Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.

BackgroundWe previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).MethodsThe original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.ResultsAt baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD.ConclusionsFunctional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.Trial registrationNCT01401062

Développement de modèles de turbulence adaptés à la simulation des écoulements de convection naturelle à haut nombre de Rayleigh

Un nouveau modèle de turbulence adapté aux écoulements turbulents soumis à laflottabilité a été développé en utilisant la configuration du canal plan vertical différentiellementchauffé comme référence. L étude des DNS disponibles pour chacun des régimes de convection amontré les défauts des relations constitutives classiques conduisant à la mauvaise représentationdes écoulements de convection naturelle. Ces modèles ne prennent en compte ni le couplage deschamps thermique et dynamique ni l anisotropie de l écoulement, tout deux induits par la flottabilité.Une approche algébrique a donc été utilisées. L hypothèse d équilibre local a été validéedans une large partie du canal sauf dans la région de paroi et au voisinage d un gradient devitesse nul, quel que soit le régime de convection. Les modèles homogènes et pariétaux pour lescorrélations de pression ont été étudiés et sélectionnés. Deux modèles EARSM et EAHFMprenant en compte les termes de flottabilité ont été développés. Ces modèles intègrent aussi destraitements spécifiques à la paroi reposant sur la pondération elliptique. Ils sont couplés à unmodèle corrigé pour mieux représenter le pic d énergie cinétique turbulente prèsde la paroi. Le modèle complet a été confronté aux DNS sur la configuration du canal pourchacun des régimes de convection à travers des tests a priori et des calculs complets montrantdes résultats très encourageants et de meilleures prévisions que les modèles classiques.A new turbulence model dedicated to buoyant flows is developped using the differentiallyheated vertical plane channel flow configuration as test case. For each convection regime,the examination of available DNS databases pointed out the failure of classical modeling topredict buoyant flows. Neither the coupling between thermics and dynamics nor the anisotropy,both due to the buoyancy, are considered by these models. So, algebraic models are used. Theweak equilibrium assumption is validated in a large part of the channel except in the wall regionand close to zero velocity gradient whatever the convection regime. The wall and homogeneousmodels for the pressure terms are investigated and selected. Then, an EARSM and an EAHFMare developped to include the buoyant terms. These models both include wall treatments. Theyare coupled with a model modified to improve the representation of the turbulentkinetic energy maximum close to the wall. The complete model is finally compared to theDNS on the channel flow configuration for all convection regime thanks to a priori tests andcomplete computations, showing encouraging results and better predictions than classical modelsTOULOUSE-ISAE (315552318) / SudocSudocFranceF

Long-term changes of serum chemokine levels in vaccinated military personnel

BACKGROUND: Members of the United States Armed Forces receive a series of vaccinations during their course of service. To investigate the influence of multiple vaccinations on innate immunity, we measured concentrations of a panel of immunomodulatory and pro-inflammatory cytokines in serum samples from a group of such individuals. RESULTS: Significantly increased levels of macrophage inflammatory protein 1α (MIP-1α), MIP-1β and interleukin 8 (IL-8) were detected. Since these cytokines are known to have anti-human immunodeficiency virus (HIV) activity, we tested the effect of serum from these individuals on HIV-1 infectivity and susceptibility of their peripheral blood mononuclear cells (PBMCs) to HIV-1 infection in vitro. Sera from vaccinated military personnel inhibited, and their PBMCs were partially resistant to, infection by HIV-1 strains tropic to CCR5 (R5), but not to CXCR4 (X4), chemokine receptor. CONCLUSION: These findings demonstrate that increased anti-HIV chemokines can be detected in vaccine recipients up to 68 weeks following immunization

Intra-arterial injection of lipid nanocapsules loaded with rhenium-188 for the radiotherapy of hepatocellular carcinomas in rats

International audienc

Evaluation of immune responses after nanovectorized internal radiotherapy for glioblastomas

Contribution issue du 4e Workshop européen, orgnaisé par le Cancéropôle Grand-Ouest du 22 au 25 septembre 2010 à l'Ile de Berder en France, autour du thème "Biology of ionizing radiation".International audienc

5-arylaminouracil derivatives as potential dual-action agents

Several 5-aminouracil derivatives that have previously been shown to inhibit Mycobacterium tuberculosis growth at concentrations of 5-40 μg/mL are demonstrated to act also as noncompetitive non-nucleoside inhibitors of HIV-1 reverse transcriptase without causing toxicity in vitro (McyrillicT-4 cells) and ex vivo (human tonsillar tissue)