Xu Chen

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis-free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

BACKGROUND: Aggressive tumor cells can form perfusable networks that mimic normal vasculature and enhance tumor growth and metastasis. A number of molecular players have been implicated in such vasculogenic mimicry, among them the receptor tyrosine kinase EphA2, which is aberrantly expressed in aggressive tumors. Here we study the role and regulation of EphA2 in vasculogenic mimicry in prostate cancer where this phenomenon is still poorly understood. METHODS: Vasculogenic mimicry was characterized by tubules whose cellular lining was negative for the endothelial cell marker CD34 but positive for periodic acid-Schiff staining, and/or contained red blood cells. Vasculogenic mimicry was assessed in 92 clinical samples of prostate cancer and analyzed in more detail in three prostate cancer cell lines kept in three-dimensional culture. Tissue samples and cell lines were also assessed for total and phosphorylated levels of EphA2 and its potential regulator, Phosphoinositide 3-Kinase (PI3K). In addition, the role of EphA2 in vasculogenic mimicry and in cell migration and invasion were investigated by manipulating the levels of EphA2 through specific siRNAs. Furthermore, the role of PI3K in vasculogenic mimicry and in regulating EphA2 was tested by application of an inhibitor, LY294002. RESULTS: Immunohistochemistry of prostate cancers showed a significant correlation between vasculogenic mimicry and high expression levels of EphA2, high Gleason scores, advanced TNM stage, and the presence of lymph node and distant metastases. Likewise, two prostate cancer cell lines (PC3 and DU-145) formed vasculogenic networks on Matrigel and expressed high EphA2 levels, while one line (LNCaP) showed no vasculogenic networks and lower EphA2 levels. Specific silencing of EphA2 in PC3 and DU-145 cells decreased vasculogenic mimicry as well as cell migration and invasion. Furthermore, high expression levels of PI3K and EphA2 phosphorylation at Ser897 significantly correlated with the presence of vasculogenic mimicry and in vitro inhibition of PI3K by LY294002 disrupted vasculogenic mimicry, potentially through a reduction of EphA2 phosphorylation at Ser897. CONCLUSIONS: The expression levels of PI3K and EphA2 are positively correlated with vasculogenic mimicry both in vivo and in vitro. Moreover, phosphorylation levels of EphA2 regulated by PI3K are also significantly associated with vasculogenic mimicry in vivo. Based on its functional implication in vasculogenic mimicry in vitro, EphA2 signaling may be a potential therapeutic target in advanced prostate cancer.

Viral hepatitis is a major public health concern in China, but data on national epidemiological characteristics are lacking. We collected reporting incidence data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in China from 2004 to 2014. Empirical mode decomposition (EMD) was performed to accurately describe the reporting incidence trends of HBV and HCV. A mathematical model was used to estimate the relative change in incidence across provinces and age groups. Nationwide, a total of 916 426 hepatitis B cases and 39 381 hepatitis C cases were recorded in 2004; the reporting incidences of HBV and HCV were 70.50/100 000 and 3.03/100 000, respectively. The overall relative changes in HBV and HCV reporting incidences in China from 2004 to 2014 were 0.98 (95% CI 0.96-1.00, P = .082) and 1.16 (95% CI 1.12-1.20, P < .001), respectively. Thirteen provinces experienced decline in HBV reporting incidence. Most provinces exhibited an increasing trend in HCV reporting incidence. People aged ≤24 displayed a significant descending trend in HBV reporting incidence; people aged ≥55 exhibited a significant increasing trend. For HCV infection, the reporting incidence increased in all age groups except the 10-14 age group. In China, the majority of provinces have experienced decline or remained stable in HBV infection but show significant increases in HCV infection. Children and adolescents are well protected from HBV infection, while relatively higher increasing rates are found among older people. HCV is much more prevalent among older people, although its emergence has shifted to younger age groups.

UNLABELLED: To evaluate the accuracy of intraocular lens (IOL) power calculation methods after laser refractive surgery in myopic eyes, a comprehensive literature search was carried out for retrospective case series studies with data on post-myopic laser surgery IOL power calculations published from January 2000 to May 2014. A metaanalysis of the 9 identified studies was performed using odds ratios in percentage of prediction error within ±0.5 or 1.0 diopter (D) of the target refraction. Compared with the Haigis-L method, the clinical history method, corneal bypass method, and Feiz-Mannis method were associated with lower odds of predication; the Masket method showed higher odds. The subgroup data showed significantly better performance of the Shammas no-history method with the Shammas post-LASIK formula than the Haigis-L method in predication error. The Masket method and the Shammas no-history method with the Shammas post-LASIK formula without historical data had more prediction accuracy than the Haigis-L method. The clinical history method, Feiz-Mannis method, and corneal bypass method, which required historical data, were less accurate in their predictions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.