Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis.

Incomplete Kawasaki disease (KD) comprises a large proportion of the total number of cases. Although it has the potential of delaying diagnosis, it is not conclusive whether an incomplete presentation is a risk factor for coronary artery abnormalities (CAAs). We performed a meta-analysis to establish the risk of CAA in 20 studies including 4,504 cases and 32,519 controls, and the risk of giant aneurysm in two studies including 5,390 cases and 37,648 controls. The pooled results indicated that incomplete KD was associated with an increased risk of CAA [odds ratio (OR) = 1.447, 95 % confidence interval (CI) = 1.158-1.808, p = 0.001]. Subgroup analyses demonstrated higher associations in patients younger than 12 months (OR = 2.023, 95 % CI = 1.252-3.271, p = 0.004), Asians and Indians (OR = 1.57, 95 % CI = 1.234-1.999, p < 0.001 and OR = 7.088, 95 % CI = 1.640-30.631, p = 0.009, respectively). Subgroup analysis according to the period of patient enrollment before and after 2004 showed increased association of incomplete KD with CAA only among studies with patients enrolled after 2004 (OR = 1.969, 95 % CI = 1.240-3.127, p = 0.004). In conclusion, incomplete KD seems to be associated with an increased risk of CAA, and this is more prominent in patients younger than 12 months, Asians and Indians.

Elevated activities of MMP-2 in the non-tumorous lung tissues of curatively resected stage I NSCLC patients are associated with tumor recurrence and a poor survival.

BACKGROUND AND OBJECTIVES: We wanted to assess whether the level of enzyme activity for a particular matrix metalloproteinase (MMP), and not the amount of expressed protein, in lung tissue could be used as a reliable prognostic biomarker for tumor recurrence leading to poorer survival in a certain subgroup of patients who have undergone curative resection for stage I human NSCLC. METHODS: We determined what type of MMP was significant for tumor recurrence by using a mouse model of pulmonary metastasis with inoculating the footpad with H460 human cancer cells. We then looked for any association between tumor recurrence and the level of enzyme activities for the selected MMP in the tumor and also in the pathologically non-tumorous tissues from 34 stage I lung cancer patients. RESULTS: We obtained H460/PM6 cells having a highly metastatic potential after six repeated cycles of pulmonary metastasis by using the mouse footpad inoculated with the metastasized cancer cells in the previous cycle. We started with human lung cancer cells, H460, and we found that among the tested MMPs we tested for, the level of MMP-2 mRNA was elevated. No significant difference was seen in the level of enzyme activity of the MMP-2 cells from the curatively resected tumor tissues of the stage I NSCLC patients who were later found with or without recurrence. However, the level of MMP-2 enzyme activity was found to be significantly different between the non-tumorous lung tissues from patients later found with and without recurrence, and it was associated with the 5-year survival rate. CONCLUSIONS: This observation suggests that the higher level of MMP-2 enzyme activity in the non-tumorous tissues from the patients could be used as a prognostic biomarker to predict post-operative tumor recurrence and survival for patients with stage I NSCLC. The elevated enzyme activity of MMP-2 in the non-tumorous tissue resected from stage I NSCLC could be used as a prognostic indicator for post-operative tumor recurrence and the patients' poor survival. Further, this could be an important aid for physicians' making decision on whether to subject particular patients to post-operative adjunct chemotherapy.

Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2.

Bcl-2 is involved in the progression of human malignancies, but the precise role and mechanism of Bcl-2 for tumor invasion and metastasis remains unclear. In this study, we have investigated the role and mechanism of Bcl-2 on tumor cell invasion and metastasis by using Bcl-2 overexpressing non-small cell lung cancer cells. Matrix metalloproteinases (MMPs) are important proteins involved in the processes of tumor invasion and metastasis. In vitro Matrigel invasion assays showed that Bcl-2 overexpression increased tumor cell invasion by 15-fold. Moreover, Bcl-2 overexpression enhanced in vivo lung metastasis by 4-fold. Consistent with its effect on invasion and metastasis, Bcl-2 overexpression induced not only MMP-2 mRNA and its protein expression, but this also activated the pro-MMP-2 protein to its active form. To explore the induction mechanism of MMP-2 by Bcl-2, we investigated the effects of Bcl-2 overexpression on MMP-2 transcriptional regulation. Nuclear run-on assays showed a 6-fold increase in the transcription rate of MMP-2 mRNA in the Bcl-2 transfectants (H157/Bcl-2) compared with that of the H157/vector control cells (H157/C). Overexpression of Bcl-2 induced the nuclear transcription factor activator protein 1 family, including the c-Jun, JunD, c-Fos, FosB, and Fra-1 proteins. Reporter assays combined with deletion mutagenesis analysis and gel shift assays showed the involvement of activator protein 1 in the activation of MMP-2 promoter activity by Bcl-2. Taken together, we have shown that Bcl-2 promotes tumor invasion and lung metastasis by inducing MMP-2 gene expression through the combined action of transcriptional and posttranslational mechanisms.

p53 and FHIT mutations and microsatellite alterations in malignancy-associated pleural effusion.

Cancer is a genetic disease and thus is influenced by oncogenes and tumor suppressor genes. To determine whether the genetic analysis of pleural fluid can be used to diagnose malignant effusion, we investigated p53 and FHIT mutations and microsatellite alterations (MA) in the pleural fluid of 40 patients with pleural effusion associated with malignancy (ME) and in the pleural fluid of 17 patients with tuberculous pleurisy (TB) as a control group. p53 mutations were detected in five ME patients (13%) and in no TB patient, and FHIT mutations were detected in seven ME patients (18%) and two TB patients (12%). For four microsatellite markers, D3S1234, D3S1285, D9S171, and TP53, in ME patients, loss of heterozygosity (LOH) was seen in 10 (25%), 5 (13%), 10 (25%), and 6 patients (15%), respectively, and microsatellite instability (MI) in 6 (15%), 0 (0%), 1 (3%), and 3 patients (8%), respectively. Using the same markers, in TB patients, LOH was seen in three (18%), one (6%), three (18%), and one (6%), respectively, and MI in one (6%), zero (0%), zero (0%), and zero (0%), respectively. Twenty-five ME cases (63%) exhibited MA (LOH or MI) in at least one marker. Moreover, in four (80%) of five ME cases with negative cytology and no carcinoembryonic antigen increase in pleural fluid, MAs were identified. In ME, positive cytology was found in 42.5%, and positive MA, using four markers, in 63%. Although still limited in terms of sensitivity and specificity, this study shows that molecular diagnostic strategies could enhance the diagnostic yield in cases of malignant effusion.