Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5′ flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors

Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage

Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on β-adrenergic versus Angiotensin II (Ang II)-dependent (Gs vs. Gαq mediated) modulation of Ca2+i-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca2+ currents and Ca2+i transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca2+ currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, β-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca2+-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca2+i-dependent hypertrophic growth response to Ang II, but not to β-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT1 signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for β-adrenergic Ca2+i-stimulation in adult myocytes

Rôles,impacts et services issus des élevages en Europe. Synthèse du rapport d’expertise scientifique collective

L’élevage, secteur majeur pour l’économie de nombreux territoires et structurant beaucoup de paysages ruraux européens, fait l’objet de controverses, depuis au moins une décennie, notamment du fait des dommages environnementaux qu’il engendre. Dans un tel contexte, il est apparu nécessaire d’étayer les débats en faisant le point sur l’état des connaissances scientifiques relatives aux rôles, impacts et services environnementaux, économiques et sociaux issus des élevages européens et leurs produits. Pour ce faire, les ministères français en charge de l’Environnement et de l’Agriculture ainsi que l’Agence de l’environnement et de la maîtrise de l’énergie (Ademe) ont sollicité l’Inra pour réaliser une expertise scientifique collective (ESCo) abordant conjointement les multiples conséquences sur les milieux et le climat, l’emploi et le travail, les marchés et certains enjeux sociaux et culturels, de la production et de la consommation humaine de produits d’origine animale (bovins, ovins, caprins, porcins et avicoles). L’analyse de ces diverses dimensions s’appuie sur les démarches d’évaluation rapportées dans la littérature scientifique internationale. Abordées, dans un premier temps, de manière analytique et globale, les connaissances ont ensuite été mobilisées par « bouquet de services » au sein de territoires contrastés. Les relations entre les différents impacts ou services permettent d’identifier des compromis et des leviers d’action envisageables pour les systèmes d’élevage. Livestock production is a sector of major economic importance that defines many European rural areas. It has become the focus of controversy over the past decade or more, particularly with regard to the environmental impacts it causes. In this context, it seemed useful to support this debate with a critical review of the state of scientific knowledge on the role, impacts, and services – environmental, economic, and social – associated with European livestock production. Accordingly, the French ministries responsible for Agriculture and the Environment, in cooperation with the French Environment and Energy Management Agency (ADEME), requested INRA to undertake a collective scientific assessment addressing the many consequences – for the environment and the climate, for employment and labor, for markets, and for a variety of social and cultural issues – related to the production and human consumption of animal products (cattle, sheep, goats, pigs, and poultry). Analysis of these diverse dimensions was based on assessment methods utilized and described in the international scientific literature. Using a broad, analytical overview as a starting point, the review proceeded by identifying the "service bundles" associated with livestock production in contrasting areas

Pre- and syn-eruptive degassing and crystallisation processes of the 2010 and 2006 eruptions of Merapi volcano, Indonesia

The 2010 eruption of Merapi (VEI 4) was the volcano’s largest since 1872. In contrast to the prolonged and effusive dome-forming eruptions typical of Merapi’s recent activity, the 2010 eruption began explosively, before a new dome was rapidly emplaced. This new dome was subsequently destroyed by explosions, generating pyroclastic density currents (PDCs), predominantly consisting of dark coloured, dense blocks of basaltic andesite dome lava. A shift towards open-vent conditions in the later stages of the eruption culminated in multiple explosions and the generation of PDCs with conspicuous grey scoria and white pumice clasts resulting from sub-plinian convective column collapse. This paper presents geochemical data for melt inclusions and their clinopyroxene hosts extracted from dense dome lava, grey scoria and white pumice generated during the peak of the 2010 eruption. These are compared with clinopyroxene-hosted melt inclusions from scoriaceous dome fragments from the prolonged dome-forming 2006 eruption, to elucidate any relationship between pre-eruptive degassing and crystallisation processes and eruptive style. Secondary ion mass spectrometry analysis of volatiles (H2O, CO2) and light lithophile elements (Li, B, Be) is augmented by electron microprobe analysis of major elements and volatiles (Cl, S, F) in melt inclusions and groundmass glass. Geobarometric analysis shows that the clinopyroxene phenocrysts crystallised at depths of up to 20 km, with the greatest calculated depths associated with phenocrysts from the white pumice. Based on their volatile contents, melt inclusions have re-equilibrated during shallower storage and/or ascent, at depths of ~0.6–9.7 km, where the Merapi magma system is interpreted to be highly interconnected and not formed of discrete magma reservoirs. Melt inclusions enriched in Li show uniform “buffered” Cl concentrations, indicating the presence of an exsolved brine phase. Boron-enriched inclusions also support the presence of a brine phase, which helped to stabilise B in the melt. Calculations based on S concentrations in melt inclusions and groundmass glass require a degassing melt volume of 0.36 km3 in order to produce the mass of SO2 emitted during the 2010 eruption. This volume is approximately an order of magnitude higher than the erupted magma (DRE) volume. The transition between the contrasting eruptive styles in 2010 and 2006 is linked to changes in magmatic flux and changes in degassing style, with the explosive activity in 2010 driven by an influx of deep magma, which overwhelmed the shallower magma system and ascended rapidly, accompanied by closed-system degassing

AusAgLCI - the business case for investment in a national life cycle inventory for horticulture

Over the last decade there has been a significant focus on the environmental impact of products and services across the economy, resulting in environmental product declarations and delivery agreements where the supplier is required to demonstrate an on-going improvement program of environmental sustainability. Once action is required, primary producers need to be able to make an objective assessment of their overall environmental impact using Life Cycle Assessment (LCA), so that "hot spots" in their production system can be identified, and options to reduce these impacts can be investigated. Country-specific Life Cycle Inventory (LCI) for agricultural products is essential for Australian agriculture to undertake environmental impact studies related to food and fibre, especially where differences in management systems and regional climate, soils and vegetation significantly affect LCA results. The goal of inventory collection for AusAgLCI is to provide underlying data to ensure Australian primary producers can readily, and objectively, demonstrate that their products are being produced in a responsible manner, in a system where environmental assessment is used to aid and drive improvements. This will assist producers to meet marketing requirements and to benchmark their production in global markets. This paper explores the relevance for horticulture industries and presents some inventory results for Australian horticultural products