129 research outputs found
Nouveaux marqueurs des glioblastomes (valeur pronostique, profil d'expression, implication dans la vascularisation et la résistance aux antiangiogéniques)
L angiogenĂšse est une composante majeure de l agressivitĂ© des tumeurs malignes comme le glioblastome (GBM). Pourtant le traitement des patients par l Avastin, un anticorps bloquant du VEGF ne leur confĂšre qu une augmentation limitĂ©e de la durĂ©e de survie sans progression. Les mĂ©canismes de rĂ©currence tumorale sont extrĂȘmement complexes. Les glioblastomes sont en effet des tumeurs particuliĂšrement hĂ©tĂ©rogĂšnes sur le plan gĂ©nĂ©tique, il existe trĂšs peu de marqueurs molĂ©culaires d expression fiables. La contribution Ă la rĂ©cidive des potentiels angiogĂ©niques, infiltrants, et souches est difficile Ă modĂ©liser. Notre laboratoire s intĂ©resse Ă la caractĂ©risation de nouveaux modulateurs de l angiogenĂšse, dont certains pourraient contribuer Ă la croissance tumorale, indĂ©pendamment ou en aval du VEGF chez les patients traitĂ©s par l Avastin. Nous avons Ă©tudiĂ© l'expression de deux gĂšnes candidats, surexprimĂ©s de façon significative dans les GBM et dont l'expression semble liĂ©e Ă l'angiogenĂšse tumorale : DPY19L1 et KIF20A. Nous avons identifiĂ© DPY19L1 comme marqueur pronostique du GBM. Ce gĂšne est exprimĂ© dans les cellules musculaires lisses, oĂč il pourrait participer Ă la rĂ©sistance de la tumeur aux anti-angiogĂ©niques, en interagissant avec la voie thrombospondine/TGFb. KIF20A quant Ă lui est exprimĂ© dans les cellules souches tumorales et semble impliquĂ© dans la vascularisation et la rĂ©sistance tumorale. Dans un second temps, nous avons Ă©tudiĂ© la façon dont les GBM Ă©chappent aux traitements anti-angiogĂ©niques, tel que l Avastin, par la mise en place d'un systĂšme d'Ă©tude in vitro et in vivo, basĂ© sur l utilisation de cellules de patients atteints de GBM, ayant la capacitĂ© de pousser sous forme de neurosphĂšres. Les cellules xĂ©nogreffĂ©es chez la souris immunodĂ©fisciente permettent le dĂ©veloppement d une tumeur trĂšs invasive, co-optive et insensible aux traitements anti-angiogĂ©niques. Ces tumeurs vont donc permettre d Ă©tudier ce mode de vascularisation participant activement Ă la rĂ©cidive de la tumeur chez les patients traitĂ©s avec l Avastin afin de dĂ©velopper des traitements contrecarrant ce mĂ©canisme. Dans ce modĂšle, seul l un des gĂšnes candidats dĂ©finis au dĂ©but de ce travail, DPY19L1, semble participer Ă la croissance tumorale.Angiogenesis is a major element driving malignancy of tumors like glioblastoma (GBM). However, Avastin,a neutralizing antibody directed against VEGF, provides only a limited therapeutical benefit in terms ofprogression free survival. The mechanisms of recurrence are complex due to extreme heterogeneity ofglioblastoma at the genetic and tissular levels. There is a lack of diagnosis and prognosis markers for GBM.The relative contribution of the angiogenic, infiltrative, and stem potentials to tumor relapse is difficult tomodel. Our laboratory aims at characterizing new modulators of tumor vascularization, some of whichcould contribute to the tumor growth and resistance, independently or downstream VEGF in patientstreated with Avastin. We have studied the expression of two candidate genes, significantly overexpressedin GBM and which expression seems to be linked to tumor vascularization: DPY19L1 and KIF20A. Weidentified DPY19L1 as a prognosis marker of GBM. This gene is expressed in smooth muscle cellsspecifically in tumoral tissue, where it could participate to tumor resistance to anti-angiogenics, byinteracting with the thrombospondin/TGFb pathway. KIF20A is expressed in glioma stem cells and seemsto be implicated in the vascularization and tumor resistance. Next, we have studied