Viotech Communications (France)

BackgroundAging signs are much visible on the surface of the skin that presents different changes: cheeks start to sag, more and deeper wrinkles appear, and pigmentation spots increase. Face diagnostic to recommend products includes assessing cutaneous micro‐relief or the micro‐depressive network on the face. Furthermore, there is an increasing demand for clinical and instrumental methods to prove the efficacy of anti‐aging treatments. As a result, very accurate and sensitive three‐dimensional (3D) devices are developed and validated to measure and quantify aging skin and to catch fine anti‐aging products acting on wrinkles and fine lines.MethodsAEVA‐HE, a non‐invasive 3D method based on fringe projection technology, is used to robustly characterize the skin micro‐relief from a full‐face acquisition and from multiple extracted zones of interest. In vitro and in vivo studies are conducted to assess the reproducibility of this system and its precision toward a standard fringe projection system, DermaTOP.ResultsThe AEVA‐HE successfully measured micro‐relief and wrinkles and demonstrated the reproducibility of measurements. AEVA‐HE parameters were found highly correlated to DermaTOP.ConclusionThe present work illustrates the performance of the AEVA‐HE device and its dedicated software kit as a precious tool for quantifying the major characteristics of wrinkles appearing with age and thus offers a high potential for assessing the effect of anti‐wrinkling products.

This chapter proposes a novel concept towards the deployment of a networked 'Media Ecosystem'. The proposed solution is based on a flexible cooperation between providers, operators, and end-users, finally enabling every user first to access the offered multimedia services in various contexts, and second to share and deliver his own audiovisual content dynamically, seamlessly, and transparently to other users. Towards this goal, the proposed concept provides content-awareness to the network environment, network- and user contextawareness to the service environment, and adapted services/content to the end user for his best service experience possible, taking the role of a consumer and/or producer.

We have characterized three different programs of activation for alloreactive CD8 T cells expressing the BM3.3 TCR, their elicitation depending on the characteristics of the stimulating peptide/MHC complex. The high-affinity interaction between the TCR and the K(b)-associated endogenous peptide pBM1 (INFDFNTI) induced a complete differentiation program into effector cells correlated with sustained ERK activation. The K(bm8) variant elicited a partial activation program with delayed T cell proliferation, poor CTL activity and undetectable ERK phosphorylation; this resulted from a low-avidity interaction of TCR BM3.3 with a newly identified endogenous peptide, pBM8 (SQYYYNSL). Interestingly, mismatched pBM1/K(bm8) complexes induced a split response in BM3.3 T cells, with total reconstitution of T cell proliferation but defective generation of CTL activity that was correlated with strong but shortened ERK phosphorylation. Crystal structures highlight the molecular basis for the higher stability of pBM8/K(bm8) compared to pBM1/K(bm8) complexes that exist in two conformers. This study illustrates the importance of the stability of both peptide/MHC and peptide/MHC-TCR interactions for induction of sustained signaling required to induce optimal CTL effector functions. Subtle allelic structural variations, amplified by peptide selection, may thus orient distinct outcomes of alloreactive TCR-based therapies.

The alloreactive BM3.3TCR interacts with high affinity with H-2Kb loaded with the endogenous peptide pBM1 (INFDFNTI), and shows low affinity cross-reactivity for H-2Kb loaded with a viral peptide VSV8 (RGYVYQGL), CTL activity requiring 10(3)-fold higher peptide concentration and being highly sensitive to inhibition by anti-CD8 monoclonal antibody. VSV8 peptides substituted with pBM1/TCR contact residues (N6 and T7) retained low affinity characteristics and among pBM1 peptides substituted with residues Q6 and/or G7 present in VSV8, only pBM1(G7) was recognized, albeit with characteristics akin to those of VSV8. Despite the difference in KD values and the faster dissociation rate of multimeric VSV8/H-2Kb as compared to pBM1/H-2Kb complexes, similar TCR occupancy could be achieved with both multimers either at 4 or 37 degrees C. Only TCR engagement with pBM1/H-2Kb, however, resulted in early (Ca2+ flux) and late (CD69 expression) activation events in naive BM3.3TCR CD8 T cells. CD8 coreceptor, essential for binding of the weak agonists, was dispensable for binding of pBM1/H-2Kb multimers and their induction of signaling in naive T cells. Hence, high number of TCR and coreceptor engagement by weak agonists fail to substitute for strong agonist TCR engagement that can be coreceptor-independent and involve a limited number of TCR.

