A Five-microRNA Signature for Survival Prognosis in Pancreatic Adenocarcinoma based on TCGA Data.

Novel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-ß, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.

Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

Cholangiocarcinoma (CCA) is a cancer type with high postoperative relapse rates and poor long-term survival largely due to tumor invasion, distant metastasis, and multidrug resistance. Deregulated microRNAs (miRNAs) are implicated in several cancer types including CCA. The specific roles of the miRNA let-7c in cholangiocarcinoma are not known and need to be further elucidated. In our translational study we show that microRNA let-7c expression was significantly downregulated in human cholangiocarcinoma tissues when compared to adjacent tissues of the same patient. Let-7c inhibited the tumorigenic properties of cholangiocarcinoma cells including their self-renewal capacity and sphere formation in vitro and subcutaneous cancer cell growth in vivo. Ectopic let-7c overexpression suppressed migration and invasion capacities of cholangiocarcinoma cell lines in vitro, however, promoted distant invasiveness in vivo. Furthermore, we found that let-7c regulated the aforementioned malignant biological properties, at least in part, through regulation of EZH2 protein expression and through the DVL3/ß-catenin axis. The miRNA let-7c thus plays an important dual role in regulating tumorigenic and metastatic abilities of human cholangiocarcinoma through mechanisms involving EZH2 protein and the DVL3/ß-catenin axis.

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin.

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

[Prenatal risk factors for neonatal asphyxia: how risk for each?].

OBJECTIVE: Neonatal asphyxia is the third leading cause of neonatal death and main cause of long-term neurodevelopmental handicap throughout the world. Prevention is more important than treatment. Most previous reports are limited to retrospective investigations of the relationships between some prenatal risk factors and low Apgar scores. This study was designed to prospectively investigate the relationship between prenatal risk factors and neonatal asphyxia and the influence of single or multiple risk factors on the incidence of neonatal asphyxia, and examine significant risk factors for neonatal asphyxia. METHODS: From April 2002 through October 2004, a total of 10 376 live-born newborns were enrolled. Forty-six prenatal risk factors were investigated. Neonatal asphyxia was diagnosed based on the following four items: 1. 1-min Apgar score or=0.10 and p<0.05 as significant. The OR and 95%CI were calculated for each significant risk factor. RESULTS: Of the 10 376 newborns, 8 530 cases (82.21%) had 1-9 risk factors, and asphyxia occurred in 117 cases (1.13%) out of the 8 530 cases. In the 1 846 cases without risk factors, none had asphyxia (x2=25.6, p<0.01). The incidence of asphyxia increased with increasing numbers of risk factors, from 0.23% in newborns with one risk factor to 14.29% in newborns who had nine risk factors (r=0.96, p<0.01). Twelve significant risk factors identified were as follows: ominous fetal heart rate patterns (OR=17.1,95%CI:11.2-25.9), placenta abruption (OR=15.2, 95% CI: 4.5-51.8), maternal lung diseases (OR=11.5, 95% CI:1.4-91.3), fetal acidosis (OR=6.1, 95% CI:1.5-24.1), placenta previa (OR=5.0,95% CI:1.5-16.9), breech delivery (OR=4.5, 95% CI: 2.1-9.9), meconium stained amniotic fluid (OR=3.2, 95% CI:2.2-4.8), forcepsjassisted delivery (OR=3.2, 95%CI: 1.1-9.9), prolonged labor (OR=2.94, 95%CI:1.5-5.8), abnormal utero contraction (OR=2.8, 95% CI:1.7-4.6), and premature delivery (OR=2.5,95%CI:1.4-4.8). Cesarean section had a protective effect (OR=0.6, 95% CI:0.4-0.9) (all p<0.05). CONCLUSIONS: It is very important to prevent perinatal asphyxia by systematically examining prenatal risk factors and giving interventions for the newborns with risk factors, especially those with the above significant risk factors or with multiple risk factors. Proper cesareon section according to indications might be helpful to decrease the incidence of birth asphyxia.

[Clinical study on improving the diagnostic criteria for neonatal asphyxia].

OBJECTIVE: Diagnosing neonatal asphyxia solely according to Apgar score may lead to misdiagnosis. The aim of this study was to explore new and more accurate diagnostic criteria for neonatal asphyxia. METHODS: Totally 10 376 live born neonates in our hospital were consecutively enrolled into the study. The following five items related to birth asphyxia, i.e., antepartum high-risk factors, Apgar scores, umbilical artery blood pH, organ injury, differential diagnosis on the causes of low Apgar score cases were examined and registered. The relationship among the first 4 items were analyzed. By differential diagnosis, the sensitivity and specificity of each index on diagnosing asphyxia and their complementary value on each other were investigated. RESULTS: The items correlated well with each other (P < 0.01 or < 0.05) but were not entirely parallel and consistent; they could complement but could not substitute for each other. The sensitivity of antepartum high-risk factors, low Apgar scores, umbilical artery blood pH < 7.00 and organ injury was 100%, 100%, 44.44% and 100%, while the specificity was 17.99%, 98.90%, 96.05% and 96.62%, respectively. Of the 230 low Apgar score cases in this series only 50.9% coincided with asphyxia. For the 230 cases, when low Apgar score was combined with umbilical artery blood pH < 7.00, the sensitivity and specificity were 41% and 99.1% and when low Apgar score was combined with umbilical artery blood pH < 7.20, the sensitivity and specificity were 100% and 29.20%, respectively. After organ injury was added, the specificity was increased to 65.49%. When differential diagnosis was further added to exclude the other causes of low Apgar score cases, the misdiagnosis rate was minimized. CONCLUSION: Up to now, no single accurate index for diagnosing neonatal asphyxia is available. In order to increase diagnostic bases and reduce misdiagnosis, the criteria of sole Apgar score should be replaced by multi-index diagnostic criteria. Based on the present study, a set of integrated diagnostic criteria for neonatal asphyxia is proposed: (1) prenatal high-risk factors, (2) low Apgar scores (respiratory depression must present), (3) umbilical artery blood pH < 7.00, if only pH < 7.20, the items (2) (4) (5) must be present, (4) hypoxic-ischemic organ injury (at least one organ dysfunction), (5) the other causes of low Apgar scores should be excluded. The last 4 indexes should all be met and the first one serves as reference. If multi-organ (three or more organs) dysfunction and (or) hypoxic-ischemic encephalopathy are present, severe asphyxia can be diagnosed.