ARPEGES, une méthode pour évaluer le potentiel de contamination des eaux de surface par les pesticides à l'échelle nationale

International audienceArpeges is an innovating and coherent method to assess the potential surface water's contamination by pesticides at the national scale. In France, it was implemented at Water Framework Directive water bodies' scale. The objectives are to identify of vulnerable zones and to determinate the main risk factors implied in pollution transfer according to the considered zones. Actually, this method allows a better understanding and a ranking of pollution's causes considering three essential aspects of the contamination: uses, environmental vulnerability to pesticides pollution and substances properties. The method is mostly based on transfer processes. In order to take into account the seasonal temporal variability, analyses are separately carried on winter and summer, and both acute and chronic approaches of the risk are considered. The segregation between these two risks is built on the different processes transfer times to reach surface waters. 18 relevant variables describing pesticides transfer are chosen (infiltration, pedology, drainage, climate, buffer zones...); they are aggregated according to up to date expert knowledge thanks to a Bayesian network to obtain pesticides contamination. This tool allows associating an uncertainty factor to each result and contributing to increase the adaptability of the method. Intermediary results as environmental vulnerabilities are relevant to identify the main causes of transfer

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1

Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers

Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment

Expression of genes for bone morphogenetic proteins BMP-2, BMP-4 and BMP-6 in various parts of the human skeleton

BACKGROUND: Differences in duration of bone healing in various parts of the human skeleton are common experience for orthopaedic surgeons. The reason for these differences is not obvious and not clear.METHODS: In this paper we decided to measure by the use of real-time RT-PCR technique the level of expression of genes for some isoforms of bone morphogenetic proteins (BMPs), whose role is proven in bone formation, bone induction and bone turnover. Seven bone samples recovered from various parts of skeletons from six cadavers of young healthy men who died in traffic accidents were collected. Activity of genes for BMP-2, -4 and -6 was measured by the use of fluorescent SYBR Green I.RESULTS: It was found that expression of m-RNA for BMP-2 and BMP-4 is higher in trabecular bone in epiphyses of long bones, cranial flat bones and corpus mandibulae then in the compact bone of diaphyses of long bones. In all samples examined the expression of m-RNA for BMP-4 was higher than for BMP-2.CONCLUSION: It was shown that m-RNA for BMP-6 is not expressed in the collected samples at all. It is postulated that differences in the level of activation of genes for BMPs is one of the important factors which determine the differences in duration of bone healing of various parts of the human skeleton.Author has checked copyrightDG 16/11/1

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

Document d'interprétation d'ARPEGES : relations entre vulnérabilités intrinsèques et conditions pédoclimatiques

[Departement_IRSTEA]Eaux [TR1_IRSTEA]QUASARE [ADD1_IRSTEA]Systèmes aquatiques soumis à des pressions multiplesLa méthode ARPEGES s'appuie sur la démarche générale de diagnostic proposée par le Comité d'orientation pour des pratiques agricoles respectueuses de l'environnement (Corpen). Cette approche descriptive et experte des milieux définit le risque de contamination comme résultant d'une conjonction entre la vulnérabilité des masses d'eau et l'utilisation de produits phytosanitaires (« pression phytosanitaire »). Ce « guide » d'interprétation est volontairement axé sur la compréhension de l'évaluation de la vulnérabilité intrinsèque des milieux et systèmes agro-pédo-climatiques et de son rôle dans les contaminations. En effet cette approche est basée sur la connaissance des milieux physiques, sur les aménagements hydrauliques, sur les zones tampons et éléments du paysage présents et sur l'expertise pluridisciplinaire existante concernant les processus des transferts hydriques et des contaminants associés. Des études sont en cours pour améliorer la détermination de la vulnérabilité spécifique en se basant sur quelques molécules d'intérêt fort. Allié à l'amélioration de la connaissance de la pression en pesticides cela permettra d'affiner les risques de contaminations et d'impacts sur les milieux aquatiques. Le risque de transfert de substances actives est déterminé en caractérisant la proximité au réseau hydrographique et les voies de circulation de l'eau dans les parcelles et le pédo-paysage. Au niveau national, la méthode ARPEGES semble se montrer parfois peu discriminante pour l'évaluation de la vulnérabilité intrinsèque. En effet cette échelle de travail oblige à faire des choix de classe qu'il conviendrait d'ajuster pour affiner les prévisions au niveau régional voire plus local. C'est par exemple le cas pour la région Bretagne, où, compte tenu des limites de classes retenues nationalement au regard de la pédologie des sols, les particularités locales sont assez peu mises en évidence. Lors des échanges, avec les Agences de l'Eau et les directions régionales de l'ONEMA, il était perceptible que cela crée des frustrations. D'autant que plus largement l'approche ARPEGES, fondée sur une prise en compte des processus physiques de vulnérabilité, a également parfois été perçue comme apportant peu de connaissances nouvelles aux personnes connaissant déjà bien leur territoire au terme de 20 ans de surveillance des masses d'eau. Toutefois il est possible et nécessaire de surmonter ces limites car: - Les démarches CORPEN locales n'ont pas abouti sur l'ensemble du territoire dans l'analyse des vulnérabilités locales. ARPEGES permet cette évaluation des contextes locaux là où ils n'existent pas, guidant l'identification des territoires d'action prioritaires. - La prise en compte à dire d'expert des processus donnent un bon niveau de compréhension des fonctionnements hydriques des territoires. - L'approche méthodologique nationale a l'avantage de passer au travers d'un même prisme l'ensemble des masses d'eau et sans doute des petites régions agricoles: cela donne donc une approche coordonnée entre bassins, agences de l'eau et permet une évaluation homogène des enjeux pour les pouvoirs publics