Integrated analysis of the prognostic value of TP53 dependent etoposide-induced gene 24 in non-small cell lung cancer.

BACKGROUND: Etoposide-induced gene 24 (EI24) is an induction target of TP53-mediated apoptosis in human cancer cells. The hypothesis of this study is that EI24 might be a prognostic biomarker of non-small cell lung carcinoma (NSCLC). MATERIAL AND METHODS: Fourteen gene expression NSCLC datasets with follow-up information (a total of 2582 accessible cases) were collected from Asia, Europe and North America. The Kaplan-Meier and Cox analyses were applied to evaluate the relation between EI24 and the outcomes of NSCLC. A gene set enrichment analysis (GSEA) was used to explore EI24 and cancer-related gene signatures. RESULTS: EI24 was significantly upregulated in mutated TP53 NSCLC samples and significantly downregulated with the increase in the TP53 expression level in NSCLC. GSEA results suggested that EI24 significantly enriched metastasis and poor prognosis gene signatures. Meanwhile, EI24 was significantly upregulated in lung adenocarcinoma compared with normal lungs (p < 0.01). It was also highly expressed in the later TNM stages and the ALK fusion+, higher MYC gene copy and EGFR wild type subgroups (p < 0.05). The Kaplan-Meier analysis demonstrated that the expression of EI24 was significantly associated with poor overall survival and disease-free survival in a dose-dependent manner in GSE31210 dataset. The C-index of Cox model with EI24 is 0.70, that is better than that with MYC (0.51), KRAS (0.51) and EGFR (0.59), which indicates better prognostic performance of EI24. The prognostic significance of EI24 for overall survival of NSCLC was validated by pooled and meta-analysis on 14 datasets. The stratification analysis revealed that EI24 prognosticated poor overall survival (HR = 3.37, 95% CI = 1.39-9.62, p < 0.05) in the TP53 wild type subgroup, but not in the mutated TP53 NSCLC subgroup. Moreover, YY1 might transcriptionally regulate EI24 in a positive manner. CONCLUSION: EI24 is a potential prognostic biomarker and impacts poor outcome in NSCLC. The prognostic significance of EI24 might rely on TP53 status.

Iron inhibits Escherichia coli topoisomerase I activity by targeting the first two zinc-binding sites in the C-terminal domain.

Escherichia coli DNA topoisomerase I (TopA) contains a 67 kDa N-terminal catalytic domain and a 30 kDa C-terminal zinc-binding region (ZD domain) which has three adjacent tetra-cysteine zinc-binding motifs. Previous studies have shown that E. coli TopA can bind both iron and zinc, and that iron binding in TopA results in failure to unwind the negatively supercoiled DNA. Here, we report that each E. coli TopA monomer binds one atom of iron via the first two zinc-binding motifs in ZD domain and both the first and second zinc-binding motifs are required for iron binding in TopA. The site-directed mutagenesis studies further reveal that while the mutation of the third zinc-binding motif has very little effect on TopA's activity, mutation of the first two zinc-binding motifs in TopA greatly diminishes the topoisomerase activity in vitro and in vivo, indicating that the first two zinc-binding motifs in TopA are crucial for its function. The DNA-binding activity assay and intrinsic tryptophan fluorescence measurements show that iron binding in TopA may decrease the single-stranded (ss) DNA-binding activity of ZD domain and also change the protein structure of TopA, which subsequently modulate topoisomerase activity.

Pleural fluid prealbumin and C-reactive protein in the differential diagnosis of infectious and malignant pleural effusions.

