Targeting Oxidative Stress With Auranofin or Prima-1Met to Circumvent p53 or Bax/Bak Deficiency in Myeloma Cells

Prima-1Met (APR-246) was previously shown to be dependent on glutathione inhibition and on ROS induction in cancer cells with mutated or deleted TP53. Because this ROS induction was, at least in part, due to a direct interference with the thioredoxin reductase enzyme, we investigated whether activity of Prima-1Met could be mimicked by auranofin, an inhibitor of the thioredoxin reductase. We thus compared the activity of auranofin and Prima-1Met in 18 myeloma cell lines and in 10 samples from patients with multiple myeloma or plasma cell leukemia. We showed that, similar to Prima-1Met, the activity of auranofin was not dependent on either TP53 status or p53 expression; was inhibited by N-acetyl-L-cysteine, a ROS scavenger; displayed a dramatic synergy with L-buthionine sulfoximine, an irreversible inhibitor of glutathione synthesis; and induced cell death that was not dependent on Bax/Bak expression. These data showed that auranofin and Prima-1Met similarly overcome cell death resistance in myeloma cells due to either p53 deficiency or to mitochondrial dysfunction

Evaluation pluridisciplinaire de la douleur chronique chez 54 patients admis en hospitalisation de jour au Centre Douleur Chronique du C.H.U. de Bordeaux en 2007 (enquête de satisfaction)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Early Triggering of Exclusive IFN-γ Responses of Human Vγ9Vδ2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells

International audiencegd T cells, a major innate-like T cell subset, are thought to play in vivo an important role in innate and adaptive immune responses to various infection agents like parasites, bacteria, or viruses but the mechanisms contributing to this immune process remain ill defined. Owing to their ability to recognize a broad set of microbial molecular patterns, TLRs represent a major innate pathway through which pathogens induce dendritic cells (DC) maturation and acquisition of immunostimulatory functions. In this study, we studied the effects of various TLR ligands on the activation of human Vg9Vd2 T cells, a main human gd PBL subset, which has been recently involved in the licensing of mycobacteria-infected DC. Both TLR3 and TLR4, but not TLR2 ligands, induced a rapid, strong, and exclusive IFN-g production by Vg9Vd2 T cells. This gd subset contributed to a large extent to the overall PBL IFN-g response induced after short-term TLR stimulation of human PBMC. Importantly, this phenomenon primarily depended on type I IFN, but not IL-12, produced by monocytic DC upon TLR engagement. Vg9Vd2 T cells were similarly activated by plasmacytoid DC upon TLR8/9 activation or Yellow Fever virus infection. Moreover TLR-induced Vg9Vd2 IFN-g noncytolytic response led to efficient DC polarization into IL-12p70-producing cells. Our results support an adjuvant role played by Vg9Vd2 T cells along microbial infections through a particular cross-talk with pathogen-associated molecular patterns-activated DC. Moreover they provide new insights into the mechanisms underlying functional activation of this unique peripheral innate-like T cell subset during viral infections

Targeting Oxidative Stress With Auranofin or Prima-1Met to Circumvent p53 or Bax/Bak Deficiency in Myeloma Cells

International audienc

Do constructed wetlands in grass strips reduce water contamination from drained fields?

International audienceThis study evaluates the efficiency of two small constructed wetlands installed in the regulatory grass strips between a drained plot and a river. The observed nitrate removal efficiencies were independent of the season or type of constructed wetland and ranged from 5.4 to 10.9% of the inlet amounts. The pesticide mass budgets ranged from −618.5 to 100%, depending on the molecule. The negative efficiencies were attributed to runoff and remobilization. In contrast, the highest efficiencies were associated with pesticides with high Koc and low DT50 (half-life) values, suggesting sorption and degradation. However, the effectiveness of these wetlands is limited for pesticides with low Koc or high DT50 values; thus, the use of these molecules must be reduced. Increasing the number of these small, inexpensive and low-maintenance wetlands in the agricultural landscape would reduce the level of water pollution whilst preserving the extent of cultivated land, but their long-term effectiveness should be evaluated

Cerebrospinal Fluid Aβ42/Aβ40 as a Means to Limiting Tube- and Storage-Dependent Pre-Analytical Variability in Clinical Setting

International audienceBackground. Alzheimer cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for Alzheimer's disease (AD) diagnosis. Unfortunately, their wider use in routine and interpretation require more standardization, particularly for the pre-analytical steps. In particular, Aβ 42 peptide measurement is strongly influenced by the type of collection tube and by repeated freeze/thaw cycles. Objective. The objectives of this study were to compare, in clinical setting the impact of collection tubes and the repetition of freeze/thaw cycles on Aβ42 and Aβ40 concentrations and consequently determine if the Aβ42/Aβ40 ratio could resolve the diagnosis difficulties related to these pre-analytical parameters. Methods. CSF from 35 patients was collected in different PP and stored at-80°C after sampling. For CSF collected in the reference tube, three successive freeze-thaw cycles were done. Aβ42 and Aβ40 concentrations were determined in each condition in order to calculate the Aβ42/Aβ40 ratio. Results. Our results showed that CSF Aβ42 and Aβ40 values were significantly different according to the type of collection tube and the number of freeze/thaw cycles. Although the calculation of the Aβ42/Aβ40 ratio eliminated the effect of PP tube-dependent variation, this was not the case for freeze-thaw cycle-associated variation. Conclusion. The use of Aβ42/Aβ40 ratio rather than Aβ42 alone could contribute towards pre-analytical standardization, thus allowing the general use of CSF AD biomarkers in routine practice

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

International audienceThe aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD 50 < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD 50 < 10 nM). Mcl-1 and Bcl-x L both confer resistance to ABT-199-specific killing and BCL2/(BCLXL+MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x L up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors

The selectivity of Marinopyrrole A to induce apoptosis in MCL1 high BCL2 low expressing myeloma cells is related to its ability to impair protein translation

International audience.