The co-inhibitory molecule PD-1 modulates disease severity in a model for an inherited, demyelinating neuropathy.

We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule "programmed death" (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phenotype of CD8+ T-lymphocytes in the P0 myelin mutants. PD-1 deficiency in P0+/- mice leads to a stronger increase of CD8+ T-lymphocytes and a substantially aggravated histological phenotype in the PNS compared to P0+/- mice expressing PD-1.

Transient widespread blood-brain barrier alterations after cerebral photothrombosis as revealed by gadofluorine M-enhanced magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use of the novel MRI contrast agent gadofluorine M (Gf) we report on imaging of transient and widespread changes of blood-brain barrier (BBB) properties as a consequence of focal photothrombotic brain lesions in rats. After i.

Hepatocyte growth factor enhances proteolysis and invasiveness of human nasopharyngeal cancer cells through activation of PI3K and JNK.

The hepatocyte growth factor (HGF) receptor, Met, is frequently overexpressed in nasopharyngeal cancer (NPC). Here, we showed for the first time that human NPC cells with high Met expression were more sensitive to the cell motility and invasion effect of HGF. The downregulation of Met by small interfering RNA decreased tumor cell invasion/migration.

Increased number of microglia in the brain of severe combined immunodeficient (SCID) mice.

To assess the in vivo influence of the systemic immune system upon microglia, six defined brain regions of adult SCID mice (n = 10) lacking functional T- and B-lymphocytes have been analyzed by NDPase histochemistry, morphometry and immunohistochemistry. Despite absence of neuropathology and lack of microglial activation, microglial numerical density was significantly increased in SCID mice. Elevation was most marked in the cerebellar granular layer (by 32.

Origin of CD11b+ macrophage-like cells in the CNS of PLP-overexpressing mice: low influx of haematogenous macrophages and unchanged blood-brain-barrier in the optic nerve.

We have recently reported that overexpression of proteolipid protein in oligodendrocytes leads to a pathologically relevant increase of both CD8+ T-lymphocytes and CD11b+ cells in the CNS. We now focussed on the origin of the CD11b+ cells in the optic nerve, a well established structure for the analysis of the mutant, using bone marrow chimeric mice. Although there is an age-related increase in CD11b+ cells in the myelinated part of the optic nerve of the mutants, the percentage of infiltrating cells was not increased, but enhanced proliferation was detectable.

Microarray Data Mining for Potential Selenium Targets in Chemoprevention of Prostate Cancer.

BACKGROUND: A previous clinical trial showed that selenium supplementation significantly reduced the incidence of prostate cancer. We report here a bioinformatics approach to gain new insights into selenium molecular targets that might be relevant to prostate cancer chemoprevention. MATERIALS AND METHODS: We first performed data mining analysis to identify genes which are consistently dysregulated in prostate cancer using published datasets from gene expression profiling of clinical prostate specimens.

Epigenetic and HIF-1 regulation of stanniocalcin-2 expression in human cancer cells.

Mammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells).

Monocyte chemoattractant protein-1 is a pathogenic component in a model for a hereditary peripheral neuropathy.

Macrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factors link the Schwann cell-based myelin mutation to the activation of endoneurial macrophages. Here we identified the chemokine monocyte chemoattractant protein-1 (MCP-1) as a first and crucial factor upregulated in Schwann cells of mice heterozygously deficient for the myelin protein zero.

The spatial and temporal distribution of heavy metals in sediments of Victoria Harbour, Hong Kong.

Victoria Harbour has received substantial loadings of pollutants from industrial and municipal wastewater discharged since the 1950s. Inputs of contaminants have declined dramatically during the last two decades as a result of better controls at the source and improved wastewater treatment facilities. To assess the spatial and temporal changes of metal contaminants in sediments in Victoria Harbour, core and grab sediments were collected.

Apoptosis induced by t10,c12-conjugated linoleic acid is mediated by an atypical endoplasmic reticulum stress response.

Conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis, in part by inducing apoptosis of preneoplastic and neoplastic mammary epithelial cells. The current study focused on the mechanism by which apoptosis is induced. In TM4t mammary tumor cells, trans-10,cis-12 (t10,c12)-CLA induced proapoptotic C/EBP-homologous protein (CHOP) concurrent with the cleavage of poly(ADP-ribose) polymerase.

The two-pore domain potassium channel TASK3 functionally impacts glioma cell death.

Two-pore domain K(+) channels, a recently discovered family of ion channels with a unique membrane topology, have been shown to be critically involved in cell death. We here address the functional role of TASK3 (TWIK-related acid-sensitive K(+) channel, KCNK9) in human glioblastoma in vitro and in vivo. Human glioma cell lines (n = 5) as well as glioma specimens (n = 5) constitutively express TASK3 mRNA and protein.

Doxorubicin and selenium cooperatively induce fas signaling in the absence of Fas/Fas ligand interaction.

Background: The synergistic effect of doxorubicin and selenium in apoptosis induction in MCF-7 breast cancer cells has been previously reported. Mitochondrial activation of caspase-9 is in part responsible for the synergy. The present study aimed at examining the death receptor pathway in activating caspase-8 by the two-drug combination.

Peroxiredoxin 1 interacts with androgen receptor and enhances its transactivation.

