Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe

Avoidance towards humans in two genetic populations of pheasants

International audienc

Production and characterization of recombinant mature Amb a 11, a new major allergen of short ragweed (Ambrosia artemisiifolia) pollen with a cysteine protease activity

Production and characterization of recombinant mature Amb a 11, a new major allergen of short ragweed (Ambrosia artemisiifolia) pollen with a cysteine protease activity. 34th. European Academy of Allergy and Clinical Immunology (EAACI

Length of pushing efforts: pushing is not playing. Reply to the article of C. Le Ray and F. Audibert

International audienceThe aim of this work is to answer constructively to C. Le Ray and F. Audibert who were surprised that the French guidelines recommended an assisted delivery after 30 min pushing, even if the fetal heart rate is reassuring. We first resumed the definition of "second stage of labor", this word including the first phase with no pushing efforts and the second phase with active pushing of the mother. With that definition, the length of the second stage is around 60 min for the primipara and 20 min for the multipara, this length being modified by the use of peridural. We then specified the physiological mechanisms influencing the acidobasic equilibrium during the pushing time. Those mechanisms are difficult to consider because foetal heart rate monitoring is often "lost" during that phase. Altogether, these factors bring incertitude about progressive foetal acidosis and incapacity to diagnose it. Finally, the literature analysis teaches us that increasing the second stage of labor (inactive plus active phases) during the normal pregnancy seems to be at low risk for the foetus within the primiparas, but display a risk for the mother and so might be limited. Comparing the delayed pushing with the immediate pushing only lead us to conclude that delayed pushing is dangerous, as is prolonged second stage. In conclusion, we think that prolonging the second stage of labor is possible but must be by increasing the inactive first phase of the second stage, especially as long as we will not get a noninvasive and reliable method allowing assessing the well-being of the foetus

Surface chemistry of gold nanoparticles produced by laser ablation in pure and saline water

Abstract Pulsed laser ablation in liquid (PLAL) is a powerful method for producing nanoparticle colloids with a long-term stability despite the absence of stabilizing organic agents. The colloid stability involves different reactivities and chemical equilibria with complex ionic-specific effects at the nanoparticle/solvent interface which must be strongly influenced by their chemical composition. In this work, the surface composition of PLAL-produced gold nanoparticles in alkaline and saline (NaBr) water is investigated by X-ray photoelectron spectroscopy on free-flying nanoparticles, exempt from any substrate or radiation damage artifact. The Au 4f photoelectron spectra with a depth profiling investigation are used to evaluate the degree of nanoparticle surface oxidation. In alkaline water, the results preclude any surface oxidation contrary to the case of nanoparticles produced in NaBr solution. In addition, the analysis of Br 3d core-level photoelectron spectra agrees with a clear signature of Br on the nanoparticle surface, which is confirmed by a specific valence band feature. This experimental study is supported by DFT calculations, evaluating the energy balance of halide adsorption on different configurations of gold surfaces including oxidation or adsorbed salts