Endothelial cell-derived interleukin-6 regulates tumor growth

Abstract Background Endothelial cells play a complex role in the pathobiology of cancer. This role is not limited to the making of blood vessels to allow for influx of oxygen and nutrients required for the high metabolic demands of tumor cells. Indeed, it has been recently shown that tumor-associated endothelial cells secrete molecules that enhance tumor cell survival and cancer stem cell self-renewal. The hypothesis underlying this work is that specific disruption of endothelial cell-initiated signaling inhibits tumor growth. Methods Conditioned medium from primary human dermal microvascular endothelial cells (HDMEC) stably transduced with silencing RNA for IL-6 (or controls) was used to evaluate the role of endothelial-derived IL-6 on the activation of key signaling pathways in tumor cells. In addition, these endothelial cells were co-transplanted with tumor cells into immunodefficient mice to determine the impact of endothelial cell-derived IL-6 on tumor growth and angiogenesis. Results We observed that tumor cells adjacent to blood vessels show strong phosphorylation of STAT3, a key mediator of tumor progression. In search for a possible mechanism for the activation of the STAT3 signaling pathway, we observed that silencing interleukin (IL)-6 in tumor-associated endothelial cells inhibited STAT3 phosphorylation in tumor cells. Notably, tumors vascularized with IL-6-silenced endothelial cells showed lower intratumoral microvessel density, lower tumor cell proliferation, and slower growth than tumors vascularized with control endothelial cells. Conclusions Collectively, these results demonstrate that IL-6 secreted by endothelial cells enhance tumor growth, and suggest that cancer patients might benefit from targeted approaches that block signaling events initiated by endothelial cells.http://deepblue.lib.umich.edu/bitstream/2027.42/109499/1/12885_2013_Article_4365.pd

Intracerebral infection with dengue-3 virus induces meningoencephalitis and behavioral changes that precede lethality in mice

<p>Abstract</p> <p>Background</p> <p>Dengue, one of the most important arboviral diseases of humans, may cause severe systemic disease. Although dengue virus (DENV) has been considered to be a non-neurotropic virus, dengue infection has been associated recently with a series of neurological syndromes, including encephalitis. In this work, we evaluated behavioral changes and inflammatory parameters in C57BL/6 mice infected with non-adapted dengue virus 3 (DENV-3) genotype I.</p> <p>Methods</p> <p>C57BL/6 mice received 4 × 10³PFU of DENV-3 by an intracranial route. We evaluated the trafficking of leukocytes in brain microvasculature using intravital microscopy, and evaluated chemokine and cytokine profiling by an ELISA test at 3 and 6 days post infection (p.i.). Furthermore, we determined myeloperoxidase activity and immune cell populations, and also performed histopathological analysis and immunostaining for the virus in brain tissue.</p> <p>Results</p> <p>All animals developed signs of encephalitis and died by day 8 p.i. Motor behavior and muscle tone and strength parameters declined at day 7 p.i. We observed increased leukocyte rolling and adhesion in brain microvasculature of infected mice at days 3 and 6 p.i. The infection was followed by significant increases in IFN-γ, TNF-α, CCL2, CCL5, CXCL1, and CXCL2. Histological analysis showed evidence of meningoencephalitis and reactive gliosis. Increased numbers of neutrophils, CD4⁺and CD8⁺T cells were detected in brain of infected animals, notably at day 6 p.i. Cells immunoreactive for anti-NS-3 were visualized throughout the brain.</p> <p>Conclusion</p> <p>Intracerebral infection with non-adapted DENV-3 induces encephalitis and behavioral changes that precede lethality in mice.</p

CADEIA TÊXTIL-VESTUÁRIO: DISCUTINDO A EXISTÊNCIA DE UM ARRANJO PRODUTIVO LOCAL NA REGIÃO METROPOLITANA DE LONDRINA-PARANÁ

The objective of this work is to discuss the existence of a cluster of textile-clothing industries in the Metropolitan Area of Londrina, and verify its level of development. After discussing the nature and characteristics of this cluster, we hope to determine whether it can be classified as a Local Production Arrangement – LPA. A review was carried out on classical studies about productive clusters and networks. To identify the level of clustering, the quotients of jobs and establishments in the textile-clothing sector were calculated based on RAIS data for the period 1995/2003, and supported by the results of two field studies. This can be described as a qualitative and quantitative study, which is supported by two field studies. The results enable us to conclude that several links in the productive chain are present in the region of Londrina, in the State of Paraná, characterized as an important cluster, whose links are fragile, therefore this can be classified as an embryonic productive local arrangement, with a high potential for development.El objetivo del artículo es discutir la existencia de una aglomeración de industrias de vestuario en la Región Metropolitana de Londrina, verificar sus características y, a partir del análisis de los indicadores de su grado de desarrollo, inferir si la aglomeración puede ser caracterizada como un Arreglo Productivo Local – APL. Los procedimientos metodológicos involucran la revisión de estudios clásicos sobre aglomeraciones productivas y de redes. Para identificar el grado de aglomeración, se realiza el cálculo de los cocientes locacionales de empleo y establecimientos del sector textil; la base de datos es la RAIS para el período 1995/2003. Para calificar las informaciones estadísticas y verificar si las características de la aglomeración permiten configurar un APL, se discuten los resultados de dos investigaciones de campo. Esta investigación es de naturaleza cuantitativa y cualitativa, descriptiva y apoyada en datos secundarios. Los resultados permiten concluir que varios eslabones de la cadena productiva están presentes en la región de Londrina - Paraná, caracterizándose como una aglomeración productiva cuyos eslabones presentan fragilidad, y que las características de la aglomeración permiten clasificarla como embrión de APL, con elevado potencial de desarrollo.O objetivo do artigo é discutir a existência de uma aglomeração de indústrias do vestuário na Região Metropolitana de Londrina, verificar suas características e, a partir da análise dos indicadores de seu grau de desenvolvimento, inferir se a aglomeração pode ser caracterizada como um Arranjo Produtivo Local – APL. Os procedimentos metodológicos envolvem a revisão de estudos clássicos sobre aglomerações produtivas e de redes. Para identificar o grau de aglomeração, realiza-se o cálculo dos quocientes locacionais de emprego e estabelecimentos do setor têxtil - a base de dados é a RAIS para o período 1995/2003. Para qualificar as informações estatísticas e verificar se as características da aglomeração permitem configurar um APL, são discutidos os resultados de duas pesquisas de campo. Esta pesquisa é de natureza quantitativa e qualitativa, descritiva e apoiada em dados secundários. Os resultados permitem concluir que vários elos da cadeia produtiva estão presentes na região de Londrina-Paraná, caracterizando-se como uma aglomeração produtiva, cujos elos apresentam fragilidade e que as características da aglomeração permitem classificá-la como embrião de APL, com elevado potencial de desenvolvimento

Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20–23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5′ end (‘seed’ region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3′ UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms

Neutralising antibodies for West Nile virus in horses from Brazilian Pantanal

Despite evidence of West Nile virus (WNV) activity in Colombia, Venezuela and Argentina, this virus has not been reported in most South American countries. In February 2009, we commenced an investigation for WNV in mosquitoes, horses and caimans from the Pantanal, Central-West Brazil. The sera of 168 horses and 30 caimans were initially tested using a flaviviruses-specific epitope-blocking enzyme-linked immunosorbent assay (blocking ELISA) for the detection of flavivirus-reactive antibodies. The seropositive samples were further tested using a plaque-reduction neutralisation test (PRNT90) for WNV and its most closely-related flaviviruses that circulate in Brazil to confirm the detection of specific virus-neutralising antibodies. Of the 93 (55.4%) blocking ELISA-seropositive horse serum samples, five (3%) were seropositive for WNV, nine (5.4%) were seropositive for St. Louis encephalitis virus, 18 (10.7%) were seropositive for Ilheus virus, three (1.8%) were seropositive for Cacipacore virus and none were seropositive for Rocio virus using PRNT90, with a criteria of > four-fold antibody titre difference. All caimans were negative for flaviviruses-specific antibodies using the blocking ELISA. No virus genome was detected from caiman blood or mosquito samples. The present study is the first report of confirmed serological evidence of WNV activity in Brazil