the way by whichGBM resist to anti-angiogenics such as Avastin, by the development of an in vitro and in vivo modelsystem, based on GBM cells cultured as neurospheres. When xenografted in immunodeficient mice, thesecells induce the growth of very invasive, co-optive tumors which are insensitive to angiogenesis inhibitors.These tumors will allow investigating alternative modes of vascularization which are actively involved intumor recurrence in patients treated with Avastin, namely co-option and transdifferentiation and theirmolecular regulation. In this model, one of the candidate genes defined at the beginning of this study,DPY19L1, seems to be implied in tumor growth and specifically labels tumor cells with co-optive andtransdifferenciating properties.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF
Evaluation de la filiÚre AVC au CHU d'Angers (la filiÚre thrombolyse et le parcours de soins des patients présentant un AVC ischémique ou un AIT)
L'Ă©valuation de l'unitĂ© neuro-vasculaire et de la filiĂšre "thrombolyse" au CHU d'Angers semblait indispensable 4 ans aprĂšs son ouverture. L'objectif Ă©tait d'Ă©valuer la prise en charge des patients victimes d'un AVC ischĂ©mique ou d'un AIT entre mai et novembre 2012 afin d'optimiser son fonctionnement. Concernant la filiĂšre thrombolyse, on note des dĂ©lais de prise en charge proches des recommandations internationales notamment pour les dĂ©lais arrivĂ©e-imagerie et arrivĂ©e-dĂ©but de thrombolyse pour les patients pris en charge sur Larrey en comparaison avec une prise en charge au SAU. Cependant, nous notons un dĂ©lai prĂ©-hospitalier encore trop long. Concernant la prise en charge en unitĂ© neuro-vasculaire, celle-ci permet, en accord avec les donnĂ©es de la littĂ©rature, une rĂ©duction des complications en comparaison avec une prise en charge en unitĂ© d'hospitalisation conventionnelle. Cependant on note certaines faiblesses concernant le bilan Ă©tiologique souvent incomplet Ă la sortie d'hospitalisation du patient et des longs dĂ©lais pour la rĂ©alisation des examens aprĂšs la sortie, notamment pour l'IRM cĂ©rĂ©brale et l'Ă©chographie cardiaque. Cette Ă©tude est extrĂȘmement encourageante et montre de vĂ©ritables progrĂšs en terme de prise en charge des patients prĂ©sentant un AVC. L'unitĂ© neuro-vasculaire du CHU d'Angers a su au cours des 4 derniĂšres annĂ©es se dĂ©velopper et occuper une place indispensable au sein du service de neurologie, du CHU mais aussi de la rĂ©gion.The evaluation of the neurovascular unit and die "thrombolysis" CHU d'Angers seemed necessary four years after its opening. The objective was to evaluate the management of patients who have suffered an ischemic stroke or TIA between May and November 2012 in order to optimize its operation.On thrombolysis sector, there deadlines care closer to international recommendations including the arrival-time imaging and arrival-early thrombolysis for patients supported on Larrey compared with care at UAA. However, we note a too long pre-hospital delay. Regarding support in neurovascular unit, it allows, in agreement with literature data, a reduction in complications compared with care in conventional hospital unit. However there is some weaknesses in the often incomplete in the hospital patient discharge and long delays in completion of the reviews after the release etiologic, including brain MRI and echocardiography. This study is extremely encouraging and shows real progress in terms of care for stroke patients. The Stroke Unit of the University Hospital of Angers knew in the past four years to develop and occupy a vital place in the Department of Neurology, University Hospital but also in the region.ANGERS-BU MĂ©decine-Pharmacie (490072105) / SudocSudocFranceF
