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CIP2A, cancerous inhibitor of protein phosphatase 2A, was initially recognized as an oncoprotein. Recently several studies revealed that CIP2A could function as a prognosis biomarker, however, the result remained not comprehensive, partly due to small number of patients included individually. Here we carried out a meta-analysis of published studies to assess the prognostic significance of CIP2A in solid tumors. All eligible studies were identified through searching PubMed, Embase and Web of Science database. In this meta-analysis, 22 studies involving 4,579 participants were included, and we verified that CIP2A over-expression was significantly related with poor overall survival (pooled HR = 1.844, 95% CI = 1.528–2.225, P<0.001) and short disease free survival (pooled HR = 1.808, 95% CI = 1.591–2.055, P<0.001) in solid tumors. Additionally, subgroup analysis suggested that the trend of a poor overall survival with an increased CIP2A expression was present in East-Asian and European patients, as well as in lung cancer and colorectal cancer. To sum up, CIP2A over-expression was associated with poor survival in human solid tumors and might be a predictive factor of poor prognosis. [ABSTRACT FROM AUTHOR]

Background: The 5-year survival rate of cancer patients is the most commonly used statistic to reflect improvements in the war against cancer. This idea, however, was refuted based on an analysis showing that changes in 5-year survival over time bear no relationship with changes in cancer mortality. Methods: Here we show that progress in the fight against cancer can be evaluated by analyzing the association between 5-year survival rates and mortality rates normalized by the incidence (mortality over incidence, MOI). Changes in mortality rates are caused by improved clinical management as well as changing incidence rates, and since the latter can mask the effects of the former, it can also mask the correlation between survival and mortality rates. However, MOI is a more robust quantity and reflects improvements in cancer outcomes by overcoming the masking effect of changing incidence rates. Using population-based statistics for the US and the European Nordic countries, we determined the association of changes in 5-year survival rates and MOI. Results: We observed a strong correlation between changes in 5-year survival rates of cancer patients and changes in the MOI for all the countries tested. This finding demonstrates that there is no reason to assume that the improvements in 5-year survival rates are artificial. We obtained consistent results when examining the subset of cancer types whose incidence did not increase, suggesting that over-diagnosis does not obscure the results. Conclusions: We have demonstrated, via the negative correlation between changes in 5-year survival rates and changes in MOI, that increases in 5-year survival rates reflect real improvements over time made in the clinical management of cancer. Furthermore, we found that increases in 5-year survival rates are not predominantly artificial byproducts of lead-time bias, as implied in the literature. The survival measure alone can therefore be used for a rough approximation of the amount of progress in the clinical management of cancer, but should ideally be used with other measures. [ABSTRACT FROM AUTHOR]

Background: Plasma kisspeptin levels dramatically increased during the first trimester of human pregnancy, which is similar to pregnancy specific glycoprotein-human chorionic gonadotropin. However, its particular role in the implantation and decidualization has not been fully unraveled. Here, the study was conducted to investigate the expression and function of kisspeptin in mouse uterus during early pregnancy and decidualization. Methodology/Principal Findings: Quantitative PCR results demonstrated that Kiss1 and GPR54 mRNA levels showed dynamic increase in the mouse uterus during early pregnancy and artificially induced decidualization in vivo. KISS-1 and GPR54 proteins were spatiotemporally expressed in decidualizing stromal cells in intact pregnant females, as well as in pseudopregnant mice undergoing artificially induced decidualization. In the ovariectomized mouse uterus, the expression of Kiss1 mRNA was upregulated after progesterone or/and estradiol treatment. Moreover, in a stromal cell culture model, the expression of Kiss1 and GPR54 mRNA gradually rise with the progression of stromal cell decidualization, whereas the attenuated expression of Kiss1 using small interfering RNA approaches significantly blocked the progression of stromal cell decidualization. Conclusion: our results demonstrated that Kiss1/GPR54 system was involved in promoting uterine decidualization during early pregnancy in mice. [ABSTRACT FROM AUTHOR]

Recent experiments showed that engineered Escherichia coli colonies grow and self-organize into periodic stripes with high and low cell densities in semi-solid agar. The stripes develop sequentially behind a radially propagating colony front, similar to the formation of many other periodic patterns in nature. These bacteria were created by genetically coupling the intracellular chemotaxis pathway of wild-type cells with a quorum sensing module through the protein CheZ. In this paper, we develop multiscale models to investigate how this intracellular pathway affects stripe formation. We first develop a detailed hybrid model that treats each cell as an individual particle and incorporates intracellular signaling via an internal ODE system. To overcome the computational cost of the hybrid model caused by the large number of cells involved, we next derive a mean-field PDE model from the hybrid model using asymptotic analysis. We show that this analysis is justified by the tight agreement between the PDE model and the hybrid model in 1D simulations. Numerical simulations of the PDE model in 2D with radial symmetry agree with experimental data semi-quantitatively. Finally, we use the PDE model to make a number of testable predictions on how the stripe patterns depend on cell-level parameters, including cell speed, cell doubling time and the turnover rate of intracellular CheZ. [ABSTRACT FROM AUTHOR]

