Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

Background: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. Results: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. Conclusions: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential

Characterization of function of the GlgA2 glycogen/starch synthase in Cyanobacterium sp. Clg1 highlights convergent evolution of glycogen metabolism into starch granule aggregation

At variance with the starch-accumulating plants and most of the glycogen-accumulating cyanobacteria, Cyanobacterium sp. CLg1 synthesizes both glycogen and starch. We now report the selection of a starchless mutant of this cyanobacterium that retains wild-type amounts of glycogen. Unlike other mutants of this type found in plants and cyanobacteria, this mutant proved to be selectively defective for one of the two types of glycogen/starch synthase: GlgA2. This enzyme is phylogenetically related to the previously reported SSIII/SSIV starch synthase that is thought to be involved in starch granule seeding in plants. This suggests that, in addition to the selective polysaccharide debranching demonstrated to be responsible for starch rather than glycogen synthesis, the nature and properties of the elongation enzyme define a novel determinant of starch versus glycogen accumulation. We show that the phylogenies of GlgA2 and of 16S ribosomal RNA display significant congruence. This suggests that this enzyme evolved together with cyanobacteria when they diversified over 2 billion years ago. However, cyanobacteria can be ruled out as direct progenitors of the SSIII/SSIV ancestral gene found in Archaeplastida. Hence, both cyanobacteria and plants recruited similar enzymes independently to perform analogous tasks, further emphasizing the importance of convergent evolution in the appearance of starch from a preexisting glycogen metabolism network.Peer Reviewe

A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor

A monoclonal anti-CD160 antibody inhibits the growth of new vessels in pathological ocular and tumor neoangiogenesis but not in healthy tissues

Comparaison biochimique du métabolisme des polysaccharides de réserve chez les Chlamydiales et les Cyanobactéries : une vision de l'évolution du métabolisme du glycogène et de l'amidon chez les eucaryotes

Le glycogène et l’amidon sont les formes de polysaccharides de réserve les plus répandues. Ils sont tous deux constitués de résidus de glucose liés en α-1,4, et branchés en α-1,6. Bien qu’ils se distinguent fortement par leurs propriétés physico-chimiques, l’amidon a évolué à partir d’un métabolisme du glycogène préexistant. Il est apparu après l’endosymbiose primaire du plaste qui a eu lieu il y a plus d’un milliard d’années entre une cellule eucaryote et une cyanobactérie. Il a été proposé que l’endosymbiose primaire du plaste ait impliqué la manipulation du métabolisme des polysaccharides de réserve par une bactérie intracellulaire obligatoire pathogène qui appartient à l’ordre des Chlamydiales. Afin de comprendre l'histoire évolutive des gènes du métabolisme du glycogène, et enquêter sur l’implication d’une bactérie de l’ordre des Chlamydiales dans l’endosymbiose plastidiale, nous nous sommes intéressés à l’évolution des polysaccharides chez les cyanobactéries et les Chlamydiales. Nous avons donc disséqué le fonctionnement de ce métabolisme chez Cyanobacterium sp. CLg1, une cyanobactérie de l’ordre des Chroococcales qui accumule simultanément de l’amidon et du glycogène. D’autres part, nous avons étudié l’évolution du métabolisme des polysaccharides de réserve chez les Chlamydiales. La plupart des enzymes du métabolisme du glycogène des Chlamydiales ont été caractérisées. Les résultats de la caractérisation renforcent notre théorie de ménage à trois et l’implication des Chlamydiales dans l’établissement de l’endosymbiose primaire du plaste. L’impact du métabolisme du glycogène des Chlamydiales sur l’évolution de celui des plantes et des animaux est discuté.Glycogen and starch are the most commonly found forms of storage polysaccharides. They both consist solely of glucose residues linked and branched respectively through α-1,4 and α-1,6 glycosidic bonds. Although they considerably differ in their physicochemical properties, starch evolved in only a few steps in eukaryotes from the pre-existing eukaryotic glycogen metabolism. It appeared, after primary plastidial endosymbiosis which took place over one billion years ago between an ancestral cyanobacterium and a heterotrophic eukaryotic host. This endosymbiosis has been recently proposed in the “Ménage à Trois Hypothesis” (MATH) to have been triggered and facilitated through manipulation of glycogen metabolism by obligate intracellular bacteria pathogens, belonging to the order Chlamydiales. In order to understand the evolutionary history of glycogen metabolism genes, and to investigate the possible nature of the Chlamydiales involvement in primary plastid endosymbiosis, we probed the evolution of storage polysaccharide metabolism in both extant Chroococcales and Chlamydiales. So we dissected the functioning of the metabolism in Cyanobacterium sp. CLg1, a cyanobacterium of order Chroococcales that simultaneously accumulate starch and glycogen. On the other hand, we investigated the evolution of storage polysaccharide metabolism in Chlamydiales. Several recombinant enzymes of glycogen metabolism were thus characterized. Our characterization strengthens the MATH and the implication of the Chlamydiales in the establishement of primary plastidial endosymbiosis. The importance of our findings with respect to the evolution of glycogen metabolism in animals and plants is discussed

