Nouvelles cibles thérapeutiques dans la polyarthrite rhumatoïde et essor de biothérapies innovantes

La polyarthrite rhumatoïde est le plus fréquent des rhumatismes inflammatoires chroniques. Cette pathologie touche environ 0,5% de la population et débute en moyenne vers 50 ans. Les causes de la maladie ne sont pas connues mais plusieurs facteurs concourent à sa survenue. Sa sévérité est la conséquence de l'inflammation chronique de la membrane synoviale articulaire. Cette inflammation entraîne progressivement la destruction de l'articulation qui contribue à une impotence fonctionnelle parfois majeure. Une meilleure connaissance des mécanismes immunopathologiques impliqués dans les pathologies rhumatismales inflammatoires a ouvert la voie à l'ère des biothérapies et des molécules dites ciblées. Certes des inconnues persistent mais la perception et la prise en charge de la polyarthrite rhumatoïde ont nettement changé. Le rituximab, anticorps monoclonal anti-CD20, qui cible une molécule membranaire exprimée par les lymphocytes B, a suscité un intérêt dans le traitement de la PR dès 1999 lorsque l'on a redécouvert le rôle des lymphocytes B dans la pathogénie de cette maladie. Deux études ont montré son efficacité dans cette pathologie. L'étude DANCER a évalué sa tolérance en association au méthotrexare et permis de préciser la dose optimale à utiliser. L'étude REFLEX de son côté a mis en évidence son efficacité chez des patients qui n'avaient pas eu de réponses satisfaisantes à un traitement par des anticorps anti-TNFa. L'abatacept (CTLA4-Ig) est une protéine de fusion également prometteuse. Ce premier agent d'une nouvelle classe thérapeutique, qui agit en modulant le signal de costimulation nécessaire à l'activation des lymphocytes T et B, a montré dans l'étude ATTAIN un bénéfice clinique à 18 mois dans les polyarthrites rhumatoïdes actives, réfractaires aux anti-TNFa. En 2003, un antagoniste du récepteur de l'interleukine-1 humaine, l'anakinra, est venu renforcer cet arsenal thérapeutique. Son administration seule ou en association au méthotrexate améliore les paramètres cliniques et radiologiques de la polyarthrite rhumatoïde.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

<it>In vivo</it> gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens

<p>Abstract</p> <p>Background</p> <p>Pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. It is critical to test new strategies, including tumor-targeted delivery of therapeutic agents. This study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector.</p> <p>Results</p> <p>Three cell surface markers were evaluated to target the transduction of cells by lentiviruses pseudotyped with a modified glycoprotein from Sindbis virus. Only Mucin-4 and the Claudin-18 proteins were found efficient for targeted lentivirus transductions <it>in vitro</it>. In subcutaneous xenografts of human pancreatic cancer cells models, Claudin-18 failed to achieve efficient gene transfer but Mucin-4 was found very potent. Human pancreatic tumor cells were modified to express a fluorescent protein detectable in live animals by bioimaging, to perform a direct non invasive and costless follow up of the tumor growth. Targeted gene transfer of a bicistronic transgene bearing a luciferase gene and the herpes simplex virus thymidine kinase gene into orthotopic grafts was carried out with Mucin-4 oncotropic lentiviruses. By contrast to the broad tropism VSV-G carrying lentivirus, this oncotropic lentivirus was found to transduce specifically tumor cells, sparing normal pancreatic cells <it>in vivo</it>. Transduced cells disappeared after ganciclovir treatment while the orthotopic tumor growth was slowed down.</p> <p>Conclusion</p> <p>This work considered for the first time three aspect of pancreatic adenocarcinoma targeted therapy. First, lentiviral transduction of human pancreatic tumor cells was possible when cells were grafted orthotopically. Second, we used a system targeting the tumor cells with cell surface antigens and sparing the normal cells. Finally, the TK/GCV anticancer system showed promising results <it>in vivo</it>. Importantly, the approach presented here appeared to be a safer, much more specific and an as efficient way to perform gene delivery in pancreatic tumors, in comparison with a broad tropism lentivirus. This study will be useful in future designing of targeted therapies for pancreatic cancer.</p

Inhibitor of Apoptosis Proteins Determine Glioblastoma Stem-Like Cells Fate in an Oxygen-Dependent Manner

International audienceIn glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and non-apoptotic processes. We previously showed that IAPs inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor-κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem-like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three-dimensional glioblastoma spheroid model in which time-of-flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein+ cells at their periphery. These oxygen-dependent GDC-0152 antitumoral effects have been confirmed on human glioblastoma explants. Notably, serine-threonine kinase activation analysis revealed that under hypoxic conditions, IAPs inhibition activated ataxia telangiectasia and Rad3-related protein signaling. Our findings provide new insights into the dual mechanism of action of IAPs inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019

FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

International audienceBACKGROUND: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. RESULTS: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. CONCLUSION: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context

Spine immobilization and neurological outcome in vertebral osteomyelitis SPONDIMMO, a prospective multicentric cohort

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Temporal Trends in Transcatheter Aortic Valve Replacement in France: FRANCE 2 to FRANCE TAVI

International audienceBackground - Transcatheter aortic valve replacement (TAVR) is standard therapy for patients with severe aortic stenosis who are at high surgical risk. However, national data regarding procedural characteristics and clinical outcomes over time are limited. Objectives - The aim of this study was to assess nationwide performance trends and clinical outcomes of TAVR during a 6-year period. Methods - TAVRs performed in 48 centers across France between January 2013 and December 2015 were prospectively included in the FRANCE TAVI (French Transcatheter Aortic Valve Implantation) registry. Findings were further compared with those reported from the FRANCE 2 (French Aortic National CoreValve and Edwards 2) registry, which captured all TAVRs performed from January 2010 to January 2012 across 34 centers. Results - A total of 12,804 patients from FRANCE TAVI and 4,165 patients from FRANCE 2 were included in this analysis. The median age of patients was 84.6 years, and 49.7% were men. FRANCE TAVI participants were older but at lower surgical risk (median logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE]: 15.0% vs. 18.4%; p < 0.001). More than 80% of patients in FRANCE TAVI underwent transfemoral TAVR. Transesophageal echocardiography guidance decreased from 60.7% to 32.3% of cases, whereas more recent procedures were increasingly performed in hybrid operating rooms (15.8% vs. 35.7%). Rates of Valve Academic Research Consortium-defined device success increased from 95.3% in FRANCE 2 to 96.8% in FRANCE TAVI (p < 0.001). In-hospital and 30-day mortality rates were 4.4% and 5.4%, respectively, in FRANCE TAVI compared with 8.2% and 10.1%, respectively, in FRANCE 2 (p < 0.001 for both). Stroke and potentially life-threatening complications, such as annulus rupture or aortic dissection, remained stable over time, whereas rates of cardiac tamponade and pacemaker implantation significantly increased. Conclusions - The FRANCE TAVI registry provided reassuring data regarding trends in TAVR performance in an all-comers population on a national scale. Nonetheless, given that TAVR indications are likely to expand to patients at lower surgical risk, concerns remain regarding potentially life-threatening complications and pacemaker implantation. (Registry of Aortic Valve Bioprostheses Established by Catheter [FRANCE TAVI]; NCT01777828)