Complement factor H (CFH) is one of the most important soluble complement regulatory proteins and is closely associated with age-related macular degeneration (AMD), the leading cause of irreversible central vision loss in the elderly population in developed countries. Our study searches to investigate whether CFH expression is changed in oxidative damaged retinal pigment epithelium (RPE) cells and the role of CFH in the in vitro neovascularization. First, it was confirmed by immunofluorescence staining that CFH was expressed by ARPE-19 cells. CFH mRNA and protein in oxidative (H2O2) damaged ARPE-19 cells were both reduced, as determined by Real-time PCR and Western blotting analysis. Enzyme-linked immunosorbent assay (ELISA) also showed that ARPE-19 cells treated with H2O2 caused an increase in C3a content, which indicates complement activation. Then, wound assays were performed to show that CFH expression suppression promoted human umbilical vein endothelial cell (HUVECs) migration. Thereafter, ARPE-19 cells were transfected with CFH-specific siRNA and CFH knockdown was confirmed with the aid of Real-time PCR, immunofluorescence staining and Western blotting. The ELISA results showed that specific CFH knockdown in ARPE-19 cells activated the complement system. Finally, in vitro matrigel tube formation assay was performed to determine whether change of CFH expression in RPE would affect tube formation by HUVECs. More tubes were formed by HUVECs co-cultured with ARPE-19 cells transfected with CFH specific-siRNA when compared with controls. Our results suggested that RPE cells might be the local CFH source, and RPE cell injuries (such as oxidative stress) may cause CFH expression suppression, which in turn may lead to complement activation and promotion of tube formation by HUVECs. This finding is of importance in elucidating the role of complement in the pathogenesis of ocular neovascularization including choroidal neovascularization. [ABSTRACT FROM AUTHOR]

Positive Transcription Elongation Factor b (P-TEFb) is a kinase consisting of Cdk9 and Cyclin T that releases RNA Polymerase II (Pol II) into active elongation. It can assemble into a larger Super Elongation Complex (SEC) consisting of additional elongation factors. Here, we use a miRNA-based approach to knock down the maternal contribution of P-TEFb and SEC components in early Drosophila embryos. P-TEFb or SEC depletion results in loss of cells from the embryo posterior and in cellularization defects. Interestingly, the expression of many patterning genes containing promoter-proximal paused Pol II is relatively normal in P-TEFb embryos. Instead, P-TEFb and SEC are required for expression of some non-paused, rapidly transcribed genes in pre-cellular embryos, including the cellularization gene Serendipity-α. We also demonstrate that another P-TEFb regulated gene, terminus, has an essential function in embryo development. Similar morphological and gene expression phenotypes were observed upon knock down of Mediator subunits, providing in vivo evidence that P-TEFb, the SEC and Mediator collaborate in transcription control. Surprisingly, P-TEFb depletion does not affect the ratio of Pol II at the promoter versus the 3’ end, despite affecting global Pol II Ser2 phosphorylation levels. Instead, Pol II occupancy is reduced at P-TEFb down-regulated genes. We conclude that a subset of non-paused, pre-cellular genes are among the most susceptible to reduced P-TEFb, SEC and Mediator levels in Drosophila embryos. [ABSTRACT FROM AUTHOR]

The latent membrane protein 1 (LMP1), which is encoded by the Epstein-Barr virus (EBV), is an important oncogenic protein that is closely related to carcinogenesis and metastasis of nasopharyngeal carcinoma (NPC), a prevalent cancer in China. We previously reported that the expression of the functional chemokine receptor CXCR4 is associated with human NPC metastasis. In this study, we show that LMP1 induces tyrosine sulfation of CXCR4 through tyrosylprotein sulfotransferase-1 (TPST-1), an enzyme that is responsible for catalysis of tyrosine sulfation in vivo, which is likely to contribute to the highly metastatic character of NPC. LMP1 could induce tyrosine sulfation of CXCR4 and its associated cell motility and invasiveness in a NPC cell culture model. In contrast, the expression of TPST-1 small interfering RNA reversed LMP1-induced tyrosine sulfation of CXCR4. LMP1 conveys signals through the epidermal growth factor receptor (EGFR) pathway, and EGFR-targeted siRNA inhibited the induction of TPST-1 by LMP1. We used a ChIP assay to show that EGFR could bind to the TPST-1 promoter in vivo under the control of LMP1. A reporter gene assay indicated that the activity of the TPST-1 promoter could be suppressed by deleting the binding site between EGFR and TPST-1. Finally, in human NPC tissues, the expression of TPST-1 and LMP1 was directly correlated and clinically, the expression of TPST-1 was associated with metastasis. These results suggest the up-regulation of TPST-1 and tyrosine sulfation of CXCR4 by LMP1 might be a potential mechanism contributing to NPC metastasis. [ABSTRACT FROM AUTHOR]

