p73, a structural and functional homologue of p53, plays an important role in modulating cell-cycle control and apoptosis. MDM2 represses the transcriptional activity of p73 and thus attenuates its activity. Based on the interaction between p73 and MDM2 in cell-cycle control and apoptosis, we investigated the association between p73 G4C14-to-A4T14 and MDM2 309T > G polymorphisms, alone and in combination, on the risk of lung cancer in a Korean population. The p73 and MDM2 genotypes were determined in 582 lung cancer patients and in 582 healthy control subjects who were frequency-matched for age and gender. The p73 AT/AT and MDM2 309 GG genotypes were associated with a nonsignificant increased risk of lung cancer (adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 0.83-2.24; and adjusted OR = 1.29, 95% CI = 0.92-1.80, respectively), compared with their wild-type genotypes, respectively. When the p73 and MDM2 polymorphisms were combined, the risk of lung cancer increased in a dose-dependent manner as the number of variant alleles increased (Ptrend = 0.01). Subjects with three or four variant alleles were at a significantly increased risk of lung cancer (adjusted OR = 1.74, 95% CI = 1.11-2.74, P = 0.02) compared to subjects with zero variant allele. These results suggest an additive effect of the p73 and MDM2 variant alleles on an increased risk of lung cancer.
The t(3;9)(q11-q12;q22) translocation associated with human extraskeletal myxoid chondrosarcomas results in a chimeric molecule in which the N-terminal domain (NTD) of the TFG (TRK-fused gene) is fused to the TEC (Translocated in Extraskeletal Chondrosarcoma) gene. Little is known about the biological function of TFG-TEC. Because the NTDs of TFG-TEC and TEC are structurally different, and the TFG itself is a cytoplasmic protein, the functional consequences of this fusion in extraskeletal myxoid chondrosarcomas were examined. The results showed that the chimeric gene encoded a nuclear protein that bound DNA with the same sequence specificity as the parental TEC protein. Comparison of the transactivation properties of TFG-TEC and TEC indicated that the former has higher transactivation activity for a known target reporter containing TEC-binding sites. Additional reporter assays for TFG (NTD) showed that the TGF (NTD) of TFG-TEC induced a 12-fold increase in the activation of luciferase from a reporter plasmid containing GAL4 binding sites when fused to the DNA-binding domain of GAL4, indicating that the TFG (NTD) of the TFG-TEC protein has intrinsic transcriptional activation properties. Finally, deletion analysis of the functional domains of TFG (NTD) indicated that the PB1 (Phox and Bem1p) and SPYGQ-rich region of TFG (NTD) were capable of activating transcription and that full integrity of TFG (NTD) was necessary for full transactivation. These results suggest that the oncogenic effect of the t(3;9) translocation may be due to the TFG-TEC chimeric protein and that fusion of the TFG (NTD) to the TEC protein produces a gain-of-function chimeric product.
BackgroundVarenicline is an effective smoking cessation aid. However, smokers prescribed with varenicline do not always receive varenicline for 12 weeks, as recommended. This study analyzed the subjects who received varenicline and investigated the effect of varenicline treatment duration on the success rate of 6-month smoking cessation.MethodsThis study retrospectively analyzed 78 subjects, who received varenicline, out of the 105 smokers that had visited the smoking cessation clinic after medical examination from September 2007 to December 2009.ResultsThe subjects were all males. Twenty-two subjects (28.2%) had varenicline treatment for 12 weeks or longer; 18 subjects (23.1%) for 8~12 weeks; 22 subjects (28.2%) for 4~8 weeks; and 16 subjects (20.5%) for less than 4 weeks. The total success rate of the 6-month smoking cessation was 47.4%. The success rate of the 6-month smoking cessation was 63.6% in the group that received varenicline for 12 weeks or longer, which was higher than 41.1% of the group that early terminated the varenicline treatment (p=0.074). The period of varenicline treatment was extended for one more week, the odds ratio of the 6-month smoking cessation success increased to 1.172-folds (p=0.004; 95% confidence interval, 1.052~1.305). Adverse events occurred in 30.8% of the subjects who received varenicline, but no serious adverse events were found.ConclusionIf varenicline treatment period is extended, the odds ratio of the success rate for the 6-month smoking cessation increases. Therefore, an effort to improve drug compliance for varenicline in clinical practices could be helpful for the long-term success of smoking cessation.
