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Zuern C.,University of Wurzburg | Zuern C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Krenacs L.,Laboratory of Tumor Pathology and Molecular Diagnostics | Starke S.,University of Wurzburg | And 8 more authors.
International Journal of Oncology | Year: 2012

The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis.

Balla B.,Semmelweis University | Tobias B.,Semmelweis University | Kosa J.P.,Semmelweis University | Podani J.,Eotvos Lorand University | And 16 more authors.
Journal of Endocrinological Investigation | Year: 2015

Objective: The aims of the present study were to examine gene and protein expression of the vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzyme in human papillary thyroid cancer (PTC), furthermore, to investigate the association between CYP24A1 expression and numerous clinical, histological parameters and somatic oncogene mutation status of thyroid tumor tissues. Materials and methods: Gene expression analysis was carried out in 100 Hungarian thyroid samples, both normal and papillary tumor tissue sections of the same patient. The specific mRNA to the selected genes was analyzed by TaqMan probe-based quantitative real-time RT-PCR. The somatic oncogene mutation states of BRAF, NRAS, HRAS and KRAS were also tested. Results: CYP24A1 mRNA expression was markedly increased in 52 cases (52 %) of the examined papillary cancers compared with that of normal thyroid tissue. There was a tendency toward difference in the distribution of high-level CYP24A1 in the PTC accompanied with somatic oncogene mutation. Positive correlation was seen between increased CYP24A1 expression rate and a group of variables reflecting tumor malignity (mainly vascular invasion, lymph node metastasis, tumor size, hypothyreosis) by principal components analysis. No significant alteration was seen in CYP27B1 gene expression between neoplastic and normal tissues. Conclusions: A definite alteration was seen in vitamin D3-inactivating CYP24A1 gene activity in PTC compared to their normal tissues on a relatively large patient population. Our findings raise the possibility that CYP24A1 may also directly be involved in thyroid carcinogenesis. © 2014 Italian Society of Endocrinology (SIE).

Mehes G.,Debrecen University | Tzankov A.,University of Basel | Hebeda K.,Radboud University Nijmegen | Anagnostopoulos I.,Charite - Medical University of Berlin | And 2 more authors.
Histopathology | Year: 2015

Aims: Myelofibrosis is the result of aberrant stromal activity which is determined routinely by reticulin staining in bone marrow biopsies. As matrix fibres are the product of activated fibroblasts, we analysed fibre accumulation compared to stromal cell activity during myelofibrosis progression using the fibroblast activation marker platelet-derived growth factor receptor β (PDGFRβ) by immunohistochemistry. Methods and results: Initial and follow-up bone marrow biopsies from 84 patients with myeloproliferative neoplasia, including 55 cases with primary myelofibrosis, were evaluated from five haematopathology centres. The stromal mass was measured by conventional reticulin staining [myelofibrosis (MF) grade, 0-3] and PDGFRβ-positive cells using a novel PDGFRβ scoring system (0-3). Results were correlated for prediction of progression. The MF grade and the PDGFRβ score showed excellent correlation (Spearman's r = 0.83, P < 0.0001). Elevated PDGFRβ scores (higher than MF-grade) predicted myelofibrosis progression in total with 43% sensitivity and 57% specificity, and short-term (within 1 year) progression with 82% sensitivity and 53% specificity. Progression of prefibrotic disease to manifest myelofibrosis could be forecast with 90% sensitivity and 75% specificity. Conclusion: PDGFRβ highlights stromal cell activation in marrow fibrosis, which is closely related to matrix accumulation, indicating a direct clinical impact especially in prefibrotic myeloproliferative disorders. © 2015 John Wiley & Sons Ltd.

Kovacs-Solyom F.,Hungarian Academy of Sciences | Blasko A.,Hungarian Academy of Sciences | Fajka-Boja R.,Hungarian Academy of Sciences | Katona R.L.,Hungarian Academy of Sciences | And 8 more authors.
Immunology Letters | Year: 2010

Galectin-1 (Gal-1) has been implicated in tumor progression partly via the induction of T-cell apoptosis. However the mechanism of Gal-1 induced T-cell death was mostly studied using recombinant, soluble Gal-1 producing controversial results. To explore the true mechanism of Gal-1 and hence tumor cell-induced T-cell death, we applied co-cultures of tumor cells and T-cells thus avoiding artificial circumstances generated using recombinant protein. T-cells died when co-cultured with Gal-1-expressing but survived with Gal-1 non-expressing tumor cells. Removing tumor cell surface Gal-1 or knocking down Gal-1 expression resulted in diminution of T-cell apoptosis. Gal-1 transgenic or soluble Gal-1 treated HeLa cells became cytotoxic. Stimulation of apoptosis required interaction between the tumor and T-cells, presence of p56lck and ZAP70, decrease of mitochondrial membrane potential and caspase activation. Hence tumor cell-derived Gal-1 might efficiently contribute to tumor self-defense. Moreover this system resolves the discrepancies obtained using recombinant Gal-1 in T-cell apoptosis studies. © 2009 Elsevier B.V. All rights reserved.

Krenacs L.,Laboratory of Tumor Pathology and Molecular Diagnostics | Toth-Liptak J.,Laboratory of Tumor Pathology and Molecular Diagnostics | Demeter J.,Semmelweis University | Piukovics K.,University of Szeged | And 4 more authors.
Virchows Archiv | Year: 2013

The Hector Battifora mesothelial epitope-1 (HBME-1) monoclonal antibody has been generated against human mesothelioma cells and recognizes a biochemically unknown membrane epitope. We have accidentally found that the HBME-1 reacts with scattered lymphocytes showing villous surface in hyperplastic lymphoid tissue. To evaluate its reactivity pattern, we have performed a consecutive immunohistochemical study in nonneoplastic bone marrow and lymphoid samples (n = 40), as well as in malignant lymphoproliferations (n = 427), including hairy cell leukemia (HCL) (n = 72), HCL variant (HCL-v) (n = 13), splenic diffuse red pulp small B cell lymphoma (SDRPL) (n = 8), splenic B cell marginal zone lymphoma (SMZL) (n = 59), and splenic B cell lymphoma/leukemia, not further classifiable on bone marrow morphology (SBCL) (n = 37) cases. The staining pattern of HBME-1 was compared to DBA.44. HBME-1+ villous lymphocytes were constantly detected in low number in nonneoplastic lymphoid tissues. With multicolor immunofluorescence staining, HBME-1+ lymphocytes showed a CD20+/CD79a+/IgM+ B cell phenotype. In B cell lymphoproliferations of villous lymphocytes, HBME-1 reactivity was demonstrated in 96 % of HCL, 39 % of HCL-v, 50 % of SDRPL, 12 % of SMZL, and 19 % of SBCL cases. Nodal and extranodal marginal zone lymphoma cases were positive in 12 % of the cases. A small minority (4 %) of the other B cell lymphomas and no T cell lymphoma revealed tumor cell reactivity with HBME-1. In conclusion, our study has established that HBME-1 reacts with a minor subset of B lymphocytes and a small proportion of B cell lymphomas, which has not been described previously. We suggest that HBME-1 can be a useful marker in the diagnosis of HCL and other indolent lymphoproliferations of villous B lymphocytes. © 2013 Springer-Verlag Berlin Heidelberg.

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