Global gene expression profiling in human lung cells exposed to cobalt.

International audienceBACKGROUND: It has been estimated that more than 1 million workers in the United States are exposed to cobalt. Occupational exposure to 59 Co occurs mainly via inhalation and leads to various lung diseases. Cobalt is classified by the IARC as a possible human carcinogen (group 2B). Although there is evidence for in vivo and in vitro toxicity, the mechanisms of cobalt-induced lung toxicity are not fully known. The purpose of this work was to identify potential signatures of acute cobalt exposure using a toxicogenomic approach. Data analysis focused on some cellular processes and protein targets that are thought to be relevant for carcinogenesis, transport and biomarker research. RESULTS: A time course transcriptome analysis was performed on A549 human pulmonary cells, leading to the identification of 85 genes which are repressed or induced in response to soluble 59 Co. A group of 29 of these genes, representing the main biological functions, was assessed by quantitative RT-PCR. The expression profiles of six of them were then tested by quantitative RT-PCR in a time-dependent manner and three modulations were confirmed by Western blotting. The 85 modulated genes include potential cobalt carriers (FBXL2, ZNT1, SLC12A5), tumor suppressors or transcription factors (MAZ, DLG1, MYC, AXL) and genes linked to the stress response (UBC, HSPCB, BNIP3L). We also identified nine genes coding for secreted proteins as candidates for biomarker research. Of those, TIMP2 was found to be down-regulated and this modulation was confirmed, in a dose-dependent manner, at protein level in the supernatant of exposed cells. CONCLUSION: Most of these genes have never been described as related to cobalt stress and provide original hypotheses for further study of the effects of this metal ion on human lung epithelial cells. A putative biomarker of cobalt toxicity was identified

Approche immunochimique et structurale des deux formes moleculaires de la creatine kinase mitochondriale

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Modified Vaccinia virus Ankara-based vaccines in the era of personalized immunotherapy of cancer

While interest in immunotherapies is renewed by the successful introduction of immune checkpoint blocking agent in the clinic, advances in genome sequencing are opening new possibilities in the design of increasingly personalized vaccines. Personalization of medicine can now be realistically contemplated at the single patient level. Unlike the previous generation of cancer vaccines, neoantigen directed vaccines would target truly specific tumor antigens resulting from acquired tumor genome mutations. Immune response induced by this next generation vaccine would not be subject to self-tolerance and will likely result to enhanced efficacy. Nevertheless, this new technologies can hold to their promises only if sponsors manage to meet several scientific, technical, logistical and regulatory challenges. In particular manufacturers will have to design, manufacture, and deliver to the patient a new pharmaceutical grade in a matters of weeks. In this paper, we briefly review current technologies currently tried at the translation of personalized vaccines and explore the possibilities offered by the Modified Vaccinia virus Ankara in this next wave of cancer vaccines

L'immuno-virothérapie oncolytique, une stratégie émergente de traitement du cancer

International audienceOncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvironment (for converting “cold” tumors into “hot” tumors), could quickly become a new valuable weapon in the oncologist’s therapeutic arsenal.L'immuno-virothérapie oncolytique consiste à utiliser des virus réplicatifs pour cibler les cellules tumorales, provoquer leur lyse sélective, et activer ainsi la réponse immunitaire anti-tumorale. Cette approche, dont le concept est relativement ancien, est devenue une réalité thérapeutique depuis 2015 avec la mise sur le marché d'un premier produit, le T-Vec, pour le traitement du mélanome métastatique. Dans cette revue, nous rappelons le principe de la thérapie oncolytique et ses effets positifs sur la réponse immunitaire anti-tumorale. Les mécanismes mis en jeu justifient notamment leur utilisation en combinaison des inhibiteurs de points de contrôle immunitaire. En parallèle des nombreuses avancées précliniques, le développement clinique est très actif. On dénombre une cinquantaine d'essais de phases I à III en cours dans une grande variété d'indications, de voies d'administration et de combinaison. Nous faisons le pari que cette classe émergente multifonctionnelle, qui permet de reprogrammer le microenvironnement tumoral (de convertir les tumeurs « froides » en tumeurs « chaudes ») pourrait devenir assez rapidement une nouvelle arme pré-cieuse dans l'arsenal thérapeutique de l'oncologue. Mots clés : immunothérapie, virus oncolytique, immunité anti-tumorale Oncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvi-ronment (for converting "cold" tumors into "hot" tumors), could quickly become a new valuable weapon in the oncologist's therapeutic arsenal

L'immuno-virothérapie oncolytique, une stratégie émergente de traitement du cancer

International audienceOncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvironment (for converting “cold” tumors into “hot” tumors), could quickly become a new valuable weapon in the oncologist’s therapeutic arsenal.L'immuno-virothérapie oncolytique consiste à utiliser des virus réplicatifs pour cibler les cellules tumorales, provoquer leur lyse sélective, et activer ainsi la réponse immunitaire anti-tumorale. Cette approche, dont le concept est relativement ancien, est devenue une réalité thérapeutique depuis 2015 avec la mise sur le marché d'un premier produit, le T-Vec, pour le traitement du mélanome métastatique. Dans cette revue, nous rappelons le principe de la thérapie oncolytique et ses effets positifs sur la réponse immunitaire anti-tumorale. Les mécanismes mis en jeu justifient notamment leur utilisation en combinaison des inhibiteurs de points de contrôle immunitaire. En parallèle des nombreuses avancées précliniques, le développement clinique est très actif. On dénombre une cinquantaine d'essais de phases I à III en cours dans une grande variété d'indications, de voies d'administration et de combinaison. Nous faisons le pari que cette classe émergente multifonctionnelle, qui permet de reprogrammer le microenvironnement tumoral (de convertir les tumeurs « froides » en tumeurs « chaudes ») pourrait devenir assez rapidement une nouvelle arme pré-cieuse dans l'arsenal thérapeutique de l'oncologue. Mots clés : immunothérapie, virus oncolytique, immunité anti-tumorale Oncolytic immuno-virotherapy consists in using replicative viruses to target tumor cells, causes their selective lysis, and thus activates the anti-tumor immune response. This approach, whose concept is relatively old, has become a therapeutic reality since 2015 with the approval of a first product, T-Vec, for the treatment of metastatic melanoma. In this review, we recall the principle of oncolytic therapy and its positive effects on the anti-tumor immune response. The mechanisms involved justify their use in combination with immune checkpoints inhibitors. In parallel with the many preclinical advances, clinical development is very active. There are about fifty trials of phases 1 to 3 in progress in a wide variety of indications, routes of administration and combination. We bet that this multifunctional emergent class, which reprograms the tumor microenvi-ronment (for converting "cold" tumors into "hot" tumors), could quickly become a new valuable weapon in the oncologist's therapeutic arsenal

La toxicologie : la multidisciplinarité au service de la sécurité sanitaire et environnementale

International audienceToxicology: a multidisciplinary approach for improving health and environmental safety Toxicology provides the scientific bases to understand and evaluate risks. Complementary physical, chemical and biological data have to be gathered to establish that transversal analysis which helps to elaborate the appropriate technical and legal measures for protecting public health and environment. Thus, risk awareness, public confidence or fear largely depend on the toxicologist expertise. By helping to determine the risk/benefit ratio of new technologies, toxicology has also become a growing challenge for economy and competitiveness. If the renewed interest for toxicology is a reason for feeling satisfied, we nevertheless have to keep in mind that this is its ability to cross other scientific fields which makes its strength and interest. Thus, multidisciplinarity represents a real asset for its future

Deciphering structure and topology of conserved COG2042 orphan proteins

Background: The cluster of orthologous group COG2042 has members in all sequencedEukaryota as well as in many Archaea. The cellular function of these proteins of ancient originremains unknown. PSI-BLAST analysis does not indicate a possible link with even remotely-relatedproteins that have been functionally or structurally characterized. As a prototype among COG2042orthologs, SSO0551 protein from the hyperthermophilic archaeon Sulfolobus solfataricus waspurified to homogeneity for biophysical characterization.Results: The untagged protein is thermostable and behaves as a monomeric protein in gel filtrationexperiment. Several mass spectrometry-based strategies were combined to obtain a set of lowresolution structural information. Kinetic data from limited proteolysis with various endoproteasesare concordant in pointing out that region Glu73-Arg78 is hyper-sensitive, and thus accessible andflexible. Lysine labeling with NHS-biotin and cross-linking with DTSSP revealed that the 35 aminoacid RLI motif at the N terminus is solvent exposed. Cross-links between Lys10-Lys14 and Lys23-Lys25 indicate that these residues are spatially close and in adequate conformation to be crosslinked. These experimental data have been used to rank multiple three-dimensional modelsgenerated by a de novo procedure.Conclusion: Our data indicate that COG2042 proteins may share a novel fold. Combiningbiophysical, mass-spectrometry data and molecular model is a useful strategy to obtain structuralinformation and to help in prioritizing targets in structural genomics program

One step immunochromatographic assay for the rapid detection of Alexandrium minutum

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Use of biotic factors to stabilize or improve the fermentative hydrogen production in mixed cultures

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Monoclonal antibody against the surface of Alexandrium minutum used in a whole-cell ELISA

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