Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target.

Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-ß-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.

The treatment response of chronically hepatitis C virus-infected patients depends on interferon concentration but not on interferon gene expression in peripheral blood mononuclear cells.

The current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome.

Improving reading and writing learning in underprivileged pluri-ethnic settings.

BACKGROUND: Many studies carried out in first language contexts tend to demonstrate the positive effects of activity programmes aimed at (1) developing metaphonological abilities and (2) developing language skills through active story listening on learning to read and to spell by first-grade students. AIMS: This study seeks to extend previous findings by (a) including children, the majority of whom have French as a second language, who attend plurilingual schools and have not been included in previous studies, and (b) providing training based on three essential principles shared by the two kinds of programmes: integrating activities into realistic literacy practice contexts; encouraging active student participation through tasks which very often require problem solving; and tackling, one after the other, different kinds of operations or strategies. SAMPLE: Three groups of students were created out a pool of 202 children enrolled in nine first-grade classes in three underprivileged pluri-ethnic schools. The control group was composed of 46 students who received typical, first-grade methods for teaching reading and spelling. Experimental group 1 (DMPA), 91 students, received a training programme aimed at metaphonological abilities development. Experimental group 2 (DLS), 65 students, received a training intended to develop language skills through active story listening and production. METHOD: The students from the three groups were evaluated at the beginning (metaphonological task I, pre-reading task) and at the end (metaphonological task II, word recognition task, text comprehension task, word spelling task) of their first year in elementary school. RESULTS: The programme for the development of metaphonological abilities enabled DMPA group students to obtain significantly higher scores than the control group on metaphonological task II and word recognition task. The DMPA group children also did significantly better than the control and the DLS groups on the word spelling task. However, the DLS group, who benefited from language skills development activities, also progressed in that they obtained significantly better results than the control group in the word recognition task. Moreover, at the end of grade one, there was no difference in the scores obtained by the groups on a comprehension questionnaire administered after the reading of the narrative text. CONCLUSION: The word reading skills of first-grade children in underprivileged pluriethnic settings can be improved through activities aimed at metaphonological abilities development or language skills development by means of active story listening and production. On the other hand, in order to develop word spelling abilities, the development of metaphonological abilities was more effective. Lastly, further research should seek to improve understanding of the absence of effects of either learning programme on narrative text comprehension.