Myocardial perfusion abnormalities are the first sign of the ischemic cascade in the development of coronary artery disease (CAD). Thus, the early detection of myocardial perfusion abnormalities is significant for the prevention of CAD. Recently, a novel noninvasive method named Cardiodynamicsgram (CDG) has been proposed for early detection of CAD. This study aims to evaluate the predictive value of CDG in myocardial perfusion abnormalities for suspected ischemic heart disease. In the study, 86 suspected patients were enrolled. Standard 12-lead ECG and CDG were performed simultaneously before single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Diagnostic accuracy of CDG for myocardial perfusion abnormalities detection is assessed using SPECT MPI as the reference standard. Of these 86 suspected patients, 37 patients were positive in CDG, 49 patients were negative in CDG. Diagnostic accuracy of CDG at presentation for myocardial perfusion abnormalities was 84.9%, sensitivity 84.0%, and specificity 89.4%. Furthermore, of the 10 patients whose SPECT MPI results are reverse redistribution, 9 patients were positive in CDG. Underlying causes of false positive CDG findings included the factors that can change the stability of cardiac electrical conduction and measurement noise. Myocardial remodeling in patients with old myocardial infarction might be the major cause of false negative findings. Results show a good consistency between the CDG and SPECT MPI in evaluating myocardial perfusion abnormalities. It suggests that CDG might be used as a cost-effective tool for assessing the myocardial perfusion abnormalities in the clinic. [ABSTRACT FROM AUTHOR]

Understanding the cellular-molecular substrates of heart disease is key to the development of cardiac specific therapies and to the prevention of off-target effects by non-cardiac targeted drugs. One of the primary targets for therapeutic intervention has been the human ether a go-go (hERG) K+ channel that, together with the KCNQ channel, controls the rate and efficiency of repolarization in human myocardial cells. Neither of these channels plays a major role in adult mouse heart function; however, we show here that the hERG homolog seizure (sei), along with KCNQ, both contribute significantly to adult heart function as they do in humans. In Drosophila, mutations in or cardiac knockdown of sei channels cause arrhythmias that become progressively more severe with age. Intracellular recordings of semi-intact heart preparations revealed that these perturbations also cause electrical remodeling that is reminiscent of the early afterdepolarizations seen in human myocardial cells defective in these channels. In contrast to KCNQ, however, mutations in sei also cause extensive structural remodeling of the myofibrillar organization, which suggests that hERG channel function has a novel link to sarcomeric and myofibrillar integrity. We conclude that deficiency of ion channels with similar electrical functions in cardiomyocytes can lead to different types or extents of electrical and/or structural remodeling impacting cardiac output. [ABSTRACT FROM AUTHOR]

Eimeria tenella is an obligate intracellular parasite that actively invades cecal epithelial cells of chickens. The basis of cell invasion is not completely understood, but some key molecules of host cell invasion have been discovered. This paper investigated the characteristics of calcium-dependent protein kinase 4 (EtCDPK4), a critical molecule in E. tenella invasion of host cells. A full-length EtCDPK4 cDNA was identified from E. tenella using rapid amplification of cDNA ends. EtCDPK4 had an open reading frame of 1803 bp encoding a protein of 600 amino acids. Quantitative real-time PCR and western blotting were used to explore differences in EtCDPK4 transcription and translation in four developmental stages of E. tenella. EtCDPK4 was expressed at higher levels in sporozoites, but translation was higher in second-generation merozoites. In vitro invasion inhibition assays explored whether EtCDPK4 was involved in invasion of DF-1 cells by E. tenella sporozoites. Polyclonal antibodies against recombinant EtCDPK4 (rEtCDPK4) inhibited parasite invasion, decreasing it by approximately 52%. Indirect immunofluorescence assays explored EtCDPK4 distribution during parasite development after E. tenella sporozoite invasion of DF-1 cells in vitro. The results showed that EtCDPK4 might be important in sporozoite invasion and development. To analyze EtCDPK4 functional domains according to the structural characteristics of EtCDPK4 and study the kinase activity of rEtCDPK4, an in vitro phosphorylation system was established. We verified that rEtCDPK4 was a protein kinase that was completely dependent on Ca2+ for enzyme activity. Specific inhibitors of rEtCDPK4 activity were screened by kinase activity in vitro. Some specific inhibitors were applied to assays of DF-1 cell invasion by E. tenella sporozoites to confirm that the inhibitors functioned in vitro. W-7, H-7, H-89, and myristoylated peptide inhibited DF-1 invasion by E. tenella sporozoites. The experimental results showed that EtCDPK4 may be involved in E. tenella invasion of chicken cecal epithelial cells. [ABSTRACT FROM AUTHOR]

