LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly.

International audienceCholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Menage a trois", The Good, the Bad and the Ugly

Open data for grapevine biology

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Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects.

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension

Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day)

Improving the « FAIRness » of Inra’s data for plant biology and breeding

INRA is involved in several projects (e.g. EU H2020 ELIXIR-Excelerate, n°676559) or global initiatives (e.g. Wheat Initiative, Research Data Alliance) contributing to the development of : (i) community recommandations for data standardisation (e.g. wheatis.org ; doi:10.1038/hortres.2016.56), (ii) data standards for phenotyping data (www.miappe.org), (iii) crop specific ontologies in the frame of the CropOntology (http://www.cropontology.org/) and (iv) standard web services (www.brapi.org). These global resources are used to capture the data produced by INRA and its partners in large scientific projects with a standard and structured vocabulary and to store them into INRA’s central repository for plant genomic, phenomic and genetic data, GnpIS (https://urgi.versailles.inra.fr/gnpis/) under the FAIR principles (https://www.force11.org/group/fairgroup/fairprinciples). For this purpose, standardization good practices are actively promoted in particular in the french community using as levers large french scientific projects centered around crop species (Wheat, Maize, Rapeseed, SunFlower, Pea and Sugar Beet) or infrastructures such as the french node of the European infrastructure for phenotyping (EMPHASIS) or the french infrastructure for biological resources for research in agriculture (AgroBRC). Recently, the standards for phenotyping data have been extended to support forest tree data in collaboration with the french node of the European infrastructure for Analysis and Experimentation on Ecosystems (AnaEE Services). Finally, these progresses in the FAIRness of our data are used to develop or contribute to federations of interoperable information systems (see for instance the Wheat community use case: doi: 10.12688/f1000research.12234.1)

BreedWheat GWAS data in GnpIS information system

Book of abstracts, ISBN: 978-2-9563873-0-5, EAN: 9782956387305Poster PI-05, p. 53BreedWheat project (https://breedwheat.fr/) aims to support the competitiveness of the French wheat breeding sector, answering to societal challenges for a sustainable and quality production. Moreover, the BreedWheat project characterize yet poorly exploited genetic resources to expand the diversity of the elite germplasm. Finally, new breeding methods are developed and evaluated for their socioeconomic impact.The URGI (Research Unit in Genomics Info) is an INRA research unit in genomics and bioinformatics dedicated to plants and their parasites. It develops and maintains an information system in genomics and genetics: GnpIS (Steinbach et al., Database 2013, doi: 10.1093/database/bat058).BreedWheat data available in GnpIS are genetic resources (collection of 5,232 accessions), polymorphisms (724,020 SNPs from 10 sources), genotyping (Affymetrix Axiom TaBW420K array), phenotyping (48,000 micro-plots in 21 locations) and Genome Wide Association Study (775,621 association results calculated from phenotyping and genotyping values): https://wheat-urgi.versailles.inra.fr/Projects/BreedWheat.GnpIS interface allows to display association values (with links to metadata, phenotyping and genotyping related values), these data can be filtered according to several criteria (eg p-val) and visualized graphically (QQplot, boxlplot based on genotyping alleles, Manhattan plot mapped to IWGSC RefSeq v1.0)

Developing grapevine FAIR Data

International audienc