Coupling biophysical and micro-economic models to assess the effect of mitigation measures on greenhouse gas emissions from agriculture
International audienceAgricultural soils are a major source of atmospheric nitrous oxide (N2O), a potent greenhouse gas (GHG). Because N2O emissions strongly depend on soil type, climate, and crop management, their inventory requires the combination of biophysical and economic modeling, to simulate farmers' behavior. Here, we coupled a biophysical soil-crop model, CERES-EGS, with an economic farm type supply model, AROPAj, at the regional scale in northern France. Response curves of N2O emissions to fertilizer nitrogen (Nf) inputs were generated with CERES-EGC, and linearized to obtain emission factors. The latter ranged from 0.001 to 0.0225 kg N2O-N kg-1 Nf, depending on soil and crop type, compared to the fixed 0.0125 value of the IPCC guidelines. The modeled emission factors were fed into the economic model AROPAj which relates farm-level GHG emissions to production factors. This resulted in a N2O efflux 20% lower than with the default IPCC method. The costs of abating GHG emissions from agriculture were calculated using a first-best tax on GHG emissions, and a second-best tax on their presumed factors (livestock size and fertilizer inputs). The first-best taxation was relatively efficient, achieving an 8\% reduction with a tax of 11 euro/t-CO2-equivalent, compared to 68 euro/t-CO2eq for the same target with the second-best scheme
From crops to products for crops: preserving the ecosystem through the use of bio-based molecules
In a context of dwindling oil reserves and environmental pressures, the chemical industry needs to innovate by developing new processes for producing bioproducts from raw plant materials. Unsaturated fatty acids from vegetable oils constitute a highly promising renewable resource that can be used to diversify productions, decreasing reliance on petroleum. A starting material rich in oleic acid has been obtained through the selection of high-oleic sunflower varieties and enzymatic hydrolysis of the oil they produce. The double bonds of this unsaturated raw material have been cleaved in green oxidizing conditions involving a biphasic lipophilic-aqueous system including hydrogen peroxide as an oxidant and a peroxo-tungsten complex Q3 {PO2[WO(O2)2]4} as a phase-transfer catalyst (PTC) and co-oxidant. This PTC efficiently transferred oxygen to the substrate in the lipophilic phase. A mono-acid (pelargonic acid) and a di-acid (azelaic acid), with shorter, unusual hydrocarbon chains not present in the natural state, were synthesized and purified through an intensive process. Pelargonic acid was then formulated as an environmentally friendly biocontrol agent for weeds. We extended this green process of oxidative scission to other fatty acids and derivatives, to obtain other short-chain acids with diverse potential applications. This production chain (crops, reaction and purification processes, products, applications) is based on a sustainable development strategy.
Dans un contexte de diminution des rĂ©serves fossiles et de pressions rĂ©glementaires et environnementales, lâindustrie chimique tend Ă innover en dĂ©veloppant de nouveaux procĂ©dĂ©s pour la production de bioproduits dâorigine vĂ©gĂ©tale. Les acides gras insaturĂ©s dâune huile vĂ©gĂ©tale constitue une ressource renouvelable prometteuse qui peut ĂȘtre utilisĂ©e pour diversifier les productions et rĂ©duire la dĂ©pendance vis-Ă -vis du pĂ©trole. Dans cet article, une matiĂšre premiĂšre riche en acide olĂ©ique a Ă©tĂ© obtenue par lâhydrolyse enzymatique de lâhuile de tournesol hautement olĂ©ique, obtenue par sĂ©lection variĂ©tale. Les doubles liaisons de cette matiĂšre premiĂšre insaturĂ©e ont Ă©tĂ© clivĂ©es dans des conditions oxydantes impliquant un systĂšme biphasique