Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as monotherapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted

Syn-rift hydrothermal circulation in the Mesozoic carbonates of the western Adriatic continental palaeomargin (Western Southalpine Domain, NW Italy)

Evidence of hydrothermal activity is reported for the Mesozoic pre- and syn-rift successions of the western Adriatic palaeomargin of the Alpine Tethys, preserved in the Western Southalpine Domain (NW Italy). The products of hydrothermal processes are represented by vein and breccia cements, as well as dolomitization and silicification of the host rocks. In the eastern part of the study area, interpreted as part of the necking zone of the continental margin, Middle Triassic dolostones and Lower Jurassic sediments are crossed by veins and hydrofracturing breccias cemented by saddle dolomite. The precipitation of dolomite cements occurred within the stratigraphic succession close to the sediment–water interface. Despite the shallow burial depth, fluid inclusion microthermometry and clumped isotopes show that hydrothermal fluids were relatively hot (80–150°C). In the western part of the study area, interpreted as part of the hyperextended distal zone, a polyphase history of host-rock fracturing is recorded, with at least two generations of veins cemented by calcite, dolomite and quartz. Vein opening and cementation occurred at shallow burial depth around the time of deposition of the syn-rift clastic succession. Fluid inclusion microthermometry on both quartz and dolomite cements indicates a fluid temperature of 90–130°C, again pointing to hydrothermal fluids. Both in Fenera-Sostegno and Montalto Dora areas, O, C and Sr isotope values, coupled with fluid inclusion and clumped isotope data, indicate that hydrothermal fluids derived from seawater interacted with crustal rocks during hydrothermal circulation. Stratigraphic and petrographic evidence, and U–Pb dating of dolomitized clasts within syn-rift sediments, document that hydrothermal fluids circulated through sediments from the latest Triassic to the Toarcian, corresponding to the entire syn-rift evolution of the western portion of the Adriatic palaeomargin. The documented hydrothermal processes are temporally correlated with regional-scale thermal events that took place in the same time interval at deeper crustal levels

Identification of a novel cord blood NK cell subpopulation expressing functional programmed death receptor-1

BackgroundNatural Killer cells (NKs) represent the innate counterpart of TCRαβ lymphocytes and are characterized by a high anti-tumor and an anti-viral cytotoxic activity. Recently, it has been demonstrated that NKs can express PD-1 as an additional inhibitory receptor. Specifically, PD-1 was identified on a subpopulation of terminally differentiated NKs from healthy adults with previous HCMV infection. So far it is unknown whether PD-1 appears during NK-cell development and whether this process is directly or indirectly related to HCMV infection.MethodsIn this study, we analyzed the expression and function of PD-1 on Cord Blood derived NKs (CB-NKs) on a large cohort of newborns through multiparametric cytofluorimetric analysis.ResultsWe identified PD-1 on CB-NKs in more than of half the newborns analyzed. PD-1 was present on CD56dim NKs, and particularly abundant on CD56neg NKs, but only rarely present on CD56bright NKs. Importantly, unlike in adult healthy donors, in CB-NKs PD-1 is co-expressed not only with KIR, but also with NKG2A. PD-1 expression was independent of HCMV mother seropositivity and occurs in the absence of HCMV infection/reactivation during pregnancy. Notably, PD-1 expressed on CB-NKs was functional and mediated negative signals when triggered.ConclusionTo our understanding, this study is the first to report PD-1 expression on CB derived NKs and its features in perinatal conditions. These data may prove important in selecting the most suitable CB derived NK cell population for the development of different immunotherapeutic treatments

Skills of the user-relevant ocean indicators

This document demonstrates the capability of seasonal forecasting systems to predict observable and user-relevant ocean climate indicators

Mediterranean monitoring and forecasting operational system for Copernicus Marine Service

