DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ER alpha-positive breast cancer cells

Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ER alpha) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ER alpha and as a strong and independent prognostic marker in ESR1 (ER alpha gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells

Monitoring the level of government trust, risk perception and intention of the general public to adopt protective measures during the influenza A (H1N1) pandemic in the Netherlands

<p>Abstract</p> <p>Background</p> <p>During the course of an influenza pandemic, governments know relatively little about the possibly changing influence of government trust, risk perception, and receipt of information on the public's intention to adopt protective measures or on the acceptance of vaccination. This study aims to identify and describe possible changes in and factors associated with public's intentions during the 2009 influenza A (H1N1) pandemic in the Netherlands.</p> <p>Methods</p> <p>Sixteen cross-sectional telephone surveys were conducted (N = 8060) between April - November 2009. From these repeated measurements three consecutive periods were categorized based on crucial events during the influenza A (H1N1) pandemic. Time trends in government trust, risk perception, intention to adopt protective measures, and the acceptance of vaccination were analysed. Factors associated with an intention to adopt protective measures or vaccination were identified.</p> <p>Results</p> <p>Trust in the government was high, but decreased over time. During the course of the pandemic, perceived vulnerability and an intention to adopt protective measures increased. Trust and vulnerability were associated with an intention to adopt protective measures in general only during period one. Higher levels of intention to receive vaccination were associated with increased government trust, fear/worry, and perceived vulnerability. In periods two and three receipt of information was positively associated with an intention to adopt protective measures. Most respondents wanted to receive information about infection prevention from municipal health services, health care providers, and the media.</p> <p>Conclusions</p> <p>The Dutch response to the H1N1 virus was relatively muted. Higher levels of trust in the government, fear/worry, and perceived vulnerability were all positively related to an intention to accept vaccination. Only fear/worry was positively linked to an intention to adopt protective measures during the entire pandemic. Risk and crisis communication by the government should focus on building and maintaining trust by providing information about preventing infection in close collaboration with municipal health services, health care providers, and the media.</p

A speciation gene for left–right reversal in snails results in anti-predator adaptation

How speciation genes can spread in a population is poorly understood. In land snails, a single gene for left–right reversal could be responsible for instant speciation, because dextral and sinistral snails have difficulty in mating. However, the traditional two-locus speciation model predicts that a mating disadvantage for the reversal should counteract this speciation. In this study, we show that specialized snake predation of the dextral majority drives prey speciation by reversal. Our experiments demonstrate that sinistral Satsuma snails (Stylommatophora: Camaenidae) survive predation by Pareas iwasakii (Colubroidea: Pareatidae). Worldwide biogeography reveals that stylommatophoran snail speciation by reversal has been accelerated in the range of pareatid snakes, especially in snails that gain stronger anti-snake defense and reproductive isolation from dextrals by sinistrality. Molecular phylogeny of Satsuma snails further provides intriguing evidence of repetitive speciation under snake predation. Our study demonstrates that a speciation gene can be fixed in populations by positive pleiotropic effects on survival

Super Resolution Microscopy Reveals that Caveolin-1 Is Required for Spatial Organization of CRFB1 and Subsequent Antiviral Signaling in Zebrafish

10.1371/journal.pone.0068759PLoS ONE87-POLN

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

In vitro evaluation of leukemia inhibitory factor receptor antagonists as candidate therapeutics for inflammatory arthritis

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are found in appreciable concentrations in synovial fluid from patients with rheumatoid arthritis (RA) but not osteoarthritis. Accordingly, both are potential therapeutic targets in inflammatory diseases of the joints. Several LIF antagonists have been developed. They have the capacity to inhibit the biologic activities of not only LIF but also other interleukin-6 (IL-6) subfamily cytokines, including OSM. Both LIF and OSM share the same receptor, which is part of a cytokine receptor super family in which the glycoprotein 130 (gp130) subunit is a common constituent. The aim of this study was to evaluate the antagonistic potentials of two LIF mutants, LIF05 and MH35-BD. Both are mutant forms of human LIF with reduced affinity for gp130 and greater LIF receptor (LIFE) binding affinity. The results, using Ba/F3 cell proliferation assay, acute-phase protein (haptoglobin) induction analysis in HepG2 human hepatoma cells, a porcine cartilage glycosantinoglycan release assessment for proteoglycan degradation, and a collagen release assay, show that these antagonists inhibit relevant LIF, OSM, and other IL-6 subfamily cytokines in vitro albeit with differential potencies and have, therefore, therapeutic potential for treatment of RA and perhaps other diseases. © Mary Ann Liebert, Inc

Generation of mutant leukaemia inhibitory factor (LIF)-IgG heavy chain fusion proteins as bivalent antagonists of LIF

Two leukaemia inhibitory factor (LIF) mutants, designated MH35-BD and LIF05, have been shown to have a capacity to inhibit the biological activities of not only human LIF (hLIF) but also other interleukin-6 (IL-6) subfamily cytokines such as human oncostatin M (hOSM). These cytokines share the same receptor complex in which the glycoprotein 130 (gp130) subunit is a common constituent. However, at low concentrations and in their monomeric forms, such molecules have a relatively short plasma half-life due to rapid clearance from the kidneys. Here, to prolong their serum half-lives, we have used a multi-step polymerase chain reaction (PCR) to fuse each of the LIF05 and MH35-BD cDNA fragments to a sequence encoding the Fc portion, and the hinge region, of the human immunoglobulin G (hIgG) heavy chain. The linking was achieved through an oligomer encoding a thrombin-sensitive peptide linker thus generating MH35-BD:Fc and LIF05:Fc, respectively. Both Fc fusion constructs were expressed in insect cell Sf21 and the proteins were purified by two successive affinity chromatography steps using nickel-nitrilotriacetic acid (Ni-NTA) agarose and protein A beads. The Ba/F3 cell-based proliferation assay was used to confirm that the proteins were biologically active. In addition, preliminary pharmacokinetics indicates that the Fc fusion constructs have a longer serum half-life compared to their non-fusion counterparts. © 2007 Elsevier B.V. All rights reserved