One of the main limitations of radioimmunotherapy (RIT) is the secondary toxicity related to the poor therapeutic indices achieved with labeled whole immunoglobulin (Ig)G or F(ab')2 fragments. To overcome this problem, we have developed a two-step targeting method, which we refer to as the Affinity Enhancement System (AES), using a radiolabeled bivalent hapten and a bispecific antibody recognizing the hapten and a target cell antigen. This method has been applied successfully to immunoscintigraphy in carcinoembryonic antigen (CEA)-expressing carcinoma patients and increased tumor to normal tissue uptake ratios have been achieved. The aim of the current study was to evaluate the application of AES to RIT of CEA-expressing solid tumors in an animal model. Nude mice grafted with LS174T human colorectal carcinoma were treated either with 111 megabecquerels (MBq) of iodine-131 labeled bivalent diethylenetriamine pentaacetic acid (DTPA) hapten 20 hours after pretargeting by anti-CEA x anti-DTPA-indium bispecific antibody or 12 MBq of iodine-131 labeled anti-CEA IgG. Treatment with the IgG induced only a growth delay of 53 +/- 5 days but all tumors progressed. Treatment with the AES was highly efficient because tumor growth inhibition was achieved over 150 days. Hematologic and overall toxicity of both treatments were equivalent. The long term tumor regression consecutive to AES RIT represents a very significant improvement over the use of directly labeled IgG. Toxicity consecutive to AES or IgG RIT were similar despite an administered activity nearly ten times higher with the AES. However, given the efficacy of the AES treatment, a lower dose may afford lower toxicity and significant antitumor effect.

The alpha-subunit of interleukin-6 (IL-6) receptor is a member of the hematopoietin receptor family. The alignment of its amino acid sequence with those of other members of this family (human somatotropin receptor/murine IL-3 receptor beta and human IL-2 receptor beta) has suggested that amino acids included in two SSFY repeats found in each of its hematopoietin receptor domains, contribute to the binding of the ligand. The involvement of these amino acids in IL-6 binding and signal transduction was studied by site-directed mutagenesis and molecular modelling. We present a computer-derived three-dimensional model of the IL-6/IL-6 receptor complex based on the structure of the human somatotropin/human somatotropin receptor complex. This model allowed the location of distinct regions important for IL-6 and gp130 binding. We show that some of the residues included in the SSFY repeats located in our IL-6 receptor model in the loops between beta-strands E and F of domain-I and B' and C', of domain-II, participate in the formation of a major IL-6-binding site. These residues are necessary for IL-6 and gp130 binding and for signal transduction. Using our IL-6 receptor mutants we mapped the epitopes of our anti-(IL-6 receptor) neutralising monoclonal antibodies to these residues. Our results demonstrate that a generic hematopoietin receptor family structural module can be used for the study of both alpha and beta receptor subunits belonging to this family.

The in vivo efficacy of 25.3 monoclonal antibody (mAb) directed against human LFA1 molecule was assessed in ten patients with steroid-resistant grade III-IV acute graft-versus-host disease (AGVHD). These patients received non-T-cell-depleted allogeneic bone marrow transplantation for aplastic anemia in two cases and hematologic malignancies in eight cases. Five grafts were fully matched, three were one antigen-mismatched, and two were two antigen-mismatched. Despite GVHD prophylaxis with cyclosporin A and short-term methotrexate, AGVHD occurred after a median of 24 days and clearly progressed under prednisone (median 2 mg/kg), given for a median of 12 days. 25.3 mAb was given at a dosage of 0.1 mg/kg in a 4-h perfusion for five daily doses without any clinical or biological side effects. Thirty percent of the patients experienced a reduction in the overall grading with two complete responses. Partial response in at least one involved organ (mostly skin) occurred in 80% of the patients. However, seven out of the eight responding patients experienced a new episode of AGVHD. This observation, which confirms that inhibiting a functional molecule is as efficient as a cytolytic therapy, offers an alternative strategy to antithymocyte globulin (ATG) and cytotoxic mAb in controlling steroid-resistant GVHD.