The MEDiterranean Monitoring and Forecasting Center (Med-MFC) is part of the Copernicus Marine Environment Monitoring Service (CMEMS, http://marine.copernicus.eu/), provided on an operational mode by Mercator Ocean in agreement with the European Commission. Specifically, Med MFC system provides regular and systematic information about the physical state of the ocean and marine ecosystems for the Mediterranean Sea. The Med-MFC service started in May 2015 from the pre-operational system developed during the MyOcean projects, consolidating the understanding of regional Mediterranean Sea dynamics, from currents to biogeochemistry to waves, interfacing with local data collection networks and guaranteeing an efficient link with other Centers in Copernicus network. The Med-MFC products include analyses, 10 days forecasts and reanalysis, describing currents, temperature, salinity, sea level and pelagic biogeochemistry. Waves products will be available in MED-MFC version in 2017. The consortium, composed of INGV (Italy), HCMR (Greece) and OGS (Italy) and coordinated by the Euro-Mediterranean Centre on Climate Change (CMCC, Italy), performs advanced R&D activities and manages the service delivery. The Med-MFC infrastructure consists of 3 Production Units (PU), for Physics, Biogechemistry and Waves, a unique Dissemination Unit (DU) and Archiving Unit (AU) and Backup Units (BU) for all principal components, guaranteeing a resilient configuration of the service and providing and efficient and robust solution for the maintenance of the service and delivery. The Med-MFC includes also an evolution plan, both in terms of research and operational activities, oriented to increase the spatial resolution of products, to start wave products dissemination, to increase temporal extent of the reanalysis products and improving ocean physical modeling for delivering new products. The scientific activities carried out in 2015 concerned some improvements in the physical, biogeochemical and wave components of the system. Regarding the currents, new grid-point EOFs have been implemented in the Med-MFC assimilation system; the climatological CMAP precipitation was replaced by the ECMWF daily precipitation; reanalysis time-series have been increased by one year. Regarding the biogeochemistry, the main scientific achievement is related to the implementation of the carbon system in the Med-MFC biogeochemistry model system already available. The new model is able to reproduce the principal spatial patterns of the carbonate system variables in the Mediterranean Sea. Further, a key result consists of the calibration of the new variables (DIC and alkalinity), which serves to the estimation of the accuracy of the new products to be released in the next version of the system (i.e. pH and pCO2 at surface). Regarding the waves, the system has been validated against in-situ and satellite observations. For example, a very good agreement between model output and in-situ observations has been obtained at offshore and/or well-exposed wave buoys in the Mediterranean Sea.PublishedVienna3SR. AMBIENTE - Servizi e ricerca per la Societ

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation

Polymer Composites Containing Gated Mesoporous Materials for On-Command Controlled Release

Polyamidic nanofibrous membranes containing gated silica mesoporous particles, acting as carriers, are described as novel hybrid composite materials for encapsulation and on-command delivery of garlic extracts. The carrier system consists of MCM-41 solids functionalized in the outer surface, with linear polyamines (solid P1) and with hydrolyzed starch (solid P2), both acting as molecular gates. Those particles were adsorbed on electospun nylon-6 nanofibrous membranes yielding to composite materials M1 and M2. FE-SEM analysis confirmed the presence of particles incorporated on the nylon nanofibers. The release of the entrapped molecules (garlic extract) from the P1, P2, M1, and M2 materials was evaluated using cyclic voltammetry measurements. Electrochemical studies showed that at acidic pH P1 and M1 were unable to release their entrapped cargo (closed gate), whereas at neutral pH both materials release their loading (open gate). Dealing with P2 and M2 materials, in the absence of pancreatin a negligible release is observed (closed gate), whereas in the presence of enzyme the load is freely to diffuse to the solution. These newly developed composite nanomaterials, provide a homogeneous easy-to-handle system with controlled delivery and bioactive-protective features, having potential applications on pharmacology, medical and engineering fields.The authors wish to express their gratitude to the Generalitat Valenciana (Grisolia scholarship 2011/012, project PROM-ETEO/2009/016), Spanish Government (MINECO Projects AGL2012-39597-C02-01, AGL2012-39597-C02-02 and MAT2012-38429-C04-01) and the CIBER-BBN for their support. IILA thanks DISTAM and Universita degli di Milano for a specialization scholarship. We would also like to thank the Institut de Ciencia dels Materials (ICMUV) and to the Microscopy Service of the Universitat Politecnica de Valencia for technical support. We thank Roquette for the Glucidex samples.Acosta Romero, C.; Pérez Esteve, E.; Fuenmayor, CA.; Benedetti, S.; Cosio, MS.; Soto Camino, J.; Sancenón Galarza, F.... (2014). Polymer Composites Containing Gated Mesoporous Materials for On-Command Controlled Release. ACS Applied Materials and Interfaces. 6(9):6453-6460. https://doi.org/10.1021/am405939y645364606