Caractérisation tribologique de films moléculaires d'acide phosphonique déposés sur une surface de cuivre

National audienceLa surface d'un substrat de cuivre a été fonctionnalisée grâce à une technique d'auto-assemblage d'une monocouche d'acide phosphonique. Après caractérisation de ce film, un excellent comportement tribologique est noté lorsqu'aucun nettoyage ultrasonore n'est effectué, pour des conditions de sollicitation de pression de 133 MPa et de vitesse de glissement de 1mm/s sur un tribomètre alternatif linéaire utilisant un frotteur en Si3N4 (μ = 0.12, durée de vie multipliée par 100). Des espèces physisorbées, sous formes d'amas de plusieurs μm3, présentes sur la monocouche semblent responsables de ce bon comportement. De premiers essais sur un tribomètre d'étirage-plan ont montré un réel potentiel de ce type de fonctionnalisation en emboutissage

The Gene expression Grade Index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1–98 trial

<p>Abstract</p> <p>Background</p> <p>We have previously shown that the Gene expression Grade Index (GGI) was able to identify two subtypes of estrogen receptor (ER)-positive tumors that were associated with statistically distinct clinical outcomes in both untreated and tamoxifen-treated patients. Here, we aim to investigate the ability of the GGI to predict relapses in postmenopausal women who were treated with tamoxifen (T) or letrozole (L) within the BIG 1–98 trial.</p> <p>Methods</p> <p>We generated gene expression profiles (Affymetrix) and computed the GGI for a matched, case-control sample of patients enrolled in the BIG 1–98 trial from the two hospitals where frozen samples were available. All relapses (cases) were identified from patients randomized to receive monotherapy or from the switching treatment arms for whom relapse occurred before the switch. Each case was randomly matched with four controls based upon nodal status and treatment (T or L). The prognostic value of GGI was assessed as a continuous predictor and divided at the median. Predictive accuracy of GGI was estimated using time-dependent area under the curve (AUC) of the ROC curves.</p> <p>Results</p> <p>Frozen samples were analyzable for 48 patients (10 cases and 38 controls). Seven of the 10 cases had been assigned to receive L. Cases and controls were comparable with respect to menopausal and nodal status, local and chemotherapy, and HER2 positivity. Cases were slightly older than controls and had a larger proportion of large, poorly differentiated ER+/PgR- tumors. The GGI was significantly and linearly related to risk of relapse: each 10-unit increase in GGI resulted in an increase of approximately 11% in the hazard rate (p = 0.02). Within the subgroups of patients with node-positive disease or who were treated with L, the hazard of relapse was significantly greater for patients with GGI at or above the median. AUC reached a maximum of 78% at 27 months.</p> <p>Conclusion</p> <p>This analysis supports the GGI as a good predictor of relapse for ER-positive patients, even among patients who receive L. Validation of these results, in a larger series from BIG 1–98, is planned using the simplified GGI represented by a smaller set of genes and tested by qRT-PCR on paraffin-embedded tissues.</p

Sources of Pre-Analytical Variations in Yield of DNA Extracted from Blood Samples: Analysis of 50,000 DNA Samples in EPIC

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies

Sources of Pre-Analytical Variations in Yield of DNA Extracted from Blood Samples: Analysis of 50,000 DNA Samples in EPIC

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Extraction et hémisynthèse d'analogues de la guttiférone A

