121 research outputs found
Insulin Granule Recruitment and Exocytosis Is Dependent on p110Ξ³ in Insulinoma and Human Ξ²-Cells
PI3KΞ³ Protects from Myocardial Ischemia and Reperfusion Injury through a Kinase-Independent Pathway
BACKGROUND: PI3Kgamma functions in the immune compartment to promote inflammation in response to G-protein-coupled receptor (GPCR) agonists and PI3Kgamma also acts within the heart itself both as a negative regulator of cardiac contractility and as a pro-survival factor. Thus, PI3Kgamma has the potential to both promote and limit M I/R injury. METHODOLOGY/PRINCIPAL FINDINGS: Complete PI3Kgamma-/- mutant mice, catalytically inactive PI3KgammaKD/KD (KD) knock-in mice, and control wild type (WT) mice were subjected to in vivo myocardial ischemia and reperfusion (M I/R) injury. Additionally, bone-marrow chimeric mice were constructed to elucidate the contribution of the inflammatory response to cardiac damage. PI3Kgamma-/- mice exhibited a significantly increased infarction size following reperfusion. Mechanistically, PI3Kgamma is required for activation of the Reperfusion Injury Salvage Kinase (RISK) pathway (AKT/ERK1/2) and regulates phospholamban phosphorylation in the acute injury response. Using bone marrow chimeras, the cardioprotective role of PI3Kgamma was mapped to non-haematopoietic cells. Importantly, this massive increase in M I/R injury in PI3Kgamma-/- mice was rescued in PI3Kgamma kinase-dead (PI3KgammaKD/KD) knock-in mice. However, PI3KgammaKD/KD mice exhibited a cardiac injury similar to wild type animals, suggesting that specific blockade of PI3Kgamma catalytic activity has no beneficial effects. CONCLUSIONS/SIGNIFICANCE: Our data show that PI3Kgamma is cardioprotective during M I/R injury independent of its catalytic kinase activity and that loss of PI3Kgamma function in the hematopoietic compartment does not affect disease outcome. Thus, clinical development of specific PI3Kgamma blockers should proceed with caution
Systematic Review of Mucosal Immunity Induced by Oral and Inactivated Poliovirus Vaccines against Virus Shedding following Oral Poliovirus Challenge
Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5β30 days after a βchallengeβ dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08β0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59β1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82β1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV
Phosphoinositide 3-KinaseΞ³ Controls the Intracellular Localization of CpG to Limit DNA-PKcs-Dependent IL-10 Production in Macrophages
Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG) stimulate innate immune responses. Phosphoinositide 3-kinase (PI3K) has been implicated in CpG-induced immune activation; however, its precise role has not yet been clarified. CpG-induced production of IL-10 was dramatically increased in macrophages deficient in PI3KΞ³ (p110Ξ³β/β). By contrast, LPS-induced production of IL-10 was unchanged in the cells. CpG-induced, but not LPS-induced, IL-10 production was almost completely abolished in SCID mice having mutations in DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Furthermore, wortmannin, an inhibitor of DNA-PKcs, completely inhibited CpG-induced IL-10 production, both in wild type and p110Ξ³β/β cells. Microscopic analyses revealed that CpG preferentially localized with DNA-PKcs in p110Ξ³β/β cells than in wild type cells. In addition, CpG was preferentially co-localized with the acidic lysosomal marker, LysoTracker, in p110Ξ³β/β cells, and with an early endosome marker, EEA1, in wild type cells. Over-expression of p110Ξ³ in Cos7 cells resulted in decreased acidification of CpG containing endosome. A similar effect was reproduced using kinase-dead mutants, but not with a ras-binding site mutant, of p110Ξ³. Thus, it is likely that p110Ξ³, in a manner independent of its kinase activity, inhibits the acidification of CpG-containing endosomes. It is considered that increased acidification of CpG-containing endosomes in p110Ξ³β/β cells enforces endosomal escape of CpG, which results in increased association of CpG with DNA-PKcs to up-regulate IL-10 production in macrophages
Multiple Phosphatidylinositol 3-Kinases Regulate Vaccinia Virus Morphogenesis
Poxvirus morphogenesis is a complex process that involves the successive wrapping of the virus in host cell membranes. We screened by plaque assay a focused library of kinase inhibitors for those that caused a reduction in viral growth and identified several compounds that selectively inhibit phosphatidylinositol 3-kinase (PI3K). Previous studies demonstrated that PI3Ks mediate poxviral entry. Using growth curves and electron microscopy in conjunction with inhibitors, we show that that PI3Ks additionally regulate morphogenesis at two distinct steps: immature to mature virion (IMV) transition, and IMV envelopment to form intracellular enveloped virions (IEV). Cells derived from animals lacking the p85 regulatory subunit of Type I PI3Ks (p85Ξ±β/βΞ²β/β) presented phenotypes similar to those observed with PI3K inhibitors. In addition, VV appear to redundantly use PI3Ks, as PI3K inhibitors further reduce plaque size and number in p85Ξ±β/βΞ²β/β cells. Together, these data provide evidence for a novel regulatory mechanism for virion morphogenesis involving phosphatidylinositol dynamics and may represent a new therapeutic target to contain poxviruses
Stage T1c prostate cancer: defining the appropriate staging evaluation and the role for pelvic lymphadenectomy
A good staging system should be able to accurately reflect the natural history of a malignant disease, to express the extent of the disease at the time of diagnosis, and stratify patients in prognostically distinctive groups. The staging system for prostate cancer, as it is today, fails to fulfill these requirements. Approximately one third of the patients who undergo surgery for complete excision of prostate cancer in fact do not have a localize disease. The incidence of tumor at the inked margin may reach 30% for T1 stage and up to 60% for clinical T2b prostate cancer according to comparision with pathologic examination of resected specimen. Several concepts have been recently proposed as a means of improving the accuracy of the available staging system. In this paper, we review current aspects of clinical and pathological staging of prostate cancer, and the importance of these new concepts on the early stages of prostate cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47057/1/345_2005_Article_BF01300182.pd
- β¦