Although hypoxia is accepted as an important microenvironmental factor influencing tumor progression and treatment response, it is usually regarded as a static global phenomenon. Consequently, less attention is given to the impact of dynamic changes in tumor oxygenation in regulating the behavior of cancer cells. Androgen receptor (AR) signaling plays a critical role in prostate cancer.

Clonal expansions of pathogenic CD8+ effector cells in the CNS of myelin mutant mice.

Tissue damage in the CNS is critically influenced by the adaptive immune system. Primary oligodendrocyte damage (by overexpression of PLP) leads to low-grade inflammation of high pathological impact, which is mediated by CD8+ T cells. To yield further insight into pathogenesis and nature of immune responses in myelin mutated mice, we here apply a detailed immunological characterization of CD8+ T cells in PLP-transgenic and aged wild type mice.

Evaluation of a peer counselling programme to sustain breastfeeding practice in Hong Kong.

Background: Peer counselling is reported to increase breastfeeding rates. We evaluated an intervention consisting of mainly telephone contact peer counselling programme on breastfeeding duration and exclusivity.

Methods: Peer counsellors (PCs) were mothers who had successfully breastfed and had received formal training.

Hormonal implications in the development and treatment of prostate cancer.

In this article, the conflicting data concerning the androgen axis and prostate cancer development are reviewed in addition to how this pathway may be exploited to prevent the development of prostate cancer. The expanding role of hormone ablative therapy alone or in conjunction with standard therapies, the controversies of timing of therapy, and the completeness of ablation and its use on an intermittent basis are reviewed.

Human peroxiredoxin 1 and 2 are not duplicate proteins: the unique presence of CYS83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2.

Human peroxiredoxins 1 and 2, also known as Prx1 and Prx2, are more than 90% homologous in their amino acid sequences. Prx1 and Prx2 are elevated in various cancers and are shown to influence diverse cellular processes. Although their growth regulatory role has traditionally been attributed to the peroxidase activity, the physiological significance of this function is unclear because the proteins are highly susceptible to inactivation by H(2)O(2).

Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss.

Conjugated linoleic acid (CLA) is a powerful anticancer agent in a number of tumor model systems; however, its precise mechanism of action remains elusive. Here, we report that t10,c12 CLA, a component of synthetic CLA supplements, induced apoptosis and G1 arrest of p53 mutant TM4t murine mammary tumor cells. Furthermore, t10,c12-CLA induced a time- and concentration-dependent cleavage of caspases-3 and -9, and release of cytochrome c from mitochondria to cytosol.

Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates.

Doxorubicin is an effective drug against breast cancer. However, the favorable therapeutic response to doxorubicin is often associated with severe toxicity. The present research was aimed at developing a strategy of increasing doxorubicin sensitivity so that lower doses may be used without compromising efficacy.

The t10,c12 isomer of conjugated linoleic acid stimulates mammary tumorigenesis in transgenic mice over-expressing erbB2 in the mammary epithelium.

Conjugated linoleic acid (CLA), a family of isomers of octadecadienoic acid, inhibits rat mammary carcinogenesis, angiogenesis, and lung metastasis from a transplantable mammary tumor. c9,t11-CLA, the predominant isomer in dairy products, and t10,c12-CLA, a component of CLA supplements, are equally effective. The objective of the current studies was to test the efficacy of these two CLA isomers in a clinically relevant breast cancer model.

Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology.

Peroxiredoxin 1 (Prx1) has been found to be elevated in several human cancers. The cell survival-enhancing function of Prx1 is traditionally attributed to its reactive oxygen species-removing capacity, although the growth-promoting role of Prx1 independent of this antioxidant activity is increasingly gaining attention. Although much progress has been made in understanding the behavior of Prx1, little information is available on the mechanism responsible for the abnormal elevation of Prx1 level in cancer.

Antigen therapy of experimental autoimmune encephalomyelitis selectively induces apoptosis of pathogenic T cells.

Administration of high-dose myelin antigen induces massive T cell apoptosis in experimental autoimmune encephalomyelitis (EAE) but the nature of the target cells remains elusive. Here we have used a cell line established in eGFP-transgenic Lewis rats to distinguish between pathogenic and bystander T cells in adoptive transfer EAE. Intravenous application of gpMBP strongly reduced the amount of encephalitogenic cells in spinal cord and spleen while the number of the other T cells remained constant.

High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis.

Radiation pneumonitis is an unpredictable complication of radiotherapy for lung cancer and a condition which can cause significant morbidity. The ability to identify patients at a high risk of developing pneumonitis is critical, since it will enable the individualization of the treatment plan. Because the cytotoxic effect of radiation is propagated through reactive oxygen species (ROS) and ROS-driven oxidative stress, the role of antioxidant defense systems in radiation pneumonitis was investigated.

Characterization of ANIT-induced toxicity using precision-cut rat and dog liver slices cultured in a dynamic organ roller system.

This article describes the toxicity of alpha-naphthylisothiocyanate (ANIT), a compound known to induce dose-dependent hepatobiliary toxicity in vivo, using the slice model. Liver slices (200 microm thick) from male Sprague-Dawley rats and male beagle dogs were cultured for 7 days while exposed to a range of ANIT concentrations (1- 100 microM for rat and 4-320 microM for dog). Tissues (and medium for dog) were evaluated using a panel of clinically relevant biomarkers for liver and histological endpoints to assess viability and proliferation.