Anticorps humanisés en thérapeutique

En 2002, il était prévu que les anticorps humanisés deviendraient une classe majeure de médicaments, notamment en cancérologie. Aujourd’hui, huit d’entre eux sont utilisés en clinique et plus de quarante font l’objet d’essais cliniques. Si leurs mécanismes d’action, multiples, sont difficiles à préciser pour un anticorps donné, les observations réalisées chez les milliers de patients déjà traités démontrent clairement leur intérêt clinique. Ils sont cependant d’utilisation délicate, en particulier lorsqu’ils modulent l’activité d’effecteurs de la réponse immune. Au cours des prochaines années, de nouveaux progrès devront être faits pour sélectionner les cibles pertinentes de ces anticorps, diminuer leur immunogénicité et réduire leur coût.Since 1997, nine humanized antibodies received the approval of the FDA to be used as drugs for the treatment of various diseases including transplant rejections, metastatic breast and colon cancers, leukaemia, non-Hodgkin lymphomas, allergic conditions or multiple sclerosis. This review describes techniques used to engineer these antibodies and presents the recent evolutions of these techniques : SDRs grafting or « abbreviated » CDRs grafting. Based on the illustrative examples of several antibodies, Mylotarg®, Herceptin® or Xolair®, the therapeutic effectiveness of humanized antibodies are underlined and, with the example of Tysabri®, the sometimes dramatic adverse effects associated with their clinical use is stressed. In a second part, this review presents some future and realistic avenues to improve the effectiveness of the humanized antibodies, to decrease their immunogenicity and to reduce their cost

Proteomic profile determination of autosomal aneuploidies by mass spectrometry on amniotic fluids

<p>Abstract</p> <p>Background</p> <p>Prenatal diagnosis of chromosomal abnormalities by cytogenetic analysis is time-consuming, expensive, and requires highly qualified technicians. Rapid diagnosis of aneuploidies followed by reassurance of women with normal results can be performed by molecular analysis of uncultured foetal cells. In the present study, we developed a proteomic fingerprinting approach coupled with a statistical classification method to improve diagnosis of aneuploidies, including trisomies 13, 18, and 21, in amniotic fluid samples.</p> <p>Results</p> <p>The proteomic spectra obtained from 52 pregnant women were compiled, normalized, and mass peaks with mass-to-charge ratios between 2.5 and 50 kDa identified. Peak information was combined together and analysed using univariate statistics. Among the 208 expressed protein peaks, 40 differed significantly between aneuploid and non aneuploid samples, with AUC diagnostic values ranging from 0.71 to 0.91. Hierarchical clustering, principal component analysis and support vector machine (SVM) analysis were performed. Two class predictor models were defined from the training set, which resulted in a prediction accuracy of 92.3% and 96.43%, respectively. Using an external and independent validation set, diagnostic accuracies were maintained at 87.5% and 91.67%, respectively.</p> <p>Conclusion</p> <p>This pilot study demonstrates the potential interest of protein expression signature in the identification of new potential biological markers that might be helpful for the rapid clinical management of high-risk pregnancies.</p

ETUDE DE LA REPONSE IMMUNE CELLULAIRE DIRIGEE CONTRE LES TUMEURS VESICALES ET INFLUENCE DE LEUR CONFORMATION SPACIALE SUR L'APOPTOSE, L'EXPRESSION GENIQUE ET LA REPONSE IMMUNE

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Les différentes voies apoptotiques induites par le lentivirus Visna (inhibition par l'AZT et corrélation avec l'apoptose, in vitro)

LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Spherical Cancer Models in Tumor Biology

Three-dimensional (3D) in vitro models have been used in cancer research as an intermediate model between in vitro cancer cell line cultures and in vivo tumor. Spherical cancer models represent major 3D in vitro models that have been described over the past 4 decades. These models have gained popularity in cancer stem cell research using tumorospheres. Thus, it is crucial to define and clarify the different spherical cancer models thus far described. Here, we focus on in vitro multicellular spheres used in cancer research. All these spherelike structures are characterized by their well-rounded shape, the presence of cancer cells, and their capacity to be maintained as free-floating cultures. We propose a rational classification of the four most commonly used spherical cancer models in cancer research based on culture methods for obtaining them and on subsequent differences in sphere biology: the multicellular tumor spheroid model, first described in the early 70s and obtained by culture of cancer cell lines under nonadherent conditions; tumorospheres, a model of cancer stem cell expansion established in a serum-free medium supplemented with growth factors; tissue-derived tumor spheres and organotypic multicellular spheroids, obtained by tumor tissue mechanical dissociation and cutting. In addition, we describe their applications to and interest in cancer research; in particular, we describe their contribution to chemoresistance, radioresistance, tumorigenicity, and invasion and migration studies. Although these models share a common 3D conformation, each displays its own intrinsic properties. Therefore, the most relevant spherical cancer model must be carefully selected, as a function of the study aim and cancer type

