derivative of MCF-7 showed an additional activation of the NF-κB transcription factor by methylglyoxal only and was altogether more sensitive to the aldehydes. Addition of the antioxidant N-acetyl cystein protected the cells, demonstrating that oxidative stress was a major cause of cell death. Conclusions. These data demonstrate that exogenous aldehyde stress is cytotoxic to mamma carcinoma cells by causing severe oxidative stress. Inhibition of aldehyde defence enzymes such as glyoxalases might therefore be a promising therapeutic option against breast cancer.
    98. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V., Berlin, Germany; 06/2014
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    ABSTRACT: The aim of the current study was to investigate the role of BRCA1 promoter methylation as predictive factor of response to platinum-taxane-based therapy in sporadic ovarian cancer. BRCA1 promoter methylation was analyzed in 42 sporadic epithelial ovarian cancers. The results were validated in a second cohort of 137 ovarian cancer patients. BRCA1 promoter methylation was observed in 35.7 % of patients in the first group and in 33.6 % in the second group. BRCA1 promoter methylation was associated with significant increase in median progression-free survival (PFS) of ovarian cancer patients receiving adjuvant platinum-taxane-based chemotherapy (P = 0.008). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to PFS (HR 0.52; 95 % CI 0.32-0.85, P = 0.009) after adjustment for other prognostic factors. Under the patients with recurrent disease, BRCA1 promoter methylation was associated with significant longer median PFS of 18.5 months in comparison with 12.8 months PFS for patients without BRCA1 promoter methylation. BRCA1 promoter methylation is predictive for better response to platinum-taxane-based therapy in EOC.
    Journal of Cancer Research and Clinical Oncology 05/2014; · 2.91 Impact Factor
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    ABSTRACT: Recent studies have suggested that Helicobacter pylori (H. pylori) constitutes a risk for the development of colonic neoplasia. Hypergastrinemia can be induced by H. pylori infection and gastrin can act as putative promoter of colorectal carcinogenesis. Aim of the study was to assess whether H. pylori infection and/or increased serum gastrin levels are associated with the occurrence of colonic neoplasms. For this, we reviewed prospectively collected data of 377 patients with a minimum age of 50 years that underwent colonoscopy. H. pylori and CagA status were determined by serology. Serum gastrin levels were measured in fasting state by commercially available assay. In H. pylori infected patients (n=138; 36.6%), the overall prevalence of colonic neoplasms was more frequent compared to H. pylori negative patients (n=239; 63.4%) (OR=2.73, 95% CI: 1.76-4.24). H. pylori infection occurred more frequently in patients with hyperplastic polyps (OR= 2.66, 95% CI: 1.23-5.74) and adenomas presenting with low grade intraepithelial neoplasia (IEN) (OR= 1.85, 95% CI: 1.14-2.99). Attributable risk for adenomas with high grade IEN and colorectal adenocarcinoma (n=14) was not assessed due to the low number of cases. The expression of CagA was also associated with an increased risk for colonic neoplasms (OR= 2.25, 95% CI: 1.29-3.94). Hypergastrinemia did not increase the risk for any colonic neoplasms and there was no difference in basal serum gastrin levels between H. pylori positive and negative patients. In conclusion, H. pylori infection, including CagA expression is associated with an increased risk for the development of colonic neoplasm. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; · 6.20 Impact Factor
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    ABSTRACT: Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE). In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and IκBα-phosphorylation. However, mRNA accumulation of the aldehyde- and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2) as well as fructosamine-3-kinase (FN3K) was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione) suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers.
