USP24 Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma.

Deubiquitinating enzymes are increasingly recognized to play important roles in cancer, with many acting as oncogenes or tumor suppressors. In this study, we employed a bioinformatics approach to screen for enzymes from this family involved in cancer and found USP24 as a potent predictor of poor outcomes in neuroblastoma, an aggressive childhood cancer. USP24 resides in a region commonly deleted in neuroblastoma, yet was independently associated with poor outcomes in this disease. Deletion of Usp24 in a murine model resulted in degradation of collapsin response mediator protein 2 (CRMP2), a regulator of axon growth, guidance, and neuronal polarity. Cells lacking USP24 had significant increases in spindle defects, chromosome missegregation, and aneuploidy, phenotypes that were rescued by the restoration of CRMP2. USP24 prevented aneuploidy by maintaining spindle-associated CRMP2, which is required for mitotic accuracy. Our findings further indicate that USP24 is a tumor suppressor that may play an important role in the pathogenesis of neuroblastoma. SIGNIFICANCE: This study identifies the chromosome instability gene USP24 as frequently deleted in neuroblastoma and provides important insight into the pathogenesis of this aggressive childhood cancer.

A clinical study of the pulse wave characteristics at the three pulse diagnosis positions of chon, gwan and cheok.

In this work, we analyze the baseline, signal strength, aortic augmentation index (AIx), radial AIx, time to reflection and P_T2 at Chon, Gwan, and Cheok, which are the three pulse diagnosis positions in Oriental medicine. For the pulse measurement, we used the SphygmoCor apparatus, which has been widely used for the evaluation of the arterial stiffness at the aorta. By two-way repeated measures analysis of variance, we tested two independent measurements for repeatability and investigated their mean differences among Chon, Gwan and Cheok. To characterize further the parameters that were shown to be different between each palpation position, we carried out Duncan's test for the multiple comparisons. The baseline and signal strength were statistically different (P < .05) among Chon, Gwan and Cheok, respectively, which supports the major hypothesis of Oriental medicine that all of the three palpation positions contain different clinical information. On the other hand, aortic AIx and time to reflection were found to be statistically different between Chon and the others, and radial AIx and P_T2 did not show any difference between pulse positions. In the clinical sense, however, the aortic AIx at each palpation position was found to fall within the 90% confidence interval of normal arterial compliance. The results of the multiple comparisons indicate that the parameters of arterial stiffness were independent of the palpation positions. This work is the first attempt to characterize quantitatively the pulse signals at Chon, Gwan and Cheok with some relevant parameters extracted from the SphygmoCor apparatus.

Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages.

Silymarin, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects. In the present study, we report the inhibitory effect of silymarin on nitric oxide production and inducible nitric-oxide synthase (iNOS) gene expression in macrophages. In vivo administration of silymarin attenuated nitric oxide production by peritoneal macrophages in lipopolysaccharide (LPS)-treated mice. Silymarin also dose dependently suppressed the LPS-induced production of nitric oxide in isolated mouse peritoneal macrophages and RAW 264.7, a murine macrophage-like cell line. Moreover, iNOS mRNA and its protein expression were completely abrogated by silymarin in LPS-stimulated RAW 264.7 cells. To further investigate the mechanism responsible for the inhibition of iNOS gene expression by silymarin, we examined the effect of silymarin on LPS-induced nuclear factor-kappaB (NF-kappaB)/Rel activation, which regulates various genes involved in immune and inflammatory response. In RAW 264.7 cells, the LPS-induced DNA binding activity of NF-kappaB/Rel was significantly inhibited by silymarin, and this effect was mediated through the inhibition of the degradation of inhibitory factor-kappaB. Silymarin also inhibited tumor necrosis factor-alpha-induced NF-kappaB/Rel activation, whereas okadaic acid-induced NF-kappaB/Rel activation was not affected. NF-kappaB/Rel-dependent reporter gene expression was also suppressed by silymarin in LPS-stimulated RAW 264.7 cells. Further study showed that silymarin suppressed the production of reactive oxygen species generated by H(2)O(2) in RAW 264.7 cells. Collectively, these results suggest that silymarin inhibits nitric oxide production and iNOS gene expression by inhibiting NF-kappaB/Rel activation. Furthermore, the radical-scavenging activity of silymarin may explain its inhibitory effect on NF-kappaB/Rel activation.