(7). This is reflected by the decrease or disappearance of BL-associated CD10 and CD77 markers and the appearance of activation markers. EBNAs 2-6 and LMPs 1, 2a, and 2b are upregulated as well. Nasopharyngeal carcinoma (NPC) represents yet a third type of EBV-host cell interaction. EBNA 1 is always expressed but EBNAs 2-6 are not. LMP 1 is detected in some 65% of NPCs (9).We have found (10, 11) that somatic cell hybrids derived from the fusion of EBV-carrying group III BL lines or LCLs with non-B-cell lines downregulate EBNAs 2-6, LMP 1, and B-cell-specific markers. This suggested that the regulation of EBNA 1, on the one hand, and EBNAs 2-6, on the other hand, can be dissociated from each other. EBNA 1 shows a dominant constitutive expression, and EBNAs 2-6, LMPs, and B-blast-specific markers are expressed in a cellphenotype-dependent fashion. The purpose of the present study was to examine whether the EBNA 2-6 expression depends on selective promoter activity. Our S1 nuclease analysis has shown that group I BL cells, NPC biopsies, and somatic cell hybrids that express only EBNA 1 utilize neither the BCR2 nor the BWR1 promoter. As our earlier findings (9,12,13) suggested that viral DNA methylation may play a role in the regulation, we investigated whether promoter activity correlated with the methylation status.
MATERIALS AND METHODSCells. The origin and EBV gene expression of all the cell lines is summarized in Table 1 The biopsies were stored frozen at -70'C until used for RNA isolation. C15, CAO, and NPCs 1 and 3 were LMP-positive whereas NPCs 2 and 4 were negative by immunoblot analysis with the S12 monoclonal antibody. They were all EBNA 1-positive (9).RNA Preparation and S1 Nuclease Assay. Total RNA from cell lines was prepared by homogenization in guanidinium isothiocyanate and ultracentrifugation through a CsCl cushion. Total RNA from NPC material was prepared by acidguanidinium thiocyanate/phenol/chloroform extraction.
Deficiency of the IL-1 receptor antagonist (DIRA) is a recently described rare autoinflammatory disease, caused by loss of function mutations in IL1RN leading to the unopposed activation of the IL-1 pathway. We describe a novel nonsense mutation in the IL1RN gene, associated with early intrauterine onset, death and multiorgan involvement in a prematurely born baby. The protein prediction model indicated that the novel Q119X mutation would result in a nonfunctional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R. Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life saving, we intend to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey. The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multiorgan failure.
Papillary thyroid cancer (PTC) constitutes more than 90% of the thyroid cancers. MAP kinase/ERK pathway plays an important role in the development of several cancers. BRAF which is a member of Raf-kinase family activates this way. BRAF gene activating mutations lead to neoplastic transformation in thyroid follicle cells. In PTC, this mutation itself is a poor prognostic sign independent of other clinicopathological characteristics. We evaluated BRAF(V600E) mutation and clinical-pathological characteristics in Turkish population with PTC. We assessed 109 patients with PTC (88 female, 21 male). The average age was 38.7 ± 9.9 (17-71). BRAF(V600E) mutation was detected using polymerase chain reaction and fluorescent melting curve analysis. The results show that BRAF(V600E) mutation rate was found in 39.45% of our patients. We observed that BRAF(V600E) mutation was significantly higher in men, in tumors larger than 1 cm in size, and in patients with classical PTC. Moreover, statistically significant correlations of BRAF(V600E) with indicators of tumor aggressiveness such as thyroid capsular invasion, multifocality, lymph node metastasis, and extrathyroidal spread were found. Patient groups below and over the age of 45 did not differ in mutation frequency. Patients with micro-PTC were evaluated separately, it was found that BRAF(V600E) mutation was more frequent in the classic type and that lymph node metastasis rate significantly increased when the mutation was present. We concluded that BRAF(V600E) was correlated with indicators of tumor aggressiveness in our study population. This fact is taken into consideration in treatment and follow-up of our patients with PTC and positive BRAF(V600E) mutation.
The family of repeats (FR) is a major upstream enhancer of the Epstein-Barr virus (EBV) latent C promoter (Cp) that controls transcription of six different latent nuclear proteins following interaction with the EBV nuclear protein EBNA1. Here, it was shown that Cp could also be activated by octamer-binding factor (Oct) proteins. Physical binding to the FR by the cellular transcription factors Oct-1 and Oct-2 was demonstrated by using an electrophoretic mobility-shift assay. Furthermore, Oct-1 in combination with co-regulator Bob.1, or Oct-2 alone, could drive transcription of a heterologous thymidine kinase promoter linked to the FR in both B cells and epithelial cells. Cp controlled by the FR was also activated by binding of Oct-2 to the FR. This may have direct implications for B cell-specific regulation of Cp.
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