    PLoS ONE 01/2014; 9(7):e101473. · 3.53 Impact Factor
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    ABSTRACT: The lysosomal cysteine carboxypeptidase cathepsin X (CTSX), localized predominantly in immune cells, has been associated with the development and progression of cancer. To determine its specific role in colorectal carcinoma (CRC), we analyzed CTSX expression in non-malignant mucosa and carcinoma of 177 patients as well as in 111 adenomas and related it with clinicopathological parameters. Further, the role of CTSX in the adhesion and invasion of the colon carcinoma cell lines HT-29 and HCT116 was investigated in an in vitro culture cell system with fibroblasts and monocytes, reflecting the situation at the tumor invasion front. Epithelial CTSX expression significantly increased from normal mucosa to adenoma and carcinoma, with highest expression levels in high grade intraepithelial neoplasia and in early tumor stages. Loss of CTSX occurred with tumor progression, and correlated with advanced local invasion, lymph node and distal metastasis, lymphatic vessel and vein invasion, tumor cell budding and poorer overall survival of patients with CRC. The subcellular distribution of CTSX changed from vesicular paranuclear expression in the tumor center to submembranous expression in cells of the invasion front. Peritumoral macrophages showed highest expression of CTSX. In vitro assays identified CTSX as relevant factor for cell-cell adhesion and tumor cell anchorage to fibroblasts and basal membrane components, whereas inhibition of CTSX caused increased invasiveness of colon carcinoma cells in mono- and co-culture. In conclusion, CTSX is involved in early tumorigenesis and in the stabilization of tumor cell formation in CRC. The results suggest that loss of CTSX may be needed for tumor cell detachment, local invasion and tumor progression. In addition, CTSX in tumor-associated macrophages indicates a role for CTSX in the anti-tumor immune response.
    Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
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    ABSTRACT: Interleukin (IL)-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF)-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK) to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents.
    PLoS ONE 01/2014; 9(6):e99296. · 3.53 Impact Factor
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    ABSTRACT: Cathepsin X (CTSX, also called cathepsin Z/P) is a cysteine protease that still plays an unknown role in human cancer. It has been shown to bind cell surface heparin sulphate proteoglycans and integrins, indicating possible functions of CTSX in cellular adhesion, phagocytosis, and immune response. Our previous studies have shown an association between Helicobacter pylori (H. pylori) infection, a strong up-regulation of CTSX, and development of gastric cancer. In this study, yeast two-hybrid analysis revealed that RPLP0, a ribosomal protein P0, interacts with the human CTSX protein in gastric cancer. The CTSX/RPLP0 interaction was confirmed by co-immunoprecipitation assays. In addition, co-localization studies in cancer cell line N87 and gastric cancer tissue samples were performed. Laserscan microscopy revealed a shuttling of RPLP0 (and CTSX) from cytoplasm to the nucleus after CTSX knockdown. Down-regulation of RPLP0 resulted in G1 arrest of gastric cancer cells, whereas knockdown of CTSX led to G1 arrest and apoptosis after 48 h. Knockdown of both proteins caused increased apoptosis. RPLP0 deficiency could suppress cell growth and cell cycle progression by down-regulating CDK2. It was further demonstrated that RPLP0 affected p21 expression, but did not change the expression of Cyclin E. Down-regulation of both proteins at least through CDK2 suggests an anti-apoptotic effect on gastric cancer cells and opens up new possibilities for apoptotic immune modulation and gastric cancer therapy.
    Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
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    ABSTRACT: The production of hydrogen peroxide (H2 O2 ) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2 O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c-Jun N-terminal Kinases (JNK) that induces p21(WAF1) . Moreover, caspases circumvented the G1/S and intra-S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2 O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2 O2 -exposed HCEC cells (C-cell cultures) was associated with (i) increased phospho-p46 JNK, (ii) decreased total JNK and phospho-p54 JNK and (iii) p21(WAF1) down-regulation. Altered JNK activation and p21(WAF1) down-regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2 O2 exposure. This may cause increased proliferation of C-cell cultures, a defining initiating feature in the inflammation-carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non-apoptotic function of caspases, causing checkpoint adaptation in C-cell cultures. Additionally, loss of cell-contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell-contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2 O2 -induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21(WAF1) , c-Fos, c-Jun/phospho-c-Jun, ATF2/phospho-ATF2, β-catenin/TCF4-signalling, c-Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression.
    Journal of Cellular and Molecular Medicine 10/2013; · 4.75 Impact Factor
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    ABSTRACT: The aim of the current study was to investigate the role of BRCA1 gene aberrations in sporadic triple-negative breast cancer (TNBC) and its impact on anthracycline-based therapy. BRCA1 promoter methylation was analyzed in 70 TNBC and compared with the clinical and pathologic characteristics. As a control group, we used 70 patients with non-TNBC. BRCA1 promoter methylation was observed in 65.2 % of patients and was similar in both groups. BRCA1 promoter methylation was associated with decreased intensity of BRCA1 protein expression (P = 0.002) and significant increase of median disease-free survival (DFS) of TNBC patients receiving adjuvant anthracycline-based chemotherapy (P = 0.001). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to DFS (HR 0.224; 95 % CI 0.092-0.546, P = 0.001) in TNBC after adjustment for other prognostic factors. In contrast, in non-TNBC, BRCA1 promoter methylation was not associated with any clinical and pathologic parameters. BRCA1 promoter methylation is a common mechanism of BRCA1 gene aberration in sporadic breast cancer and is predictive for better response to anthracycline-based therapies.
