Heterogeneous nuclear ribonucleoprotein K (hnRNP K) mediates antiapoptotic activity in part by inducing downstream antiapoptotic genes. To systematically identify hnRNP K targets in nasopharyngeal carcinoma (NPC), affymetrix chips were used to identify genes that were both overexpressed in primary NPC and downregulated by hnRNP K knockdown in NPC-TW02 cells. The resulting gene set included the antiapoptotic gene, FLIP, which was selected for further study. In cells treated with hnRNP K siRNA, TRAIL-induced apoptosis was enhanced and the FLIP protein level was reduced. Promoter, DNA pull-down and chromatin-immunoprecipitation assays revealed that hnRNP K directly interacts with the poly(C) element on the FLIP promoter, resulting in transcriptional activation. Through iTRAQ-mass spectrometric identification of proteins differentially associated with the poly(C) element or its mutant, nucleolin was determined to be a cofactor of hnRNP K for FLIP activation. Furthermore, FLIP was highly expressed in tumor cells, and this high-level expression was significantly correlated with high-level hnRNP K expression (P ¼ 0.002) and poor overall survival (P ¼ 0.015) as examined in 67 NPC tissues. A multivariate analysis confirmed that FLIP was an independent prognostic factor for NPC. Taken together, these findings indicate that FLIP expression is transcriptionally regulated by hnRNP K and nucleolin, and may be a potential prognostic and therapeutic marker for NPC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) belongs to the hnRNP family of proteins. The members of this family interact directly with DNA and RNA through their K-homology domains and regulate gene expression at multiple levels, including transcription, RNA splicing, RNA stability and translation.1-2 The expression of hnRNP K has been shown to be aberrantly increased in numerous cancers, [3][4][5][6] and we recently reported that high-level hnRNP K expression is correlated with poorer overall survival (OS) and decreased metastasis-free survival among nasopharyngeal carcinoma (NPC) patients.5 Our findings were consistent with those from clinical correlation studies in oral squamous cell carcinoma 4 and prostate cancer. HnRNP K is a nucleocytoplasmic shuttling protein that is primarily located in the nucleus for transcriptional regulation. However, cytoplasmic accumulation of hnRNP K through ERK-mediated phosphorylation of hnRNP K serines-284 and -353 has been reported in cervical carcinoma HeLa, 7 chronic myelogenous leukemia 8 and NPC 9 cells. The tumorigenic activity of hnRNP K appears to be conferred through its ability to increase proliferation, 10 antiapoptotic effects, 9 clonogenic potential 8 and metastasis. 11 These functions may be due, at least in part, to the ability of hnRNP K to upregulate the c-myc, 8,12 thymidine phosphorylase (TP) 9 and eIF4E 10 genes through transcriptional or post-transcriptional regulation. However, the full spectrum of targets regulated by hnRNP K has not as yet been systematically examined.The acquisition of resistance to ...

This study was undertaken to establish reference values of exhaled nitric oxide fraction (FeNO) and its determinants in healthy Asian children.693 healthy Asian children aged 5-18 yrs were assessed using a single-breath online FeNO measurement (exhaled flow 50 mL?s -1 ), questionnaires, anthropometric measurements, spirometry and total and specific immunoglobulin (Ig) E.Geometric mean FeNO and the upper 95% CI were 13.7 ppb and 49.7 ppb, respectively, for healthy children, and 11.2 ppb and 30.2 ppb, respectively, for those without allergic sensitisation. FeNO was positively associated with age, allergic sensitisation, total IgE, ambient nitric oxide, measurement in the afternoon, and drinking water within 1 h before testing, and was negatively associated with weight. In healthy children without allergic sensitisation, age was the single best explanatory variable. The FeNO predicted values were 1-2 ppb higher in Asian than in Caucasian children in earlier studies, while the upper 95% CI were 9-10 ppb higher.In conclusion, the upper limits of normal FeNO in Asian children depend on age, from 21 ppb in young children to 39 ppb in adolescents. Ethnicity, age, allergic sensitisation, total IgE, ambient nitric oxide, time of testing, drinking water and weight are important determinants.

FeNO measurement discriminates children with and without allergic sensitization independent of allergic symptoms. On the other hand, low FeNO levels in children may help exclude allergic asthma but high levels may be caused by allergic sensitization, older age, rhinitis, and lower BMI, in addition to asthma.

The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the halflife of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT-PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP Kmediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.

Of all patients with systemic lupus erythematosus (SLE), 15-20% are diagnosed during childhood, with disease onset prior to the age of 16 years. Because disease expression in SLE is influenced by environment factors and differs between racial and ethnic groups. The aims of this review were to describe prevalence, clinical manifestations, common infectious complications, and outcome of pediatric-onset SLE in Asia. The prevalence of pediatric-onset SLE was 6.3-19.3 per 100,000 in Asia. The ratio of female to male was 4.7-6.2. The mean age at diagnosis of pediatric-onset SLE was 8.6-13.5 years. The most common clinical features of pediatric-onset SLE in Asia were cutaneous rashes, arthritis, hematological involvement and nephritis. The occurrence of nephritis varies from 29% to 81%. The most common histopathology of lupus nephritis was diffuse proliferative glomerulonephritis (WHO Class-IV) which occurred in 39.4-54% of case of lupus nephritis. Pediatric-onset SLE patients with infections have poor outcomes than uninfected patients. Gram-negative bacilli are the most common microorganisms responsible for bacteremia in Asian patients with SLE. Recurrent major infections predict poorer disease outcome and associated organ damage in pediatric-onset SLE. Improving the survival of SLE patients was reported in Asia in recent decades. The survival was 92% at the age of 5 years, 86% at 10 years and 79% at 15 years in children with SLE in Taiwan in 2008.