ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing

Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the “A Disintegrin And Metalloproteases” (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and γδ T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X

Revisión sistemática de evaluaciones económicas de los sistemas de telemonitorización en los marcapasos.

Introducción y objetivos: En la última década, la telemedicina aplicada a la monitorización de marcapasos cardiacos ha experimentado un extraordinario crecimiento. Se desconoce si esta tecnología tiene una eficiencia diferente de la convencional. El objetivo del estudio es realizar una revisión sistemática analizando la evidencia disponible con respecto al consumo de recursos y los resultados en salud en ambas modalidades de seguimiento. Métodos: La búsqueda se realizó en 11 bases de datos y se incluyeron estudios publicados hasta noviembre de 2014. Los criterios de inclusión fueron: a) diseño experimental u observacional; b) estudios basados en evaluaciones económicas completas; c) pacientes con marcapasos, y d) telemonitorización comparada con la modalidad hospitalaria.post-print284 K

Activin A Induces Langerhans Cell Differentiation In Vitro and in Human Skin Explants

Langerhans cells (LC) represent a well characterized subset of dendritic cells located in the epidermis of skin and mucosae. In vivo, they originate from resident and blood-borne precursors in the presence of keratinocyte-derived TGFβ. Ιn vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGFβ. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGFβ family member induced by pro-inflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGFβ. Activin A-induced LC are Langerin+, Birbeck granules+, E-cadherin+, CLA+ and CCR6+ and possess typical APC functions. In human skin explants, intradermal injection of Activin A increased the number of CD1a+ and Langerin+ cells in both the epidermis and dermis by promoting the differentiation of resident precursor cells. High levels of Activin A were present in the upper epidermal layers and in the dermis of Lichen Planus biopsies in association with a marked infiltration of CD1a+ and Langerin+ cells. This study reports that Activin A induces the differentiation of circulating CD14+ cells into LC. Since Activin A is abundantly produced during inflammatory conditions which are also characterized by increased numbers of LC, we propose that this cytokine represents a new pathway, alternative to TGFβ, responsible for LC differentiation during inflammatory/autoimmune conditions

Impact of Plants in Isolation: The EDEN-ISS Human Factors Investigation in Antarctica

The EDEN-ISS is a greenhouse project at the Neumayer Station III in Antarctica. For the first time, this greenhouse supplied the station with fresh food and enabled research regarding sustainable and autonomous food production from Earth to Space. To investigate the plants’ impact on the crew (biophilia), a debriefing, questionnaires, and behavioral observation were used. The results show that the crew was satisfied with the consumption of fresh vegetables, which are usually not available in Antarctica. All (9 of 9 crew members) also agreed on the positive psychological and physiological impact of the plants on their well-being. The investigation will be repeated with the next crew of the Neumayer Station III and will also be proposed for comparison at stations like Concordia

Impact of Plants in Isolation: The EDEN-ISS Human Factors Investigation in Antarctica

The EDEN-ISS is a greenhouse project at the Neumayer Station III in Antarctica. For the first time, this greenhouse supplied the station with fresh food and enabled research regarding sustainable and autonomous food production from Earth to Space. To investigate the plants’ impact on the crew (biophilia), a debriefing, questionnaires, and behavioral observation were used. The results show that the crew was satisfied with the consumption of fresh vegetables, which are usually not available in Antarctica. All (9 of 9 crew members) also agreed on the positive psychological and physiological impact of the plants on their well-being. The investigation will be repeated with the next crew of the Neumayer Station III and will also be proposed for comparison at stations like Concordia