In this study, we investigated the impact of Nardosinone, a bioactive component in Nardostachys root, on the proliferation and differentiation of neural stem cells. The neural stem cells were isolated from cerebrums of embryonic day 14 CD1 mice. The proliferation of cells was monitored using the cell counting kit-8 assay, bromodeoxyuridine incorporation and cell cycle analysis. Cell migration and differentiation were investigated with the neurosphere assay and cell specific markers, respectively. The results showed that Nardosinone promotes cells proliferation and increases cells migration distance in a dose-dependent manner. Nardosinone also induces the selective differentiation of neural stem cells to neurons and oligodendrocytes, as indicated by the expression of microtubule-associated protein-2 and myelin basic protein, respectively. Nardosinone also increases the expression of phospho-extracellular signal-regulated kinase and phospho-cAMP response element binding protein during proliferation and differentiation. In conclusion, this study reveals the regulatory effects of Nardosinone on neural stem cells, which may have significant implications for the treatment of brain injury and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background and Objective: S100A8 and S100A9, two members of the S100 protein family, have been reported in association with the tumor cell differentiation and tumor progression. Previous study has showed that their expression in stromal cells of colorectal carcinoma (CRC) is associated with tumor size. Here, we investigated the clinical significances of S100A8 and S100A9 in tumor cells of CRC and their underlying molecular mechanisms. Methods: Expression of S100A8 and S100A9 in colorectal carcinoma and matching distal normal tissues were measured by reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. CRC cell lines treated with the recombinant S100A8 and S100A9 proteins were used to analyze the roles and molecular mechanisms of the two proteins in CRC in vitro. Results: S100A8 and S100A9 were elevated in more than 50% of CRC tissues and their expression in tumor cells was associated with differentiation, Dukes stage and lymph node metastasis. The CRC cell lines treatment with recombinant S100A8 and S100A9 proteins promoted the viability and migration of CRC cells. Furthermore, the two recombinant proteins also resulted in the increased levels of β-catenin and its target genes c-myc and MMP7. β-catenin over-expression in CRC cells by Adβ-catenin increased cell viability and migration. β-catenin knock-down by Adsiβ-catenin reduced cell viability and migration. Furthermore, β-catenin knockdown also partially abolished the promotive effects of recombinant S100A8 and S100A9 proteins on the viability and migration of CRC cells. Conclusions: Our work demonstrated that S100A8 and S100A9 are linked to the CRC progression, and one of the underlying molecular mechanisms is that extracellular S100A8 and S100A9 proteins contribute to colorectal carcinoma cell survival and migration via Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Background: The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and allows the modulation of cancer growth, invasion and angiogenesis. To date, studies investigated the association between a functional polymorphism in PAI-1 (4G/5G) and risk of cancer have shown inclusive results. Methods: A meta-analysis based on 25 case-control studies was performed to address this issue. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with I2 test. Results: Overall, a significant increased risk of cancer was associated with the PAI-1 4G/4G polymorphism for the allele contrast (4G vs. 5G: OR = 1.10, CI = 1.03–1.18, I2 = 49.5%), the additive genetic model (4G/4G vs. 5G/5G: OR = 1.21, CI = 1.06–1.39, I2 = 51.9%), the recessive genetic model (4G/4G vs. 4G/5G+5G/5G: OR = 1.11, CI = 1.04–1.18, I2 = 20.8%). In the subgroup analysis by ethnicity, the results indicated that individuals with 4G/4G genotype had a significantly higher cancer risk among Caucasians (4G/4G vs. 5G/5G: OR = 1.31, 95%CI = 1.09–1.59, I2 = 59.6%; 4G/4G vs. 4G/5G: OR = 1.12, 95%CI = 1.04–1.21, I2 = 3.6%; recessive model: OR = 1.12, 95%CI = 1.05–1.21, I2 = 25.3%). Conclusions: The results of the present meta-analysis support an association between the PAI-1 4G/5G polymorphism and increasing cancer risk, especially among Caucasians, and those with 4G allele have a high risk to develop colorectal cancer and endometrial cancer. [ABSTRACT FROM AUTHOR]