La inobservancia a la ley orgánica de transporte terrestre, tránsito y seguridad vial de los ciudadanos por el desconocimiento de la normativa vigente.

Este fenómeno social se ha evidenciado con mayor incidencia en las actividades reguladas por la Ley Orgánica de Transporte Terrestre, Tránsito y Seguridad Vial tanto a nivel nacional como local, y se ha materializado diariamente con un alto índice de accidentes de tránsito, sin que hasta el momento se puedan visualizar cambios de comportamiento en la sociedad ecuatoriana, a pesar de los esfuerzos que el Estado ha desarrollado en procura de mejorar esta conducta social. Este comportamiento social, nos lleva a enfrentar una realidad que se presenta con elevados índices de mortalidad como producto de los accidentes de tránsito, determinándose que la principal causa de este mal social recae sobre la inobservancia a la Norma de Tránsito por la falta de concientización, conocimiento y respeto de los conductores y peatones, actores principales del sistema de transito. Este, es un hecho que podría revertirse buscando un medio que nos permita crear una cultura de respeto de las normas establecidas, y para el caso que es de nuestro interés, el respeto a la norma de tránsito, consideramos, que educar desde las edades tempranas y brindar conocimientos acerca de la seguridad vial que hoy es parte integral de nuestro convivir diario, lograríamos para lo posterior un cambio generacional de actitud frente al sistema de transito, cimentando y reforzando estos conocimientos en las edades medias y adultas donde se hace imprescindible un mayor desenvolvimiento frente a la Seguridad vial, mejorando el tráfico en las ciudades vanguardistas actuales y logrando prevenir y disminuir los accidentes de tránsito y con ellos sus consecuencias. Para crear este cambio, en lo que al cumplimiento de las normas se refiere, hemos creído conveniente proponer una reforma a la Decima Séptima Disposición Transitoria del Título VIII de La Ley Orgánica de Educación Intercultural, la misma que busca concientizar a las nuevas generaciones, a través de la capacitación y crear la cultura de respeto y cumplimiento de la Ley establecida, de tal forma que, se logre reducir los índices de accidentes de tránsito a través de ese cambio generacional y cultural

Safety and efficacy of atezolizumab in patients with autoimmune disease: subgroup analysis of the SAUL study in locally advanced/metastatic urinary tract carcinoma

Aim Patients with pre-existing autoimmune disease (AID) are typically excluded from clinical trials of immune checkpoint inhibitors, and there are limited data on outcomes in this population. The single-arm international SAUL study of atezolizumab enrolled a broader ‘real-world’ patient population. We present outcomes in patients with a history of AID. Methods Patients with locally advanced/metastatic urinary tract carcinoma received atezolizumab 1200 mg every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary end-point was safety. Overall survival (OS) was a secondary end-point. Subgroup analyses of AID patients were prespecified. Results Thirty-five of 997 treated patients had AID at baseline, most commonly psoriasis ( n = 15). Compared with non-AID patients, AID patients experienced numerically more adverse events (AEs) of special interest (46% versus 30%; grade ≥3 14% versus 6%) and treatment-related grade 3/4 AEs (26% versus 12%), but without relevant increases in treatment-related deaths (0% versus 1%) or AEs necessitating treatment discontinuation (9% versus 6%). Pre-existing AID worsened in four patients (11%; two flares in two patients); three of the six flares resolved, one was resolving, and two were unresolved. Efficacy was similar in AID and non-AID patients (median OS, 8.2 versus 8.8 months, respectively; median progression-free survival, 4.4 versus 2.2 months; disease control rate, 51% versus 39%). Conclusions In 35 atezolizumab-treated patients with pre-existing AID, incidences of special- interest and treatment-related AEs appeared acceptable. AEs were manageable, rarely requiring atezolizumab discontinuation. Treating these patients requires caution, but pre-existing AID does not preclude atezolizumab therapy

