Junghwa Lee

Use of RNA interference to elucidate the effect of MYCN on cell cycle in neuroblastoma

MYCN amplification marks poor prognosis in neuroblastoma (NB) tumors. In evaluating the mechanisms by which retinoic acid (RA) or nerve growth factor (NGF) decrease cell number in MYCN amplified NB cells, we have identified a number of proteins whose expression either decreases (E2F, CDC2, CDK6, cyclin dependent kinase activity) or increases (p27) in association with a decrease in MYCN expression. However, it was still unclear which were MYCN dependent effects or not.

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

Background Resistance to intravenous immunoglobulin (IVIG) occurs in 10–20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels. Method We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis. Results Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders. Conclusions Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

Mutation analysis of hepatitis B virus promoters in chronically infected children

Summary.Hepatitis B viral (HBV) infection in early childhood is one of the leading causes of chronic hepatitis and liver cirrhosis that eventually lead to hepatic carcinoma. Despite the nationwide immunization programs to curtail the vertical transmission of HBV, childhood HBV infection through mothers is still occurring in Korea. As one of the efforts to understand the childhood HBV infection in Korea, four HBV promoter sequences in the sera of the chronically infected children were analyzed. Children harbored diverse viral variants as most of the chronically infected adult patients, but the deletion mutations were rare. The dominant viral sequences in the children were highly similar to the ones in the respective mothers, indicating that the maternal viruses were most likely transmitted to the children. The mutations in X, S1, S2/S promoters did not seem to show any correlation to the severity of the disease nor ages of the children. The mutations that showed some correlation to the severity of the disease were the mutations in C promoter, but the mutations did not seem to be vertically transmitted. Finally, the children with the elevated ALT/AST levels tended to have more child-specific variants suggesting that the accumulation of host-specific mutations might be associated with the development of clinical symptoms.

Overall Outcome of Kawasaki Disease

To assess the overall outcome of Kawasaki disease, patients with a discharge diagnosis of Kawasaki disease at Korea University Medical Center from 1999 to 2001 were retrospectively evaluated. A total of 99 patients were diagnosed. The American Heart Association (AHA) criteria were met in 65 patients (66%) and 63 of them received intravenous immune globulin (IVIG, 2g/kg). Fifty patients responded afebrile within 5 days (IVIG-responsive) and 13 patients did not (IVIG-non-responsive). Within 2 months, 2 patients in the IVIG-responsive group developed coronary abnormalities compared to 3 patients in the IVIG-non-responsive group (4% vs 23%). None of whom met AHA criteria and did not received IVIG were febrile more than 5 days nor developed coronary abnormalities. In 34 patients who did not meet complete AHA criteria, 28 patients received IVIG and 25 patients were IVIG-responsive. Coronary abnormalities were developed in 4 in the IVIG-responsive group compared to none in the IVIG-non-responsive group (16% vs 0%). All 6 patients who did not meet complete AHA criteria and did not received IVIG were febrile more than 5 days and 2 of them developed coronary abnormalities. Taken together, coronary abnormalities were developed in 9 patients of 91 who were treated with IVIG compared to 2 patients of 8 who were not treated with IVIG (10% vs 25%). In conclusion coronary abnormalities were developed in 11 of 99 patients with Kawasaki disease (11%).