The brownish spots have higher reliability for screening in early cancer of the mouth floor, hypopharynx, and epiglottis, but not in other mucosal sites. Mucosal sites with type 2a epithelium have a higher tendency of demonstrating brownish spots.

In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.

This study investigated the mechanism by which the transcription factor Sp1 is degraded in prostate cancer cells. We recently developed a thiazolidinedione derivative, (Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexyl)-thiazolidine-2,4-dione (OSU-CG12), that induces Sp1 degradation in a manner paralleling that of glucose starvation. Based on our finding that thiazolidinediones suppress ␤-catenin and cyclin D1 by up-regulating the E3 ligase SCF ␤-TrCP , we hypothesized that ␤-transducin repeat-containing protein (␤-TrCP) targets Sp1 for proteasomal degradation in response to glucose starvation or OSU-CG12. Here we show that either treatment of LNCaP cells increased specific binding of Sp1 with ␤-TrCP. This direct binding was confirmed by in vitro pull-down analysis with bacterially expressed ␤-TrCP. Although ectopic expression of ␤-TrCP enhanced the ability of OSU-CG12 to facilitate Sp1 degradation, suppression of endogenous ␤-TrCP function by a dominant-negative mutant or small interfering RNA-mediated knockdown blocked OSU-CG12-facilitated Sp1 ubiquitination and/or degradation. Sp1 contains a C-terminal conventional DSG destruction box ( 727 DSGAGS 732 ) that mediates ␤-TrCP recognition and encompasses a glycogen synthase kinase 3␤ (GSK3␤) phosphorylation motif (SXXXS). Pharmacological and molecular genetic approaches and mutational analyses indicate that extracellular signal-regulated kinasemediated phosphorylation of Thr739 and GSK3␤-mediated phosphorylation of Ser728 and Ser732 were critical for Sp1 degradation. The ability of OSU-CG12 to mimic glucose starvation to activate ␤-TrCP-mediated Sp1 degradation has translational potential to foster novel strategies for cancer therapy.In addition to maintaining the basal transcription of housekeeping genes, increasing evidence indicates that the transcription factor Sp1 also plays an important role in regulating the expression of a host of key effectors of signaling pathways governing cell cycle progression, cell proliferation, angiogenesis, apoptosis, and metastasis (Wierstra, 2008). These target proteins include receptor tyrosine kinases and their growth factor ligands, cyclin-dependent kinase inhibitors, c-Myc, Mdm2, Mcl-1, survivin, XIAP, Fas ligand, PUMA, and death receptor 5 (Wierstra, 2008). Moreover, Sp1

Due to the limited information of the contribution of various antibiotic resistance mechanisms in clinical Burkholderia cepacia complex isolates, Antibiotic resistance mechanisms, including integron analysis, identification of quinolone resistance-determining region mutations, measurement of efflux pump activity, and sequence analysis of efflux pump regulators, were investigated in 66 clinical B. cepacia complex isolates. Species were identified via recA-RFLP and MALDI-TOF. Four genomovars were identified by recA-RFLP. B. cenocepacia (genomovar III) was the most prevalent genomovar (90.1%). Most isolates (60/66, 90.9%) were correctly identified by MALDI-TOF analysis. Clonal relatedness determined by PFGE analysis revealed 30 pulsotypes, including two major pulsotypes that comprised 22.7% and 18.2% of the isolates, respectively. Seventeen (25.8%) isolates harboured class 1 integron with various combinations of resistance genes. Among six levofloxacin-resistant isolates, five had single-base substitutions in the gyrA gene and three demonstrated efflux pump activities. Among the 42 isolates exhibiting resistance to at least one antimicrobial agent, 94.4% ceftazidime-resistant isolates (17/18) and 72.7% chloramphenicol-resistant isolates (16/22) demonstrated efflux pump activity. Quantitation of efflux pump RNA level and sequence analysis revealed that over-expression of the RND-3 efflux pump was attributable to specific mutations in the RND-3 efflux pump regulator gene. In conclusion, high-level expression of efflux pumps is prevalent in B. cepacia complex isolates. Mutations in the RND-3 efflux pump regulator gene are the major cause of efflux pump activity, resulting in the resistance to antibiotics in clinical B. cepacia complex isolates.

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