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Abstract: Background: Hereditary renal cell carcinoma (RCC) constitutes about 5% of all RCCs. The most common and well studied syndromes include, VHL, HLRCC, BHD, Familial Oncocytoma, RCC Papillary Type 1, TSC, RCC associated with Succinate dehydrogenase B (SHDB) mutations and others. Several genes, including VHL, MET, FLCN, FH and genes encoding the succinate dehydrogenase (SDH) subunits B/C/D have been identified as causative. However, the genetic basis of a significant percentage of familial RCC, some with clear cell morphology remain unknown. BAP1 (BRCA1 associated protein-1), a tumor suppressor gene that encodes a nuclear deubiquitinase, is inactivated in 15% of sporadic clear cell RCCs and its loss was associated with high tumor grade and poor prognosis. In this study, we investigated the possible role of this gene in the spectrum of RCC part of hereditary syndromes. Materials and Methods: To elucidate the role of BAP1 in all the spectrum of hereditary RCC, we studied by IHC a panel of RCCs which covers the spectrum of kidney cancers and included 10 VHL tumors, 6 HLRCCs, 8 chromophobe, 5 Hereditary Papillary Type 1, 6 Oncocytomas, 3 BHD (hybrid), and 24 sporadic clear cell RCCs. To analyze the BAP1 expression in these tumors, formalin fixed paraffin embedded (FFPE) tissues were immunostained with mouse monoclonal anti-human BAP1 antibody (Clone C-4, Santa Cruz). Results: We found that all the tumors except two showed positive nuclear staining for BAP1. The two negative cases that were negative for BAP1 were Clear cell type and belonged to two siblings. Molecular analysis in a prepublished study showed both patients harboring the p.L14H mutation. Conclusion: Our study supports the hypothesis that BAP1 mutations can play a role in hereditary syndromes predominantly in clear cell tumors. Staining for BAP1 should be done when there is no definite known mutation in a clear cell cancer but the patient gives history of familial kidney cancer. The two related patients who had similar mutations had aggressive, metastatic disease, which suggests that probably BAP1 does play a role in hereditary RCC clear cell type. Keywords: Hereditary kidney cancer, BAP1, mutation, immunohistochemistry.Download Full Article |
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Abstract: Aim: To study the effect of long-term impact of mouse interferon-beta (IFN-b) on the behavior of mouse melanoma cells in vitro and in vivo and the expression of epithelial-mesenchymal transition (EMT) associated proteins. Materials and Methods: Studies were performed on mouse B16 melanoma cells as a tumor model (MM-4 cell line). Immunocytochemical and tumor cell biology approaches have been used in this study. Results: Long-time treatmentof MM-4 melanoma cellswith low-dose IFN-b (1/2 of IC50) leads to change their morphology, significant inhibition of cell growth and plating efficiency, suppression of cell migration and anchorage-independent growth in semisolid agar. Moreover, IFN-modification of melanoma cells is accompanied by the significant suppression of their malignancy in vivo: growth of tumor induced by IFN-treated cells has inhibited on 50% and growth of metastases - on 90%. Also, IFN-modification of MM-4 cells affects on the expression of proteins involved in cell cycle regulation and inhibits expression of some molecules of adhesion (N-, VE-cadherins), but not influence on the expression of EMT-associated Twist and Slug proteins and E-cadherin. Conclusions: Long-term impact of mouse IFN-beta in low dose on melanoma cells in vitro changes their phenotype and inhibits their proliferative potential, signs of malignancy in vitro, tumorigenicity and metastatic ability in vivo. Loss of malignancy is associated with inhibition of N- and VE-cadherins expression, but not associated with the change of expression and subcellular localization of E-cadherin and EMT transcription factors Twist and Slug. Keywords: Cadherins, anchorage-independent growth, changes of phenotype, tumorigenicity,metastasis.Download Full Article |
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Abstract: Tumor microenvironment, known to exert regulatory functions on tumor cells, plays an important role when a human tumor is xenografted into immunodeficient mice. Primary human tumors xenografts represent a promising strategy to study new therapeutic’s efficacy or to understand the mechanisms implicated in tumor relapse. The development of xenografts is linked not only to the aggressivity of the tumor cells, but also to the tumor microenvironment. Tumor xenograft cell proliferation is dependent on microenvironment modifications such as angiogenesis and human blood vessel replacement, host immune cells and the presence of growth factors. The characterisation and a better knowledge of these factors allow for a more appropriate use of xenograft animal models in the evaluation of new antitumor treatments. In this review, we describe the different factors linked to the tumor microenvironment and their impact on the take rate when human tumors are xenografted into immunodeficient mice. Keywords: Xenograft, tumor microenvironment, human tumor, immunodeficient mice, murine stroma, human stroma.Download Full Article |
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Abstract: We previously showed that in low- as well as in high-grade astrocytomas IL-8 overexpression is triggered by prostaglandin E2 (PGE2) through the upregulation of the transcription factors CCAAT/enhancer-binding protein-β (C/EBP-β) and C/EBP homologous protein (CHOP). Here we investigated the signal transduction pathways and the molecular mechanisms underlying the PGE2-dependent IL-8 gene expression in astrocytomas. Low- and high-grade PGE2-treated astrocytoma cells were transfected with wild-type and mutated IL-8 promoter constructs in the presence of various signal transduction pathway inhibitors, and cotransfected with transcription factor overexpressing plasmids or small-interfering RNAs. p38MAPK, C/EBP-β, and CHOP phosphorylation was analyzed by Western blotting. Electrophoretic mobility shift assay and chromatin immunoprecipitation evaluated the in vitro and in vivo binding of CHOP and C/EBP-β to IL-8 promoter. The results obtained allowed us to find out the signaling pathways triggered by PGE2 and responsible for the activation of the transcription factors involved in the overproduction of IL-8 by astrocytoma. Therefore, it can be argued that the inhibition of the PGE2 downstream pathways may represent a novel therapeutic approach for the treatment of patients with astrocytoma. Keywords: Astrocytoma, IL-8, PGE2, p38MAPK.Download Full Article |
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Abstract: Mixed medullary papillary carcinoma (MMPC) is a rare variant of papillary thyroid carcinoma, according to the WHO classification and it presents as a single lesion histologically composed of two distinct and intermingled neoplastic cell patterns. The histogenesis is still debatable. The lymph node metastases are usually present at the time of the diagnosis and distal metastases may appear late during follow-up. At least 13 similar lesions have been reported in the literature. We describe the case of a 61-year-old woman with a mixed medullary papillary carcinoma found in a hyperfunctioning thyroid nodule and negative pre-surgical serum calcitonin. After surgery, the patient started suppressive L-thyroxine therapy and underwent radioiodine ablation. The follow-up for both papillary and medullary components has shown no signs of persistence or recurrence of disease five years after surgery. However, the rarity of the MMPCs makes the management and the prognosis of these tumors still unclear. Keywords: Mixed medullary papillary carcinoma, calcitonin, hyperfunctioning thyroid nodule, thyroid ultrasound, fine needle aspiration, thyroidectomy.Download Full Article |