An Overview of l-Amino Acid Oxidase Functions from Bacteria to Mammals: Focus on the Immunoregulatory Phenylalanine Oxidase IL4I1

l-amino acid oxidases are flavin adenine dinucleotide-dependent enzymes present in all major kingdom of life, from bacteria to mammals. They participate in defense mechanisms by limiting the growth of most bacteria and parasites. A few mammalian LAAOs have been described, of which the enzyme “interleukin-4 induced gene 1” (IL4I1) is the best characterized. IL4I1 mainly oxidizes l-phenylalanine. It is a secreted enzyme physiologically produced by antigen presenting cells of the myeloid and B cell lineages and T helper type (Th) 17 cells. Important roles of IL4I1 in the fine control of the adaptive immune response in mice and humans have emerged during the last few years. Indeed, IL4I1 inhibits T cell proliferation and cytokine production and facilitates naïve CD4+ T-cell differentiation into regulatory T cells in vitro by limiting the capacity of T lymphocytes to respond to clonal receptor stimulation. It may also play a role in controlling the germinal center reaction for antibody production and limiting Th1 and Th17 responses. IL4I1 is expressed in tumor-associated macrophages of most human cancers and in some tumor cell types. Such expression, associated with its capacity to facilitate tumor growth by inhibiting the anti-tumor T-cell response, makes IL4I1 a new potential druggable target in the field of immunomodulation in cancer

Étude de la voie de signalisation IL-4/IL-13 dans les lymphomes B primitifs du médiastin

Les lymphomes B primitifs du médiastin (LBPMs) constituent une entité anatomo-clinique particulière au sein des lymphomes diffus à grandes cellules B. Les analyses du transcriptome des LBPMs ont montré une forte expression des gènes induits par l IL-4 ou l IL-13 et des effecteurs de cette voie de signalisation. L objectif de ce travail a été d étudier la voie IL-4/IL-13 dans les LBPMs. Dans une 1ere partie, nous avons montré que le facteur de signalisation et de transcription 6 (STAT6) est constitutivement phosphorylé et possède une activité de liaison à l ADN dans les lignées dérivées de LBPM (MedB1, Karpas1106). Le STAT6 phosphorylé (-P) est présent dans les noyaux des cellules tumorales de LBPMs (73% des cas). Cette activation est due en partie à l activité de la kinase JAK2 et aux altérations du gène régulant négativement cette voie de signalisation, SOCS1. Dans une 2eme partie, nous avons étudié le rôle de STAT6 dans la physiopathologie de ces lymphomes en inhibant son expression par un siRNA dans les lignées. Nous avons montré une diminution de la prolifération et une augmentation de la mort cellulaire, ainsi qu une diminution du taux du mRNA Bcl-xL dans les cellules MedB1. Nous avons observé une corrélation entre l accumulation nucléaire de STAT6-P et l expression cytoplasmique de Bcl-xL dans les cellules tumorales. Enfin, nous avons mis récemment en évidence des mutations du domaine de liaison à l ADN de STAT6, dans 35% des LBPMs. L étude des mécanismes oncogéniques activés dans la voie IL-4/IL-13 devrait permettre de comprendre le dysfonctionnement cellulaire à l origine des LBPMs et pourrait aussi donner de nouvelles cibles pour le diagnostic et la thérapiePrimary mediastinal large B-cell lymphomas (PMBCLs) are a particular anatomo-clinical entity among diffuse large B-cell lymphomas (DLBCLs). The transcriptome analyses of PMBCLs showed high expression of genes activated by IL-4 or IL-13 and effectors of this signaling pathway. The objective of this work was study the IL-4 / IL-13 signaling pathway in PMBCLs. In a 1st part, we demonstrated that signal transducer and activator of transcription 6 (STAT6) is constitutively phosphorylated and exhibits DNA binding activity in PMBCL derived cell lines (MedB1, Karpas1106). This phosphorylated STAT6 (P-) is present in nuclei of PMBCL neoplastic cells (73 % of cases). This activation is partially due to the activity of JAK2 kinase and to the alteration of a gene which regulates negatively this signalling pathway, SOCS1. In a 2nd part, we studied the STAT6 role in physiopathology of these lymphomas by inhibiting its expression with a siRNA in cell lines. We showed proliferation decrease and cell death increase, as well as diminution of Bcl-xL mRNA in MedB1 cells. We observed a correlation between P-STAT6 nuclear accumulation and Bcl-xL cytoplasmic expression in neoplastic cells. In a last part, we recently demonstrate mutations of STAT6 DNA binding domain, in 35 % of PMBCLs. The study of oncogenic mechanisms activated in IL-4/IL-13 signaling pathway could allow to understand the cellular dysfunction at the origin of the PMBCLs and could also identify new targets for the diagnostic and the therapyPARIS-EST-Université (770839901) / SudocSudocFranceF