Clinical history and physical examination are helpful in indicating the potential causes of pleural effusions (PEs). However, the accurate diagnosis and establishment of the causes of PE is an ongoing challenge in daily clinical practice. The primary aim of this study was to distinguish between infectious PE and malignant PE (MPE) by measuring two major acute phase response biomarkers: prealbumin (PA) and C-reactive protein (CRP). The study was a prospective trial involving 151 patients who were diagnosed with infectious PE or MPE. Patients with infectious PE were divided into two subgroups: tuberculous PE (TBPE) and parapneumonic PE (PNPE). A further 58 patients with PEs that showed no evidence of MPE, TBPE or PNPE were classified as the chronic non-specific PE (NSPE) group. Demographic characteristics and pleural fluids of the subjects were collected consecutively. The discriminative properties of pleural fluid routine biochemistries, and PA and CRP were evaluated. PA, CRP and classical fluid parameters were also applied to classify patients with infectious PE and MPE. Receiver operating characteristics (ROC) analysis established the cutoffs of PA and CRP for discriminating between groups. Pleural fluid PA levels were significantly higher in the MPE group (n=47) than in the infectious PE group (n=104). Pleural fluid CRP levels were significantly higher in the infectious PE group than in the MPE group. Pleural fluid PA levels were identified to be moderately negatively correlated with CRP levels in the MPE group, with a statistically significant correlation coefficient of -0.352. The ROC curve showed that the sensitivity and specificity of PA for the diagnosis of MPE were 0.851 and 0.548, respectively, at the cutoff of 28.3 mg/l. The area under the curve (AUC) was 0.784 (95% CI, 0.707-0.861). Using CRP as a diagnostic parameter resulted in an comparable AUC of 0.810 (95% CI, 0.736-0.885), at the cutoff of 35.2 mg/l. Combinations of PA and CRP resulted in incrementally discriminating values for MPE, with a sensitivity of 0.617 and a specificity of 0.903. The measurement of PA and CRP levels in pleural fluid may be a useful adjunctive test in PE, as a potential differentiator between infectious PE and MPE.

Serum angiopoietin-2 and ß-hCG as predictors of prolonged uterine bleeding after medical abortion in the first trimester.

OBJECTIVE: The combination of mifepristone and misoprostol is an established method for induction of early first trimester abortion, but there is no consensus about the best evaluation of treatment outcome. We evaluate serum Angiopoietin-2 (Ang-2) and ß human chorionic gonadotropin (ß-hCG) in women who had undergone a medical abortion as markers of prolonged uterine bleeding (PUB). METHODS: Prospective trial involving 2843 women attending an gynecology outpatient clinic who following a medical abortion with mifepristone and misoprostol, the study cohort was divided into women with duration of uterine bleeding >14 days (PUB) and women with duration of uterine bleeding ≤14 days (normal uterine bleeding, NUB). Serum determinations of Ang-2 levels by ELISA and ß-hCG levels by electrochemiluminiscence immunoassay. Receiver Operating Characteristics (ROC) analyses were calculated and plotted for the diagnostic accuracy of serum ß-hCG and Ang-2 concentration to discriminate PUB and NUB. RESULTS: Baseline characteristics for both groups were similar, Only duration of bleeding showed a significant difference between the PUB group and NUB group. Ang-2 serum levels moderately correlated with serum ß-hCG levels with statistically significant correlation coefficients of 0.536. Serum ß-hCG and Ang-2 levels on day 7 and on day 14 after medical abortion were signifcantly higher in PUB group than in NUB group. Plotted as ROC curves, ß-hCG area under curve (AUC) was 0.65 (95% CI, 0.53-0.76) on day 7, rising to AUC = 0.83 (95% CI, 0.75-0.92) on day 14. Using Ang-2 on day 7 and day 14 as predictive parameter resulted in an analogous AUC (AUC = 0.61 on day 7, AUC = 0.78 on day 14). CONCLUSIONS: Both parameters are clinically useful as a diagnostic test in predicting PUB after medical abortion, and can be helpful in uncertain clinical situations, but should be considered as supplementary to a general clinical evaluation.

[Diagnostic value of serum angiopoietin-2 level in pancreatic cancer].

OBJECTIVE: To evaluate the diagnostic value of serum angiopoietin-2 (Ang-2) level in pancreatic cancer patients. METHODS: Serum Ang-2 level was measured by enzyme-linked immunosorbent assays (ELISA) in samples from 116 patients with pancreatic cancer, 50 patients with chronic pancreatitis, and 50 normal control subjects. RESULTS: The serum Ang-2 level in patients with pancreatic cancer [(1539.0 ± 449.3) ng/L] was significantly higher than those in patients with pancreatitis [(1044.6 ± 246.1) ng/L, P < 0.01] and normal control subjects [(1075.6 ± 228.2) ng/L, P < 0.01]. There was no significant difference of serum Ang-2 levels between patients with pancreatitis and normal controls. Pancreatic caner patients with lymph node metastasis had a significantly higher serum Ang-2 level [(1890.1 ± 354.9) ng/L] than those without metastasis [(1212.1 ± 224.2) ng/L, P < 0.01]. The area under ROC curve of serum Ang-2 level for diagnosis of pancreatic cancer was 0.819. CONCLUSION: The serum Ang-2 level can be a useful indicator for diagnosis of pancreatic cancer.