aqueux-lipophile, avec le peroxyde dâhydrogĂšne comme oxydant et le complexe peroxo-tungtĂšne Q3{PO2[WO(O2)2]4} comme catalyseur de transfert de phase (CTP) et co-oxydant. Ce CTP a permis dâassurer un transfert efficace vers le substrat en phase lipophile. Un mono-acide (acide pĂ©largonique) et un di-acide (acide azĂ©laĂŻque) Ă chaĂźnes impaires plus courtes, peu prĂ©sentes Ă lâĂ©tat naturel, ont Ă©tĂ© ainsi synthĂ©tisĂ©s et purifiĂ©s grĂące Ă un procĂ©dĂ© intensifiĂ©. Lâacide pĂ©largonique a Ă©tĂ© formulĂ© en tant quâagent de biocontrĂŽle Ă©cocompatible. Ce procĂ©dĂ© vert de scission oxydante a Ă©tĂ© appliquĂ© Ă dâautres acides gras et Ă leurs dĂ©rivĂ©s pour obtenir de nouveaux acides Ă chaĂźnes courtes ayant diffĂ©rentes applications potentielles. Cette filiĂšre de production (culture, procĂ©dĂ©s de transformation et de purification, produits et leurs application) est basĂ©e sur une stratĂ©gie de dĂ©veloppement durable
A repetitive probe for FISH analysis of bovine interphase nuclei
The purpose of this study was to generate repetitive DNA sequence probes for the analysis of interphase nuclei by fluorescent in situ hybridisation (FISH). Such probes are useful for the diagnosis of chromosomal abnormalities in bovine preimplanted embryos. Of the seven probes (E1A, E4A, Ba, H1A, W18, W22, W5) that were generated and partially sequenced, five corresponded to previously described Bos taurus repetitive DNA (E1A, E4A, Ba, W18, W5), one probe (W22) shared no homology with other DNA sequences and one (H1A) displayed a significant homology with Rattus norvegicus mRNA for secretin receptor transmembrane domain 3. Fluorescent in situ hybridisation was performed on metaphase bovine fibroblast cells and showed that five of the seven probes hybridised most centromeres (E1A, E4A, Ba, W18, W22), one labelled the arms of all chromosomes (W5) and the H1A probe was specific to three chromosomes (ch14, ch20, and ch25). Moreover, FISH with H1A resulted in interpretable signals on interphase nuclei in 88% of the cases, while the other probes yielded only dispersed overlapping signals
Coupling biophysical and micro-economic models to assess the effect of mitigation measures on greenhouse gas emissions from agriculture
Agricultural soils are a major source of atmospheric nitrous oxide (N2O), a potent greenhouse gas (GHG). Because N2O emissions strongly depend on soil type, climate, and crop management, their inventory requires the combination of biophysical and economic modeling, to simulate farmers' behavior. Here, we coupled a biophysical soil-crop model, CERES-EGS, with an economic farm type supply model, AROPAj, at the regional scale in northern France. Response curves of N2O emissions to fertilizer nitrogen (Nf) inputs were generated with CERES-EGC, and linearized to obtain emission factors. The latter ranged from 0.001 to 0.0225 kg N2O-N kg-1 Nf, depending on soil and crop type, compared to the fixed 0.0125 value of the IPCC guidelines. The modeled emission factors were fed into the economic model AROPAj which relates farm-level GHG emissions to production factors. This resulted in a N2O efflux 20% lower than with the default IPCC method. The costs of abating GHG emissions from agriculture were calculated using a first-best tax on GHG emissions, and a second-best tax on their presumed factors (livestock size and fertilizer inputs). The first-best taxation was relatively efficient, achieving an 8\% reduction with a tax of 11 euro/t-CO2-equivalent, compared to 68 euro/t-CO2eq for the same target with the second-best scheme.nitrous oxide; agro-ecosystem model; economic modeling; greenhouse gas; mitigation measures
Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export
Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4+ and CD8+ thymocytes in adult mice (39±10Ă106 in transgenic mice and 12±5Ă106 in age-matched controls). Furthermore, thymocyte export was disturbed
Nouveaux procédés verts d'oxydation de l'acide oléique
Dans un contexte de rarĂ©faction des ressources pĂ©troliĂšres et de pressions environnementales, l industrie chimique a besoin d'innover en dĂ©veloppant de nouvelles filiĂšres destinĂ©es Ă l'Ă©laboration de bioproduits, Ă partir de matiĂšres premiĂšres d'origine vĂ©gĂ©tale. Les acides gras insaturĂ©s obtenus Ă partir des huiles vĂ©gĂ©tales, constituent ainsi une ressource renouvelable Ă fort potentiel permettant de diversifier les approvisionnements d'origine pĂ©troliĂšre. Notre intĂ©rĂȘt s'est portĂ© sur la rĂ©action de scission oxydative d acides gras insaturĂ©s pour conduire Ă des monoacides et diacides Ă chaĂźnes courtes et impaires, peu ou pas disponibles Ă l Ă©tat naturel. Ce type de chaĂźnes hydrocarbonĂ©es est recherchĂ© dans l industrie, car elles possĂšdent des propriĂ©tĂ©s spĂ©cifiques, mais elles ne sont actuellement produites qu'Ă partir de ressources fossiles. L'objectif Ă©tait donc de mettre au point un procĂ©dĂ© de clivage oxydatif performant, moins onĂ©reux et moins polluant que l ozonolyse, le seul procĂ©dĂ© industriel opĂ©rationnel. Les conditions oxydantes sĂ©lectionnĂ©es font appel Ă l eau oxygĂ©nĂ©e en tant qu oxydant, associĂ©e Ă un catalyseur de transfert de phase, sans avoir recours Ă un solvant organique. Plusieurs catalyseurs de transfert de phase Q3{PO4[WO(O2)2]4} ont Ă©tĂ© prĂ©parĂ©s Ă partir de l acide tungstophosphorique, d eau oxygĂ©nĂ©e et d'un sel d ammonium quaternaire (Q+,Cl-), afin de comparer leur efficacitĂ© Ă transfĂ©rer l'oxygĂšne vers le substrat en phase organique. Une optimisation des paramĂštres rĂ©actionnels a Ă©tĂ© effectuĂ©e avec le catalyseur le plus performant. De plus, deux protocoles ont Ă©tĂ© mis au point, pour la prĂ©paration in-situ du catalyseur et pour sa rĂ©cupĂ©ration en fin de rĂ©action. Le procĂ©dĂ© a Ă©tĂ© gĂ©nĂ©ralisĂ© Ă des dĂ©rivĂ©s d acides gras dans le but d obtenir d'autres acides Ă chaĂźnes courtes, rĂ©pondant Ă une large gamme d'applications. Le gain environnemental liĂ© Ă ce nouveau procĂ©dĂ© a Ă©tĂ© Ă©valuĂ© par le calcul d indicateurs verts. Afin d envisager un recyclage plus aisĂ© du catalyseur, l anion oxodiperoxotungstate {PO4[WO(O2)2]4}3-, l espĂšce active du catalyseur, a Ă©tĂ© supportĂ© sur des rĂ©sines Ă©changeuses d anions. Deux types de rĂ©sines macroporeuses ont Ă©tĂ© testĂ©es : des rĂ©sines commerciales (Amberlite IRA 900 et Lewatit K7367) et des rĂ©sines modifiĂ©es (type Merrifield). Nous avons montrĂ© que ces derniĂšres conduisent Ă de meilleurs rendements de scission oxydative de l acide olĂ©ique que les rĂ©sines commerciales, et ce, malgrĂ© la prĂ©sence de solvants. Cependant, l immobilisation de l anion oxodiperoxotungstate sur les rĂ©sines commerciales a permis la synthĂšse en une seule Ă©tape d acĂ©tals, composĂ©s prĂ©sentant un grand intĂ©rĂȘt pour la synthĂšse de dĂ©rivĂ©s Ă haute valeur ajoutĂ©e. En utilisant l acĂ©tone, Ă la fois comme rĂ©actif et solvant, nous avons obtenu de bons rendements en cĂ©tal. De plus, la rĂ©action d acĂ©talisation one-pot de l acide olĂ©ique a pu ĂȘtre Ă©tendue Ă d autres solvants (alcools), offrant la possibilitĂ© de synthĂ©tiser un large panel d acĂ©tals. Le procĂ©dĂ© dĂ©veloppĂ© est particuliĂšrement intĂ©ressant car il conduit directement Ă la synthĂšse d acĂ©tals ou de cĂ©tals Ă partir d un acide gras insaturĂ© biosourcĂ©, en Ă©vitant les Ă©tapes de rĂ©actions intermĂ©diaires.In a context of scarce oil resources and environmental pressures, the chemical industry needs to innovate by developing new production chains aiming the design of bioproducts from biobased raw materials. Unsaturated fatty acids derived from vegetable oils, thus represents