    Breast Cancer Research and Treatment 09/2013; · 4.47 Impact Factor
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    ABSTRACT: A 61-year-old woman presented with a 2-month-history of progressive deterioration, increasing exertional dyspnoea and pain in the right upper abdomen (past medical history: bronchial asthma and hypertension). The physical examination showed mild generalized weakness, tenderness in the right upper abdomen, and ascites.Laboratory studies did not reveal any hormonal abnormalities. A CT angiogram revealed a mass of the right adrenal gland with distinct invasion into the inferior vena cava, and tumour thrombosis that extended proximally into the right atrium. Distally, the tumour ended at the caudate lobe of the liver with an extensive peripherally engulfed thrombus from the inferior vena cava down to the common iliac -veins.An open right adrenalectomy with resection of the periadrenal tissue and exstirpation of the intracaval tumour thrombus (by cavotomy under digital occlusion of the blood flow from the vena cava into the right atrium - cardiac surgeon) was carried out with no significant postoperative complications. Subsequently, the patient underwent adjuvant mitotane therapy for 3 years. So far, no recurrence has occurred during a course of 7 years.Tumour induced thrombotic occlusion of the inferior vena cava and other veins is rare, especially with right atrium involvement. In the absence of other effective treatment options, the combination of radical resection and adjuvant mitotane therapy remains the only successful curative treatment for primary invasive pararenal gland carcinoma.
    Aktuelle Urologie 09/2013; 44(5):375-80. · 0.47 Impact Factor
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    ABSTRACT: Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress-based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21(WAF1) , but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21(WAF1) protein expression, suggesting p21(WAF1) transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2-binding sequence in the p21(WAF1) promoter. p-ATF2 was found to interact with p-c-Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21(WAF1) downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4-dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti-cancer therapies.
    Journal of Cellular and Molecular Medicine 06/2013; · 4.75 Impact Factor
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    ABSTRACT: Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H2 O2 ). A population of HCEC survived H2 O2 -induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21(WAF1) and γ-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of γ-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G1 -phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non-apoptotic function by promoting cells through G1 - and S-phase by overriding the G1 /S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G2 /M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via γ-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX. As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo.
    Journal of Cellular and Molecular Medicine 06/2013; · 4.75 Impact Factor
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    ABSTRACT: GPER-1 protein expression was immunohistochemically examined in 164 primary breast cancer specimens and their matched normal breast epithelium. GPER-1 down-regulation correlated significantly with increased histological grading (p = .015), lymph node metastases (p = .032), and negative estrogen receptor status (p = .018). The decrease of GPER-1 expression in breast cancer tissue, relative to normal tissue, was associated with poor overall survival (p = .043) and disease-free survival (p = .037) and remained a significant unfavorable factor in multivariate analysis for DFS (HR = 1.569; 95% CI, 1.024-2.797; p = .041) and OS (HR = 2.082; 95% CI, 1.248-4.773; p = .039). Thus aberrant GPER-1 expression seems to be an important factor in breast cancer progression.
    Cancer Investigation 06/2013; 31(5):309-315. · 2.24 Impact Factor
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    ABSTRACT: Both gastrointestinal stromal tumors (GIST) and liposarcoma originate from mesenchymal tissue. Their coincidence requires a specific expertise in the diagnostic and therapeutic management. An unusual exemplary case is described representing a 47-year old female patient with a gastric GIST and a monstrous retroperitoneal liposarcoma with infiltration of the left kidney. The gastric tumor lesion was removed with a tangential resection of the gastric wall; the retroperitoneal tumor lesion was resected including the left kidney. Both tumors were resected with no macroscopic tumor residual. The technically difficult surgical intervention did not show any postoperative complication, and the postoperative course was also uneventful. The complete tumor resection is the treatment of choice in mesenchymal tumors (aim: R0). Depending on histologic tumor classification, resection status and tumor sensitivity, a subsequent radiation and/or chemotherapy is necessary, which allowed to achieve a postoperative tumor-free survival of 6 years including a good quality of life.