La guttiférone A , appartenant à la famille des PPAPs ou Acyle Phloroglucinol Polycycliques Polyprénylées, est une molécule extraite à partir d un arbre tropicale, le Symphonia globulifera. Cette matière première est abondante et peut être facilement obtenue. De plus, elle présente de nombreuses activités biologiques, lui conférant un potentiel pharmacologique très intéressant. Trois approches ont été effectuées durant ces travaux. La première fût l utilisation de microorganismes pour effectuer des biotransformations. L utilisation de levures a permis de synthétiser la 3,16-oxy-guttiférone A, forme xanthone de la guttiférone. Le second axe a été d utiliser des outils chimiques pour obtenir des dérivés de la guttiférone A. Dans un premier temps, une vingtaine d analogues éther et ester du catéchol a été synthétisée, certains de ces composés ont montré un meilleur indice de sélectivité sur les parasites. Une synthèse sélective de xanthone par une réaction de couplage phénolique oxydatif a également été étudiée. Nous avons pu obtenir par cette approche la 3,16-oxy-guttiférone A, la 1,16-oxy-guttiférone A et la 1,12-oxy-guttiférone A. Ces réactions ont aussi donné accès à des dérivés xanthone hydroxylée jamais décrits dans la littérature. Enfin, un travail préliminaire de phytochimie sur les graines et feuilles du Symphonia globulifera a été réalisé, permettant d isoler des analogues de la guttiférone A, la guttiférone C et D, ainsi que d autres molécules comme des bisflavonoides et des xanthones.Guttiferone A, belonging to the PPAPs family (Polycyclic Polyprenylated Acylphloroglucinols), is extracted from a tropical tree called Symphonia globulifera. This raw material is abundant and can be easily obtained. In addition, it has many biological activities, giving it a very interesting pharmacological potential. Three approaches were used in this work. The first was the use of microorganisms to perform biotransformations. The use of yeast allow the synthesis of 3,16-oxy-guttiférone A, a xanthone derivative of guttiferone A. The second theme was the use of chemical tools for guttiferone A derivation. First, twenty ether and ester catechol analogs were synthesized, some of these compounds showed a better selectivity index of parasites. Selective synthesis of xanthone by phenolic oxidative coupling reaction was also studied. We obtained by this approach the 3.16-oxy-guttiferone A, 1,16-oxy-guttiferone A and 1,12-oxy-guttiferone A. These reactions have also provided some hydroxylated xanthone never described before in the literature. Finally, preliminary phytochemical work on seeds and leaves of Symphonia globulifera lead to the isolation of guttiférone A analogues such as guttiférone C and D, as well as other molecules such as bisflavonoides and xanthones.PARIS5-Bibliotheque electronique (751069902) / SudocPARIS-BIUM-Bib. électronique (751069903) / SudocSudocFranceF

Etude chimique de Caulerpa taxifolia

PARIS-BIUP (751062107) / SudocSudocFranceF

Evolution des études pharmaceutiques en France (étude du devenir des docteurs de 2006 à 2011)

PARIS-BIUP (751062107) / SudocSudocFranceF

Tamarindus indica L.

PARIS-BIUP (751062107) / SudocSudocFranceF

Synthèse et évaluation biologique de décalines et pipéridines à visée anti-Alzheimer et d'acridones à visée anti-tumorale

Dans une première partie, une présentation succinte de la maladie d Alzheimer et de ses différentes stratégies thérapeutiques est rappelée. La conception de décalines et de pipéridines fonctionnalisées, et l évaluation de leurs propriétés anticholinestérasiques, antiinflammatoires et neuroprotectrices est ensuite présentée. Concernant les décalines, la synthèse du composé clé 3,7-dinitro-11-oxa-tricyclo[6.2.1.01.6]undec-9-ene est détaillée. S ensuit la présentation des différents types de réactions engagées à partir de ce synthon en vue de l obtention de composés bioactifs, notamment les réactions d ouverture de l endoxyde (première série), puis les autres réactions considérants les fonctions nitro et la double liaison (seconde série). Les pipéridines fonctionnalisées dérivent quant à elle de la lactone de l acide 4-hydroxypipécolique. Deux voies générales d ouverture de cette lactone sont exposées : une réaction de type Wittig sur l aldol, ou bien une attaque nucléophile ; afin d introduire une chaîne fonctionnalisée et d ouvrir un accès à de nouvelles séries bicycliques. Les principaux résultats biologiques de ces composés sont également présentés. Une seconde partie concerne la synthèse d acridones à visée antitumorales analogues simplifiés des furanoacridones précédemment développés au laboratoire. L évaluation biologique de cette première série de composés a en effet montré le caractère hautement actif de la fonction époxyde portée par un cycle furanique accolé aux chromophores acridoniques. L allylation des noyaux 1,3-dihydroxyacridoniques puis leur fonctionnalisation en époxydes a été réalisée. L évaluation de leurs propriétés antitumorales in vitro est présentée.The first part of this work recalls a general introduction for Alzheimer Disease and its treatments. Functionalized decalins and piperidines compounds have been synthesized and their anticholinesterasic, anti-inflammatory and neuroprotective properties were evaluated. Synthetic approaches to decalins and their synthesized derived from the key compound 3,7-dinitro-11-oxa-tricyclo [6.2.1.01.6] undec-9-ene, is described. Different types of reactions towards bioactive compounds, including the endoxyde opening reactions (first series), and other reactions to functionalize the nitro group and the double bond (second series) are developed. Regarding the synthesis of functionalized piperidines derived from the lactone of 4-hydroxypipecolic acid, two general pathways for lactone ring-opening are investigated. For a first serie of compounds a Wittig type reaction on the corresponding lactol is considered. For the second serie, a nucleophilic attack on the lactone is considered to introduce a functionalized chain. This work opens access to new bicyclic series. In a second part of this work, the synthesis of simplified acridones derived from the highly cytotoxic furanic parent compounds is described: O-allylation and functionalization into epoxides and esters of 1,3-dihydroxyacridones. Evaluation of their antitumor properties is also well presented.PARIS-BIUP (751062107) / SudocSudocFranceF