Human extraskeletal myxoid chondrosarcoma (EMC) is caused by a chromosomal translocation that involves TEC (translocated in extraskeletal myxoid chondrosarcoma), and either EWS (Ewing's sarcoma) or hTAF II 68 (human TATA-binding proteinassociated factor II 68), which generates EWS-TEC or hTAF II 68-TEC fusion proteins, respectively. Although there has been a great deal of progress in characterizing EWS-TEC, there is relatively little known about the biological function of hTAF II 68-TEC. We have examined the functional consequences of the fusion of the amino terminal domain (NTD) of hTAF II 68 to TEC in EMC. The chimeric gene encodes a nuclear protein that binds DNA with the same sequence specificity as parental TEC. Nuclear localization of hTAF II 68-TEC was dependent on the DNA binding domain, and we identified a cluster of basic amino acids in the DNA binding domain, KRRR, that specifically mediate the nuclear localization of hTAF II 68-TEC. The transactivation activity of hTAF II 68-TEC was higher than TEC towards a known target promoter that contained several TEC binding sites. Finally, deletion analysis of hTAF II 68-TEC indicated that the hTAF II 68 NTD, and the AF1 and AF2 domains of hTAF II 68-TEC are necessary for full transactivation potential. These results suggest that the oncogenic effect of the t(9;17) translocation may be due to the hTAF II 68-TEC chimeric protein and that fusion of the hTAF II 68 NTD to the TEC protein produces a gain of function chimeric product. ' 2008 Wiley-Liss, Inc.Key words: hTAF II 68-TEC; chromosomal translocation; fusion protein; transactivation; nuclear localization signal; human extraskeletal chondrosarcoma The loss of cellular growth regulation that gives rise to tumorigenesis originates with genetic changes in the cell. The t(9;17)(q22;q11.2) chromosomal translocation is associated with human extraskeletal myxoid chondrosarcoma (EMC), and results in the generation of a chimeric molecule consisting of the NTD of hTAF II 68 (also named TAF2N and RBP56) fused to full-length translocated in extraskeletal myxoid chondrosarcoma (TEC). 1,2 Human EMC is a soft tissue tumor of uncertain histogenetic origin that arises primarily in the musculature, most commonly in the thigh and knee. 3,4 hTAF II 68 encodes a putative RNA/single stranded DNA-binding protein that associates with TFIID and RNA polymerase II. 5 The gene for hTAF II 68 was originally identified because of its homology to the proto-oncogenes EWS and TLS (Translocated in lymphosarcoma), a member of the EWS gene family. 5,6 EWS and TLS are involved in several tumor-related chromosomal translocations that result in gene fusions with a number of putative transcription factors, such as Fli-1, ERG, ETV1, E1A-F, FEV, WT1, ATF1, CHOP and TEC. 7,8 In each case, the translocation produces a chimeric molecule containing the NTD of EWS or TLS fused to the DNA binding domain of its partner. Recently, a new translocation involving the EWS gene was identified in some bone and softtissue tumors. 9 In these tumors, a t(6;22)(p21;...
Mycobacterium celatum is a nontuberculous mycobacterium that rarely causes pulmonary disease in immunocompetent subjects. We describe the successful treatment of M. celatum lung disease with antimicobacterial chemotherapy and combined pulmonary resection. A 33-year-old woman was referred to our hospital with a 3-month history of a productive cough. Her medical history included pulmonary tuberculosis 14 years earlier. Her chest X-ray revealed a large cavitary lesion in the left upper lobe. The sputum smear was positive for acid-fast bacilli, and M. celatum was subsequently identified in more than three sputum cultures, using molecular methods. After 1 year of therapy with clarithromycin, ethambutol, and ciprofloxacin, the patient underwent a pulmonary resection for a persistent cavitary lesion. The patient was considered cured after receiving 12 months of postoperative antimycobacterial chemotherapy. There has been no recurrence of disease for 18 months after treatment completion. In summary, M. celatum is an infrequent cause of potentially treatable pulmonary disease in immunocompetent subjects. Patients with M. celatum pulmonary disease who can tolerate resectional surgery might be considered for surgery, especially in cases of persistent cavitary lesions despite antimycobacterial chemotherapy.
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