renewable resources with a great potential, allowing to diversify petroleum based supplies. Our interest is focused on the oxidative cleavage reaction of unsaturated fatty acids to yield mono-acids and di-acids with shorter and odd hydrocarbon chains, which are not available at a natural state. Such hydrocarbon chains are attractive for industry because they meet specific properties. But, they are currently only produced from fossil resources. Therefore, the objective was to develop an efficient method for oxidative cleavage, less expensive and less polluting than ozonolysis, the only operational industrial process. The selected oxidizing conditions employs hydrogen peroxide as oxidant, together with a phase transfer catalyst, without using an organic solvent. Several phase transfer catalysts Q3{PO4[WO(O2)2]4} were prepared from tungstophosphoric acid, hydrogen peroxide and a quaternary ammonium salt (Q+,Cl-), in order to compare their effectiveness in transferring oxygen to the substrate in the organic phase. An optimization of reaction parameters was carried out with the most performing catalyst. In addition, two protocols have been developed for the in-situ preparation of the catalyst and its recovery after reaction. The method was extended to fatty acids derivatives, in order to obtain other short chain acids, having a wide range of applications. The environmental benefits associated with this new method were evaluated by calculating green indicators. To consider an easier recycling of the catalyst, the oxodiperoxotungstate anion {PO4[WO(O2)2]4}3-, the active species of the catalyst was supported on anion-exchange resins. Two types of macroporous resins were tested: commercial resins (Amberlite IRA 900 and Lewatit K7367) and modified resins (type Merrifield). We showed that the modified resins, lead to the oxidative cleavage of oleic acid with higher yields than commercial ones, despite the presence of solvent. However, the immobilisation of the oxodiperoxtungstate anion on commercial resins allows the one-step synthesis of acetals, compounds of great interest for the synthesis of derivatives with a high added value. Using acetone as both reagent and solvent, we obtained good yields in ketal. Furthermore, the "one-pot" acetalization reaction of oleic acid was extended to other solvents (alcohols) as an opportunity to synthesize a wide range of acetals. The developed process is particularly interesting as it leads to the direct synthesis of ketal or acetals from an unsaturated fatty acid, avoiding the intermediate reaction stepsTOULOUSE-INP (315552154) / SudocSudocFranceF
Patient/family views on data sharing in rare diseases: study in the European LeukoTreat project.: Survey assessing data sharing in leukodystrophies
International audienceThe purpose of this study was to explore patient and family views on the sharing of their medical data in the context of compiling a European leukodystrophies database. A survey questionnaire was delivered with help from referral centers and the European Leukodystrophies Association, and the questionnaires returned were both quantitatively and qualitatively analyzed. This study found that patients/families were strongly in favor of participating. Patients/families hold great hope and trust in the development of this type of research. They have a strong need for information and transparency on database governance, the conditions framing access to data, all research conducted, partnerships with the pharmaceutical industry, and they also need access to results. Our findings bring ethics-driven arguments for a process combining initial broad consent with ongoing information. On both, we propose key item-deliverables to database participants
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