    Polish Journal of Surgery 05/2013; 85(5):284-8.
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    ABSTRACT: History and admission findings: A 61-year-old woman presented with a 2-month-history of progressive deterioration, increasing exertional dyspnoea and pain in the right upper abdomen (past medical history: bronchial asthma and hypertension). The physical examination showed mild generalized weakness, tenderness in the right upper abdomen, and ascites.Investigations: Laboratory studies did not reveal any hormonal abnormalities. A CT angiogram revealed a mass of the right adrenal gland with distinct invasion into the inferior vena cava, and tumour thrombosis that extended proximally into the right atrium. Distally, the tumour ended at the caudate lobe of the liver with an extensive peripherally engulfed thrombus from the inferior vena cava down to the common iliac veins.Treatment and course: An open right adrenalectomy with resection of the periadrenal tissue and extirpation of the intracaval tumour thrombus (by cavotomy under digital occlusion of the blood flow from the vena cava into the right atrium) was carried out with no significant postoperative complications. Subsequently, the patient underwent adjuvant mitotane therapy for three years. So far, no recurrence has occurred during a course of 7 years.Conclusion: Tumour induced thrombotic occlusion of the inferior vena cava and other veins is rare, especially with right atrium involvement. In the absence of other effective treatment options, the combination of radical resection and adjuvant mitotane therapy remains the only successful curative treatment for primary invasive adrenal gland carcinoma.
    DMW - Deutsche Medizinische Wochenschrift 02/2013; 138(6):260-5. · 0.65 Impact Factor
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    ABSTRACT: Lymphocyte activation is crucial for the generation of immune responses. In vitro studies have demonstrated that TRAPs are critical regulators of lymphocyte activation. However, more recent in vivo studies have demonstrated that with the exception of LAT, TRAPs, such as SIT, NTAL, and LAX, only minimally affect immune cell functions. Additional studies have suggested that the mild or the apparent lack of a phenotype displayed by most TRAP KO mice may be explained by functional redundancy among this family of adaptors. In fact, it has been shown that the phenotype of NTAL/LAT or SIT/TRIM double-deficient mice is more severe than that of the single KOs. Here, we have evaluated whether SIT and the related transmembrane adaptor LAX have overlapping functions by generating SIT/LAX DKO mice. We show that DKO, in contrast to single KO mice, accumulate large numbers of activated CD4(+) T cells in the spleen. Moreover, conventional B cells from DKO mice are hyperproliferative upon CD40 stimulation. Additionally, we found that DKO mice displayed an expansion of the B1 cell pool in the peritoneal cavity, hypergammaglobulinaemia, and an enhanced immune response to the T1-independent antigen, TNP-LPS. Finally, we demonstrate that SIT/LAX double deficiency resulted in a more pronounced breakdown of peripheral tolerance and the development of autoimmunity characterized by ANAs and renal disease (glomerulonephritis and proteinuria). Collectively, our data indicate that SIT and LAX are important negative regulators of immune responses that functionally cooperate.
    Journal of leukocyte biology 01/2013; · 4.99 Impact Factor
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    ABSTRACT: Helicobacter pylori are responsible for the induction of chronic gastric inflammation progressing to atrophy, metaplasia, and gastric cancer. The overexpression of Cathepsin X/Z (Ctsz) in H. pylori-infected mucosa and gastric cancer is mediated predominantly by an augmented migration of ctsz(-/-)positive macrophages and the up-regulation of Ctsz in tumor epithelium. To explore the Ctsz-function in the context of chronic inflammation and the development of preneoplastic lesions, we used Ctsz-deficient mice in a H. pylori gastritis model. Ctsz (-/-) and wild-type (wt) mice were infected with H. pylori strain SS1. The mice were sacrificed at 24, 36, and 50 weeks post infection (wpi). The stomach was removed, and gastric strips were snap-frozen or embedded and stained with H&E. Tissue sections were scored for epithelial lesions and inflammation. Ki-67 and F4/80 immunostaining were used to measure epithelial cell proliferation and macrophage infiltration, respectively. The upregulation of compensating cathepsins and cytokines were confirmed by Western blotting and quantitative RT-PCR. SS1-infected wt and ctsz (-/-) mice showed strong inflammation, foveolar hyperplasia, atrophy, and cystically-dilated glands. However, at 50 wpi, ctsz (-/-) mice developed significantly more severe spasmolytic polypeptide-expressing metaplasia (SPEM), showed enhanced epithelial proliferation, and higher levels of infiltrating macrophages. Induction of cytokines was higher and significantly prolonged in ctsz (-/-) mice compared to wt. Ctsz deficiency supports H. pylori-dependent development of chronic gastritis up to metaplasia, indicating a protective, but not proteolytic, function of Ctsz in inflammatory gastric disease.
