Predictive Factors of Sensitivity to Elisidepsin,a Novel Kahalalide F-Derived Marine Compound

Elisidepsin (PM02734, Irvalec^®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.     

Nutrient Fluxes in Sediment (NH4 + and PO4 -3) in N.W. Coastal Lagoon Mexico Associated with an Agroindustrial Basin

In order to balance the impact of agricultural development on land around coastal lagoons with the protection of aquatic resources, knowledge of the role of the sedimentary phase in the entrapment or availability of nutrients in the water column in areas affected by agroindustrial outlets is important. The Ensenada del Pabellon coastal on the Pacific coast of Mexico was chosen to be analyzed. The input of ammonium and orthophosphate from sediment using semicontrolled benthic chambers near a sugar cane factory outlet was compared to non altered sediment. Phosphate and ammonia loading from agroindustrial outlets has been the primary cause of eutrophication. The inputs of ammonium and orthophosphates from the sediment to the water column depend on their concentration in the agroindustrial outlet's waste water, the local morphology, the tide, and biotic assimilation, in order of importance. Sediment in non-altered revealed maxima of 7.8 mg m^-2 d^-1 of NH⁺ ₄ and 1.4 mg m^-2 d^-1 of PO^-3_₄, whereas in one outlet that greatly transfigures the environment, maxima of 223 mg m^-2 d^-1 of NH⁺ ₄ and 67 mg m^-2 d^-1 of PO^-3_₄ were recorded, which represent an increase greater than 20 times the normal diffusion. These figures varied markedly in space and time. Results from the study indicated that existing levels of nutrient could endanger the future of this ecosystem, including its sustainable fisheries.     

Finding niches for whole-farm design models – contradictio in terminis?

Whole-farm design models quantitatively analyze the effects of a variety of potential changes at the farm system level. Science-driven technical information is confronted with value-driven objectives of farmers or other social groupings under explicit assumptions with respect to exogenous variables that are important drivers of agricultural systems (e.g., market conditions). Hence, farm design is an outcome of objective specification and the potential of a system. In recent publications, whole-farm design modelling has been proposed to enhance (farm) innovation processes. A number of operational modelling tools now offers the opportunity to assess the true potential of whole-farm design modelling to enhance innovation. In this paper, we demonstrate that it is not trivial to find niches for the application of goal-based farm models. Model outcomes appeared not to match questions of farm managers monitoring and learning from their own and other farmers’ practices. However, our research indicates that whole-farm design modelling possesses the capabilities to make a valuable contribution to reframing. Reframing is the phenomenon that people feel an urge to discuss and reconsider current objectives and perspectives on a problem. Reframing might take place in a situation (i) of mutually felt dependency between stakeholders, (ii) in which there is sufficient pressure and urgency for stakeholders to explore new problem definitions and make progress. Furthermore, our research suggests that the way the researcher enters a likely niche to introduce a model and/or his or her position in this niche may have significant implications for the potential of models to enhance an innovation process. Therefore, we hypothesize that the chances of capitalizing on modelling expertise are likely to be higher when researchers with such expertise are a logical and more or less permanent component of ongoing trajectories than when these researchers come from outside to purposefully search for a niche.     

A 3-year assessment of nitrous oxide emission factors for urine and dung of grazing sheep in a subtropical ecosystem

Purpose

Grazing livestock has strong impact on global nitrous oxide (N₂O) emissions by providing N sources through excreta. The scarcity of information on factors influencing N₂O emissions from sheep excreta in subtropical ecosystems such as those of Southern Brazil led us to conduct field trials in three different winter pasture seasons on an integrated crop–livestock system (ICL) in order to assess N₂O emission factors (EF-N₂O) in response to variable rates of urine and dung.

Materials and methods

The equivalent urine-N loading rates for the three winter seasons (2009, 2010, and 2013) ranged from 96 to 478 kg ha^?1, and the dung-N rates applied in 2009 and 2010 were 81 and 76 kg ha^?1, respectively. Air was sampled from closed static chambers (0.20 m in diameter) for approximately 40 days after excreta application and analyzed for N₂O by gas chromatography.

Results and discussion

Soil N₂O-N fluxes spanned the ranges 4 to 353 μg m^?2 h^?1 in 2009, ??47 to 976 μg m^?2 h^?1 in 2010, and 46 to 339 μg m^?2 h^?1 in 2013. Urine addition resulted in N₂O-N peaks within for up to 20–30 days after application in the 3 years, and the strength of the peaks was linearly related to the N rate used. Emission factors of N₂O (EF-N₂O, % of N applied that is emitted as N₂O) of urine ranged from 0.06 to 0.34% and were essentially independent of N rate applied. By considering a ratio of N excreted by urine and dung of 60:40, a single combined excretal EF-N₂O of 0.14% was estimated.

Conclusions

Our findings showed higher mean EF-N₂O for sheep urine than that for dung (0.21% vs 0.03%), irrespective of the occurrence or not of urine patches overlap. This value is much lower than default value of 1% of IPCC’s Tier 1 and reinforces the needs of its revision.

     

Histological and morphometric lesions in the pre-clinical,developmental phase of insulin-induced laminitis in Standardbred horses

Lamellar pathology in experimentally-induced equine laminitis associated with euglycaemic hyperinsulinaemia is substantial by the acute, clinical phase (～48 h post-induction). However, lamellar pathology of the developmental, pre-clinical phase requires evaluation. The aim of this study was to analyse lamellar lesions both qualitatively and quantitatively, 6, 12 and 24 h after the commencement of hyperinsulinaemia. Histological and histomorphometrical analyses of lamellar pathology at each time-point included assessment of lamellar length and width, epidermal cell proliferation and death, basement membrane (BM) pathology and leucocyte infiltration. Archived lamellar tissue from control horses and those with acute, insulin-induced laminitis (48 h) was also assessed for cellular proliferative activity by counting the number of cells showing positive nuclear immuno labelling for TPX2.Decreased secondary epidermal lamellar (SEL) width and increased histomorphological evidence of SEL epidermal basal (and supra-basal) cell death occurred early in disease progression (6 h). Increased cellular proliferation in SELs, infiltration of the dermis with small numbers of leucocytes and BM damage occurred later (24 and 48 h). Some lesions, such as narrowing of the SELs, were progressive over this time period (6–48 h). Cellular pathology preceded leucocyte infiltration and BM pathology, indicating that the latter changes may be secondary or downstream events in hyperinsulinaemic laminitis.