ABSTRACT
To investigate the effects of Glatiramer Acetate (GA) on B cells by an integrated computational and experimental approach. GA is an immunomodulatory drug approved for the treatment of multiple sclerosis (MS). GA effect on B cells is yet to be fully elucidated. We compared transcriptional profiles of B cells from treatment-naïve relapsing remitting MS patients, treated or not with GA for 6 hours in vitro, and of B cells before and after six months of GA administration in vivo. Microarrays were analyzed with two different computational approaches, one for functional analysis of pathways (Gene Set Enrichment Analysis) and one for the identification of new drug targets (Mode-of-action by Network Analysis). GA modulates the expression of genes involved in immune response and apoptosis. A differential expression of genes encoding ion channels, mostly regulating Ca2+ homeostasis in endoplasmic reticulum (ER) was also observed. Microfluorimetric analysis confirmed this finding, showing a specific GA effect on ER Ca2+ concentration. Our findings unveils a GA regulatory effect on the immune response by influencing B cell phenotype and function. In particular, our results highlight a new functional role for GA in modulating Ca2+ homeostasis in these cells.
Subject(s)
B-Lymphocytes/metabolism , Gene Expression Regulation/drug effects , Glatiramer Acetate/administration & dosage , Homeostasis/drug effects , Ion Channels/biosynthesis , Multiple Sclerosis, Relapsing-Remitting/metabolism , B-Lymphocytes/pathology , Calcium/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Female , Humans , Male , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/pathologyABSTRACT
This corrects the article DOI: 10.1038/leu.2017.64.
ABSTRACT
Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance between miR-194-5p and its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation and survival of normal hematopoietic progenitors. In acute myeloid leukemias this balance is perturbed, locking cells into an immature, potentially 'immortal' state. Enhanced expression of miR-194-5p by treatment with the histone deacetylase inhibitor SAHA or by exogenous miR-194-5p expression re-sensitizes cells to differentiation and apoptosis by inducing BCLAF1 to shuttle between nucleus and cytosol. miR-194-5p/BCLAF1 balance was found commonly deregulated in 60 primary acute myeloid leukemia patients and was largely restored by ex vivo SAHA treatment. Our findings link treatment responsiveness to re-instatement of miR-194-5p/BCLAF1 balance.
Subject(s)
Gene Expression Regulation , Leukemia, Myeloid, Acute/pathology , MicroRNAs/genetics , Repressor Proteins/genetics , Tumor Suppressor Proteins/genetics , Apoptosis , Cell Cycle , Cell Differentiation , Cell Line, Tumor , Down-Regulation , Humans , Leukemia, Myeloid, Acute/geneticsABSTRACT
A new technique is presented for the treatment of mammary ptosis and hypertrophy. Its originality lies in the absence of skin resection and the use of the preserved derma for the reconstruction of the breast. In simple ptose, the derma will increase the stability of the mammary gland. In hypertrophy, the derma replaces the mammary gland, reducing the size of the secondary involutions.