    PLoS ONE 01/2013; 8(7):e70242. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function that is regulated by cell-cell contacts. The aim of the study was to investigate the expression pattern of selected components involved in the formation of tight junctions in relation to GERD. METHODS: Eighty-four patients with GERD-related symptoms with endoscopic signs (erosive: n = 47) or without them (non-erosive: n = 37) as well as 26 patients lacking GERD-specific symptoms as controls were included. Endoscopic and histological characterization of esophagitis was performed according to the Los Angeles and adapted Ismeil-Beigi criteria, respectively. Mucosal biopsies from distal esophagus were taken for analysis by histopathology, immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (RT-PCR) of five genes encoding tight junction components [Occludin, Claudin-1, -2, Zona occludens (ZO-1, -2)]. RESULTS: Histopathology confirmed GERD-specific alterations as dilated intercellular spaces in the esophageal mucosa of patients with GERD compared to controls (P < 0.05). Claudin-1 and -2 were 2- to 6-fold upregulation on transcript (P < 0.01) and in part on protein level (P < 0.015) in GERD, while subgroup analysis of revealed this upregulation for ERD only. In both erosive and non-erosive reflux disease, expression levels of Occludin and ZO-1,-2 were not significantly affected. Notably, the induced expression of both claudins did not correlate with histopathological parameters (basal cell hyperplasia, dilated intercellular spaces) in patients with GERD. CONCLUSIONS: Taken together, the missing correlation between the expression of tight junction-related components and histomorphological GERD-specific alterations does not support a major role of the five proteins studied in the pathogenesis of GERD.
    BMC Gastroenterology 09/2012; 12(1):128. · 2.11 Impact Factor

Publication Stats

6k Citations
1,416.19 Total Impact Points

Institutions

  • 1993–2014
    • Otto-von-Guericke-Universität Magdeburg
      • • Institute for Pathology
      • • Clinic for Gastroenterology, Hepatology and Infectiology
      • • Institute for Molecular Biology and Medical Chemistry
      Magdeburg, Saxony-Anhalt, Germany
    • Kanazawa University
      • Department of Orthopaedic Surgery
      Kanazawa-shi, Ishikawa-ken, Japan
  • 2011
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
    • St. Mark's Hospital
      Harrow, England, United Kingdom
  • 2002–2010
    • University Hospital Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 2007–2008
    • Klinikum Nürnberg
      Nuremberg, Bavaria, Germany
  • 2004–2008
    • American University of Beirut
      • Department of Biology
      Beirut, Mohafazat Beyrouth, Lebanon
    • Heinrich-Heine-Universität Düsseldorf
      • Institut für Neuropathologie
      Düsseldorf, North Rhine-Westphalia, Germany
    • Medical University of Gdansk
      Danzig, Pomeranian Voivodeship, Poland
  • 2006
    • Semmelweis University
      • Faculty of Medicine
      Budapest, Budapest fovaros, Hungary
  • 2001–2005
    • Medical University of Lublin
      • Department of Gynecology
      Lublin, Lublin Voivodeship, Poland
  • 2003–2004
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 1971–1994
    • University of Münster
      • • Gerhard-Domagk-Institute of Pathology
      • • Institute of Applied Physics
      Münster, North Rhine-Westphalia, Germany
    • University of Bonn
      • Medizinische Klinik und Poliklinik I
      Bonn, North Rhine-Westphalia, Germany
    • Fachhochschule Münster
      Muenster, North Rhine-Westphalia, Germany
  • 1992
    • Kyoto University
      Kioto, Kyōto, Japan
  • 1975
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 1972
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany