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Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis-free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis.

Helicobacter pylori causes chronic gastritis and avoids elimination by the immune system of the infected host. The commensal bacterium Lactobacillus acidophilus has been suggested to exert beneficial effects as a supplement during H. pylori eradication therapy. In the present study, we applied whole-genome microarray analysis to compare the immune responses induced in murine bone marrow-derived macrophages (BMDMs) stimulated with L. acidophilus , H. pylori , or both bacteria in combination. While L. acidophilus induced a Th1-polarizing response characterized by high expression of interferon beta (IFN-β) and interleukin 12 (IL-12), H. pylori strongly induced the innate cytokines IL-1β and IL-1α. In BMDMs prestimulated with L. acidophilus , H. pylori blocked the expression of L. acidophilus -induced IFN-β and IL-12 and suppressed the expression of key regulators of the Rho, Rac, and Cdc42 GTPases. The inhibition of L. acidophilus -induced IFN-β was independent of H. pylori viability and the virulence factor CagPAI; however, a vacuolating cytotoxin ( vacA ) mutant was unable to block IFN-β. Confocal microscopy demonstrated that the addition of H. pylori to L. acidophilus -stimulated BMDMs redirects intracellular processing, leading to an accumulation of L. acidophilus in the endosomal and lysosomal compartments. Thus, our findings indicate that H. pylori inhibits the development of a strong Th1-polarizing response in BMDMs stimulated with L. acidophilus by blocking the production of IFN-β in a VacA-dependent manner. We suggest that this abrogation is caused by a redirection of the endocytotic pathway in the processing of L. acidophilus . IMPORTANCE Approximately half of the world’s population is infected with Helicobacter pylori . The factors that allow this pathogen to persist in the stomach and cause chronic infections have not yet been fully elucidated. In particular, how H. pylori avoids killing by macrophages, one of the main types of immune cell underlying the epithelium, remains elusive. Here we have shown that the H. pylori virulence factor VacA plays a key role by blocking the activation of innate cytokines induced by the probiotic Lactobacillus acidophilus in macrophages and suppresses the expression of key regulators required for the organization and dynamics of the intracellular cytoskeleton. Our results identify potential targets for the treatment of H. pylori infection and vaccination, since specific inhibition of the toxin VacA possibly allows the activation of an efficient immune response and thereby eradication of H. pylori in the host. Approximately half of the world’s population is infected with Helicobacter pylori . The factors that allow this pathogen to persist in the stomach and cause chronic infections have not yet been fully elucidated. In particular, how H. pylori avoids killing by macrophages, one of the main types of immune cell underlying the epithelium, remains elusive. Here we have shown that the H. pylori virulence factor VacA plays a key role by blocking the activation of innate cytokines induced by the probiotic Lactobacillus acidophilus in macrophages and suppresses the expression of key regulators required for the organization and dynamics of the intracellular cytoskeleton. Our results identify potential targets for the treatment of H. pylori infection and vaccination, since specific inhibition of the toxin VacA possibly allows the activation of an efficient immune response and thereby eradication of H. pylori in the host.

The interferons (IFNs) are a pleiotropic family of cytokines that perform fundamental functions in protecting host organisms from disease and in maintaining homeostasis. Like other multifunctional cytokines, excessive or inappropriate activity can cause toxicity and even death. Therefore, host organisms have evolved specific and highly regulated mechanisms to control the temporal and tissue specificity of production of IFNs and the selection of pathways and genes to be activated as the effectors of the IFN response in cells. There are now numerous microarray datasets available to enable a “global” analysis of the genes involved in the IFN response. This article describes the INTERFEROME database, which assimilates the available expression profiling data and its contents and enables the definition of IFN-regulated genes, discovery of pathways, regulatory networks, and tissue specificities of the IFN response.

The Toll-like receptors (TLRs) are innate sensors that recognize both microbial and endogenous ligands, initiating the host defense response. TLRs initiate the potent proinflammatory response to infection, are the target for adjuvants, and are essential for the establishment and maturation of adaptive immunity. As such they have been the interest of widespread research and the target of therapeutic intervention on multiple diseases. It has become apparent that expression of a subset of TLRs (TLR1, TLR2, TLR3, TLR5, and TLR7) is induced by Type I interferons (IFN). The role and impact of IFN expression on TLR responses is therefore critical in understanding the role of TLRs in disease, particularly as IFN itself is a downstream gene induced by specific TLRs. In this review we discuss the function and role of IFN-regulated TLRs in disease and how the role of IFN may impact upon TLR induction of the immune response in diseases, particularly in mouse models.

It would make the rest of the world look such idiots. \"The World Cup ... yeah I guess we won it. Is that a big deal? Were there many other countries in it? Who else was playing?\"

Sir: Your series on the Universal Declaration of Human Rights included Article 23 - \"Everyone has the right to work...\" If this is so, why are we doing so much to eliminate jobs? It's not only the crumbling industries, but the everyday jobs from ticket collecting to directory inquiries. And this in a world where the only natural resource that is on the increase is human labour.

Saudi Arabian Oil Minister Ali al-Naimi said in comments carried by the official Saudi Press Agency that \"Saudi Arabia tried in the past to play the role of the swing producer, i.e. reduce production to maintain a specific price, but the result was unfavorable to the kingdom.\"