Fluconazole Resistance and Virulence in In Vitro Induced-Fluconazole Resistant Strains and in Clinical Fluconazole Resistant Strain of <i>Cryptococcus deuterogattii</i>

Neuromeningeal cryptococcosis is a life-threatening infection of the central nervous system, caused by encapsulated yeast belonging to the Cryptococcus neoformans and Cryptococcus gattii species complexes. Recent data showed that virulence and antifungal resistance are variable for yeasts belonging to the C. gattii species complex. There is an increase in resistance to fluconazole for yeasts of the C. gattii species complex and the virulence is variable according to the genotype. In the present study, (i) we explored and compared the mechanisms of resistance to fluconazole between C. deuterogattii clinically resistant strains and induced fluconazole-resistant strains by exposure to fluconazole in vitro, and (ii) we studied their virulence in the Galleria mellonella study model. We demonstrated that the fluconazole resistance mechanisms involved were different between clinically resistant strains and induced resistant strains. We also demonstrated that fluconazole-induced resistant strains are less virulent when compared to the original susceptible strains. On the contrary, the clinically resistant strain tested maintains its virulence compared to fluconazole-susceptible strains of the same sequence type

Fate of steroid hormones and endocrine activities in swine manure disposal and treatment facilities

International audienceManure may contain high concern endocrine-disrupting compounds (EDCs) such as steroid hormones, naturally produced by pigs, which are present at mu g L-1 levels. Manure may also contain other EDCs such as nonylphenols (NP), polycyclic aromatic hydrocarbons (PAHs) and dioxins. Thus, once manure is applied to the land as soil fertilizer these compounds may reach aquifers and consequently living organisms, inducing abnormal endocrine responses. In France, manure is generally stored in anaerobic tanks prior spreading on land; when nitrogen removal is requested, manure is treated by aerobic processes before spreading. However, little is known about the fate of hormones and multiple endocrine-disrupting activities in such manure disposal and treatment systems. Here, we determined the fate of hormones and diverse endocrine activities during manure storage and treatment by combining chemical analysis and in vitro quantification of estrogen (ER), aryl hydrocarbon (AhR), androgen (AR), pregnane-X (PXR) and peroxysome proliferator-activated gamma (PPAR gamma) receptor-mediated activities. Our results show that manure contains large quantities of hormones and activates ER and AhR, two of the nuclear receptors studied. Most of these endocrine activities were found in the solid fraction of manure and appeared to be induced mainly by hormones and other unidentified pollutants. Hormones, ER and AhR activities found in manure were poorly removed during manure storage but were efficiently removed by aerobic treatment of manure

Exposure of Cryptococcus neoformans to Seven Commonly Used Agricultural Azole Fungicides Induces Resistance to Fluconazole as Well as Cross-Resistance to Voriconazole, Posaconazole, Itraconazole and Isavuconazole

International audienceCross-resistance to medical azoles by exposure to azole pesticides is well documented for Aspergillus family fungi but is poorly evaluated for other environmental pathogen fungi, particularly for yeasts belonging to the Cryptococcus neoformans/Cryptococcus gattii species complexes. Methods: One thousand C. neoformans yeast were exposed to various concentrations of seven different commonly used azole pesticides. Clones surviving exposure were picked randomly, and their minimal inhibitory concentrations (MICs) of fluconazole, voriconazole, posaconazole, itraconazole and isavuconazole were assessed. Results: Depending on the pesticide used for exposure, up to 13.3% of selected Cryptococcus colonies showed a phenotype of resistance to fluconazole, and among them, several showed cross-resistance to another or several other medical azoles. Molecular mechanisms involved in the resistance setups seem to be dependent on ERG11 and AFR1 gene overexpression. Conclusion: Exposure to any of the seven azole pesticides tested is capable of increasing the MIC of fluconazole in C. neoformans, including up to the level of the fluconazole-resistant phenotype, as well as generating cross-resistance to other medical azoles in some cases