Deletion of PKBα/Akt1 Affects Thymic Development

BACKGROUND: The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether PKB mediates PI3K signaling in the thymus, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBalpha(-/-) neonates and an accumulation of early thymocyte subsets in PKBalpha(-/-) adult mice. Using thymic grafting and fetal liver cell transfer experiments, the latter finding was specifically attributed to the lack of PKBalpha within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBalpha in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. CONCLUSIONS/SIGNIFICANCE: This report highlights the specific requirements of PKBalpha for thymic development and opens up new prospects as to the mechanism downstream of PKBalpha in early thymocytes

A New Approach for Increasing Ascorbyl Palmitate Stability by Addition of Non-irritant Co-antioxidant

The aim of this work was to test innovative approach for enhancing ascorbyl palmitate stability in microemulsions for topical application by addition of newly synthesized co-antioxidant 4-(tridecyloxy)benzaldehyde oxime (TDBO) and to investigate its antioxidant activity and finally to evaluate cytotoxicity of TDBO-loaded microemulsions on keratinocyte cells. TDBO significantly increased ascorbyl palmitate stability in oil-dispersed-in-water (o/w) microemulsions, most presumably due to reduction of ascorbyl palmitate radical back to ascorbyl palmitate, since TDBO free-radical scavenging activity was confirmed. Cytotoxicity experiments demonstrated no significant change in cell viability or morphology in the presence of TDBO-loaded microemulsions regarding unloaded microemulsions, although greater cytotoxicity was observed with increased microemulsion concentrations. Therefore, the incorporation of TDBO as non-cytotoxic co-antioxidant in o/w microemulsions is a promising new strategy for enhancing ascorbyl palmitate stability that could be used to support antioxidant network in the skin

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies2. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology3. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a a 'pill' that awakens the innate immune system to kill cancer metastases. © 2014 Macmillan Publishers Limited.Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Choidas, Axel. Lead Discovery Center GmbH; AlemaniaFil: Wallner, Stephanie. Medizinische Universitat Innsbruck; AustriaFil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Jamieson, Amanda M.. University Brown; Estados UnidosFil: Langdon, Wallace Y.. University of Western Australia; AustraliaFil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; AustriaFil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; AlemaniaFil: Eickhoff, Jan. Lead Discovery Center GmbH; AlemaniaFil: Menninger, Sascha. Lead Discovery Center GmbH; AlemaniaFil: Unger, Anke. Lead Discovery Center GmbH; AlemaniaFil: Torka, Robert. Institute for Biochemistry Max-Planck; AlemaniaFil: Gruber, Thomas. Medizinische Universitat Innsbruck; AustriaFil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; AustriaFil: Baier, Gottfried. Medizinische Universitat Innsbruck; AustriaFil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; AustriaFil: Ullrich, Axel. Institute for Biochemistry Max-Planck; AlemaniaFil: Klebl, Bert M.. Lead Discovery Center GmbH; AlemaniaFil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austri