Modélisation du profil utilisateur et personnalisation dans les espaces de vie intelligents

Personalization in smart spaces is usually limited to enhance the Human machine interface and to customize the environement services according to the user preferences. In addition, the aim of smart living spaces is to provide autonomy and assistance to people with disabilities and elderly people in order to increase their independence. However, these objectives remain far from achievement due to the complexity of this domain wich requires a big motivation and needs a wide collaboration of many partners (industrial, research, government, etc.), and involvement of several disciplines (engineer, ergonomics , doctors, etc.). The work done in this thesis extends the personalisation concept in smart environments in order to take into account the specific characteristics and needs of dependent people through the user centred technologies. The approach we have adopted for the provision of personalized services within smart environments dedicated to dependant pepole is based on the identification and detection of the handicap situations in these spaces. The underlying concept of this approach is built upon two models (user model and environment model) and the matching between them. The user model extrapolates the model proposed by Amato in order to be more generic and to support all user profiles, especially users with special needs. The environment model is organised as a hierarchical structure based on categories. The matching is a virtual relationship based on observation of real situations and on the semantic of the user and the environment model attributes ; it represents the interactions between these attributes giving the handicap situation. However, to define the user model attributes we have developed systems based on sensors (CyberGlove, STS, etc.). which allow us to quantify some user characteristics such as user hand force and user hand work space. To identify the matching between both user and environment models, we have developed an evaluation strategy relying on qualitative and quantitative methods. The qualitative method is based on observation process while the quantitative method is based on software tools. For the formal representation of our terminological knowledge, we have used a Description Logic (DL). Our concept was implemented using ontology and Semantic web and was developed as a framework named SMF (Semantic Matching Framework) and then integrated within the Smart Home platform. A demonstrator prototype was evaluated in an experimental environment with dependant users and presented during the Smart Home Workshop held in INT. The evaluation phase was performed with users in three experimental sites : the rehabilitation hospital of Garches, the French Muscular dystrophies Association (AFM) and the geriatrics Broca Hospital.EVRY-BU (912282101) / SudocEVRY-INT (912282302) / SudocSudocFranceF

Évaluation des performances épuratoires d’un bassin de filtration des eaux usées - étude de cas

L’administration locale du secteur de l’hydraulique de la région de Tizi Ouzou (Algérie) a entrepris un vaste programme de réalisation de bassins de filtration en 1996. Après deux décennies d’exploitation de ces ouvrages, il nous a semblé nécessaire de faire le point sur leur retour d’expérience. L’objectif de cette étude est de tester l’efficacité de ce système épuratoire des eaux usées par l’analyse d’un bassin de filtration témoin de cette région. L’idée est de déterminer les caractéristiques des effluents à l’entrée et à la sortie de l’ouvrage, en se basant sur l’analyse de six paramètres qui sont la température, la turbidité, le pH, les matières en suspension, la demande biologique en oxygène à cinq jours (DBO5) et la demande chimique en oxygène (DCO). Un suivi journalier de ces paramètres a été réalisé pour lequel un protocole expérimental avec une démarche rigoureuse et cohérente des principales étapes a été développé. Sur la base des résultats obtenus, nous avons pu évaluer les performances épuratoires de ce bassin de filtration, analysées par rapport au taux d'élimination de la pollution de l'eau. Ceci nous a permis de recommander le dimensionnement et la conception d'une filière d'épuration utilisant un bassin de filtration combiné judicieusement à un bassin de décantation afin d’atteindre une meilleure performance épuratoire.The local authority of the hydraulic sector in the region of Tizi Ouzou (Algeria) has undertaken a vast programme of filtering basins in 1996. After two decades of operation of these structures, it seemed necessary to evaluate their feedback. The objective of this study is to test the efficiency of this wastewater purifying system by analyzing a sample filtration basin from this region. The idea was to determine the effluent characteristics at the inlet and outlet of the basin, based on the analysis of six parameters which are the temperature, turbidity, pH, suspended matter, chemical oxygen demand (COD), and five-day biological oxygen demand (BOD5). A daily monitoring of these parameters was performed for which an experimental protocol with a rigorous and consistent approach for the major steps has been developed. The results showed that we were able to assess the purification performance of the filtration basin which is analyzed with respect to the elimination rate of water pollution. These results enabled us to suggest the dimensioning and design of a wastewater treatment structure combining a filtration basin and a sedimentation basin to obtain a better purification performance