Utilisation d'un dendrimère phosphoré comme une nouvelle approche thérapeutique de la polyarthrite rhumatoïde

Les dendrimères sont des molécules de synthèse qui trouvent leurs applications dans plusieurs domaines, notamment biomédical. Il a été montré que le dendrimère phosphoré ABP a la propriété de se fixer aux monocytes. Il s'ensuit une internalisation du dendrimère et une activation des monocytes vers une voie anti-inflammatoire. Nous avons exploité cette propriété anti-inflammatoire pour évaluer le potentiel thérapeutique du dendrimère ABP dans la Polyarthrite Rhumatoïde, une maladie inflammatoire auto-immune au cours de laquelle les monocytes jouent un rôle majeur. Nous avons montré que l'injection intraveineuse du dendrimère ABP de façon hebdomadaire à une dose de 10 mg/kg supprime totalement l'arthrite développée par les souris IL1-ra-/- au bout de 6 semaines de traitement. Nous avons observé chez les souris IL-1ra-/- traitées par ABP une diminution de l'expression des médiateurs de l'inflammation jusqu'au niveau de celui des souris non arthritiques. Ces observations ont été confirmées sur un autre modèle d'arthrite induite par le transfert de sérum de souris K/BxN. Nous avons également montré que le dendrimère ABP possède des propriétés anti-ostéoclastiques in vivo. Nous avons déterminé in vitro le mécanisme par lequel le dendrimère ABP inhibe la différenciation des monocytes en ostéoclastes. En effet, nous avons montré que le dendrimère ABP affecte la différenciation des monocytes murins et humains en ostéoclastes en inhibant l'expression du récepteur du M-CSF, c-FMS. Cette étude pré-clinique suggère que le dendrimère ABP pourrait être considéré comme un médicament candidat pour le traitement de la PR.Dendrimers are synthetic molecules with layered architectures which show promise in several fields, particularly in the biomedical field. It has been reported that an azabisphophonate (ABP)-capped dendrimer selectively targets monocytes and directs them towards anti-inflammatory activation. We explored this anti-inflammatory property to assess the therapeutic potentiel of dendrimer ABP in the treatment of Rheumatoid Arthritis, an auto-immune inflammatory disease in which monocytes play an important role. We have shown that weekly intravenous injections of dendrimer ABP at a dose of 10 mg/kg totally inhibited the development of inflammatory arthritis in IL-1ra-/- mice, a model of RA, within 6 weeks. We have shown that the levels of inflammatory cytokines where reduced in ABP-treated IL-1ra-/- mice and reached that of normal mice. These observations were also made in the K/BxN serum-induced arthritis model. We also have shown that dendrimer ABP exhibited anti-osteoclastic properties in vivo. We have demonstrated in vitro that dendrimer ABP inhibited the differentiation of mice and human monocytes into osteoclasts, by inhibiting the expression of c-FMS, (the M-CSF receptor). This pre-clinical study suggests that dendrimer ABP should be considered as a potential nanotherapeutic for Rheumatoid Arthritis

EVER Proteins, Key Elements of the Natural Anti-Human Papillomavirus Barrier, Are Regulated upon T-Cell Activation

Human papillomaviruses (HPV) cause a variety of mucosal and skin lesions ranging from benign proliferations to invasive carcinomas. The clinical manifestations of infection are determined by host-related factors that define the natural anti-HPV barrier. Key elements of this barrier are the EVER1 and EVER2 proteins, as deficiency in either one of the EVER proteins leads to Epidermodysplasia Verruciformis (EV), a genodermatosis associated with HPV-induced skin carcinoma. Although EVERs have been shown to regulate zinc homeostasis in keratinocytes, their expression and function in other cell types that may participate to the anti-HPV barrier remain to be investigated. In this work, we demonstrate that EVER genes are expressed in different tissues, and most notably in lymphocytes. Interestingly, in contrast to the skin, where EVER2 transcripts are hardly detectable, EVER genes are both abundantly expressed in murine and human T cells. Activation of CD4+ and CD8+ T cells via the TCR triggers a rapid and profound decrease in EVER expression, accompanied by an accumulation of free Zn2+ ions. Thus, EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes. Consistent with this hypothesis, we show that the concentration of Zn2+ ions is elevated in lymphoblastoid cells or primary T cells from EVER2-deficient patients. Interestingly, we also show that Zn2+ excess blocks T-cell activation and proliferation. Therefore, EVER proteins appear as key components of the activation-dependent regulation of Zn2+ concentration in T cells. However, the impact of EVER-deficiency in T cells on EV pathogenesis remains to be elucidated

Procesos de aplicación conceptual y práctico de la normatividad tributaria en contextos investigativos procedimentales tributarios para el fortalecimiento de las competencias disciplinares y profesionales

La presente investigación planteó como objetivo realizar las memorias con las temáticas investigativas que se desarrollaron en el Seminario de Investigación Aplicada, con el fin de actualizar en los participantes y fortalecer sus conocimientos específicos en materia tributaria con base en los temas investigativos dispuestos y orientados por cada docente desde su inicio, elaboración, construcción y presentación ante los docentes evaluadores. Los trabajos cumplen su fin primordial con es fortalecer con los desarrollos temático de cada módulo visto en el SIA sus capacidades y competencias profesionales especialmente en el contexto tributario, en cumplimiento al requerimiento para otorgar al título de Especialistas en Gerencia Tributaria. Luego las memorias compiladas son el resultado de los trabajos presentados y evaluados oportunamente por cada docente comprometido con la calidad en cuanto a las temáticas investigativas, calidad de los contenidos, talleres teóricos prácticos, elementos metodológicos y de más lineamentos institucionales y del programa. La importancia de las memorias radica en su contenido el cual desglosa definiciones, conceptos, desarrollos teóricos prácticos, constituyéndose en un ejemplar de consulta investigativa en áreas de conocimiento fiscal y tributario en el marco de la Ley 1819 de 2016 y sus decretos reglamentarios, en síntesis al interior encontraremos fundamentos teóricos prácticos, procedimentales y resolutivos de casos especiales de Gravamen a los Movimientos Financieros, Monotributo, Renta Personas Naturales, Renta Personas Jurídicas, Procedimiento Tributario, Impuestos Distritales, Normas internacionales de Información Financiera Pymes, entre otros temas

Utilisation d'un dendrimère phosphoré comme une nouvelle approche thérapeutique de la polyarthrite rhumatoïde

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Anti-Inflammatory Properties of Dendrimers per se

International audienc

Frequency and route of administration in the treatment of experimental arthritis by phosphorus-based dendrimer

International audienc

A Phosphorus-Based Dendrimer Targets Inflammation and Osteoclastogenesis in Experimental Arthritis

Comment in Experimental arthritis: Dendrimer drug mends monocytes. [Nat Rev Rheumatol. 2011]International audienceDendrimers are highly branched "tree-like" polymers that have demonstrated therapeutic potential in drug delivery, medical imaging, and tissue engineering in recent years. In addition, we have shown that an azabisphosphonate (ABP)-capped dendrimer selectively targets monocytes and directs them toward anti-inflammatory activation. We explored this property to assess the therapeutic potential of dendrimer ABP in the treatment of an inflammatory disease, rheumatoid arthritis. Intravenous injections of dendrimer ABP inhibited the development of inflammatory arthritis in two animal models: IL-1ra(-/-) mice and mice undergoing K/BxN serum transfer. Suppression of disease was characterized by normal synovial membranes, reduced levels of inflammatory cytokines, and the absence of cartilage destruction and bone erosion. Dendrimer ABP also exhibited anti-osteoclastic activity on mouse and human cells, mediated by c-FMS (cellular-feline McDonough strain sarcoma virus oncogene homolog) inhibition. These preclinical demonstrations suggest the potential use of dendrimer ABP as a nanotherapeutic for rheumatoid arthritis

<i>EVER1</i> and <i>EVER2</i> are expressed in lymphocytes.

<p><b>A.</b> Expression of <i>EVER1</i> and <i>EVER2</i> genes in different mouse organs was assessed by qRT-PCR. Expression in the spleen was set as 100%. For each organ at least 3 independent experiments were performed. <b>B.</b> Expression of <i>EVER1</i> and <i>EVER2</i> genes in murine T and B cells was determined by qRT-PCR. At least 3 independent experiments were performed for each cell type. Expression of EVER1 protein in murine splenocytes (<b>C</b>) and purified T cells (<b>D</b>) was determined by western blot. An EVER1-specific antibody (Abcam; ab67326) was used. A single band at ≈100 kDa was detected (predicted EVER1 MW = 91 kDa). <b>E.</b> 293 T cells were transfected with plasmids encoding either EVER1-FLAG or EVER2-FLAG fusion protein. The fusion protein was immunoprecipitated with anti-FLAG antibody and subsequently a western-blot was performed using the anti-FLAG antibody or two different anti-EVER1 antibodies (Ab n^o1 - Abcam; ab67326; Ab n°2 - Osenses; OSR00223W).</p

Zinc homeostasis in T cells.

<p>Purified murine naive CD8+ (A) or CD4+ T cells (B) were activated with immobilized anti-CD3 and anti-CD28 Abs and expression of the <i>ZIP10</i> zinc transporter and <i>EVER1</i> genes was determined by qRT-PCR at the indicated time points. Data are from 3 independent experiments. Total amount of free zinc was determined in murine CD8+ (<b>C</b>) or CD4+ T cells (<b>D</b>) after 24 h incubation in standard medium (medium), in medium supplemented with IL-2 (IL-2), or with anti-CD3/anti-CD28 Abs in the presence of IL-2 (CD3/CD28). The content of free zinc was measured by flow cytometry with FluoZin-3, a zinc ion-specific indicator. The total amount of free zinc per cell was calculated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039995#s3" target="_blank">materials and methods</a> and normalized for the unstimulated cells (medium) values (100%). Purified naive CD8+ (<b>E</b>) or CD4+ T cells (<b>F</b>) were stimulated by immobilized anti-CD3 and anti-CD28 Abs in the presence of IL-2 and IL-12. The expression of <i>metallothionein 2</i> (MT-2) was assessed by qRT-PCR. Data are representative of 3 independent experiments. <b>G</b>. Murine naive CD8+ or CD4+ T cells were activated (CD3/CD28) or not (control) by immobilized anti-CD3 and anti-CD28 Abs for 24 h The concentration of free zinc was then measured by flow cytometry with FluoZin-3. <b>H</b>. Purified murine naive CD8+ T cells were activated with immobilized anti-CD3 and anti-CD28 Abs. At the indicated time the zinc ionophore pyrithione (PY) was added to the medium at different concentrations. Radiolabeled thymidine was added 24 hrs after initiation of the cell culture, and proliferation was assessed on the basis of the thymidine incorporation 24 h later.</p

The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS0000479