Editorial: Immunosuppressive Amino Acid Catabolizing Enzymes in Heallth and Disease

International audienc

A polymeric europium complex with the ligand thiophene-2-carboxylic acid: Synthesis, structural and spectroscopic characterization

A polymeric complex [Eu(α-tpc)3(α-Htpc) 2]n and its characterization by single crystal X-ray and thermal analysis, infrared and photoluminescence spectroscopies are described. The compound crystallizes in the monoclinic Cc space group. The asymmetric unit is formed from a europium ion bonded to one carboxyl oxygen of five different thiophene carboxylic moieties. Three of these moieties are deprotonated and bridge between neighboring europium ions giving rise to an infinite polymer along the c axis. Besides the europium characteristic emission lines, the emission spectra show unambiguously the crystal size effect on the 5D0 → 7F0 transition. The complex thermal decomposition at 220 C leads to a stable luminescent complex in which the 5D0 → 7F4 transition reveals a monomeric characteristic. The Judd-Ofelt intensity parameters to the polymeric and the monomeric compound with the same ligand and coordination number were compared. © 2013 Published by Elsevier Ltd

What role for AHR activation in IL4I1-mediated immunosuppression ?

International audienceThe amino-acid catabolizing enzyme Interleukin-4 induced gene 1 (IL4I1) remains poorly characterized despite it is emerging as a pertinent therapeutic target for cancer. IL4I1 is secreted in the synaptic cleft by antigen-presenting cells. It inhibits TCR signaling, modulates naïve T cell differentiation and limits effector T cell proliferation. IL4I1 expression in tumors shapes the tumor microenvironment and impairs the antitumor cytotoxic T cell response, thereby facilitating cancer immune escape. Several mechanisms participate in these effects. Recent data suggest a role of new IL4I1 metabolites in activation of the aryl-hydrocarbon receptor (AHR). Here, we observe that expression of IL4I1 is poorly correlated with that of validated targets of AHR in human cancers. Moreover, dendritic cells do not upregulate AHR target genes in relation with IL4I1 expression in vivo. Finally, IL4I1 activity towards tryptophan leading to production of AHR-activating products is very low, and should be negligible when tryptophan-degrading enzymes of higher affinity compete for the substrate. We recently showed that IL4I1 expression by dendritic cells directly regulates immune synapse formation and modulates the repertoire and memory differentiation of responding CD8 T cells after viral infection. Thus, IL4I1 may restrain tumor control through regulating the priming of tumor-specific CD8 T cells, independently of AHR activation

Antibacterial Properties of the Mammalian L-Amino Acid Oxidase IL4I1

L-amino acid oxidases (LAAO) are flavoproteins that catalyze the oxidative deamination of L-amino acids to a keto-acid along with the production of H(2)O(2) and ammonia. Interleukin 4 induced gene 1 (IL4I1) is a secreted LAAO expressed by macrophages and dendritic cells stimulated by microbial derived products or interferons, which is endowed with immunoregulatory properties. It is the first LAAO described in mammalian innate immune cells. In this work, we show that this enzyme blocks the in vitro and in vivo growth of Gram negative and Gram positive bacteria. This antibiotic effect is primarily mediated by H(2)O(2) production but is amplified by basification of the medium due to the accumulation of ammonia. The depletion of phenylalanine (the primary amino acid catabolized by IL4I1) may also participate in the in vivo inhibition of staphylococci growth. Thus, IL4I1 plays a distinct role compared to other antibacterial enzymes produced by mononuclear phagocytes