EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets.

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

The role of acetone in the [omim][BF4]-mediated adverse effects on tissues of mussels, human lymphocytes and the fruit fly Drosophila melanogaster.

The present study investigated [omim][BF4]-mediated adverse effects on biological models widely used in toxicological studies. Specifically, mussels of the genus Mytilus, human lymphocytes and fruit flies of the species Drosophila melanogaster, were exposed to [omim][BF4] at concentrations ranging from micro- to milligrams per liter, with or without the presence of acetone as a carrier solvent and thereafter [omim][BF4]-mediated adverse effects were analyzed appropriately (stress indices, such as lipid peroxidation byproducts, acetylcholinesterase/AChE activity and micronucleus/MN formation frequency, in mussel gills, Cytokinesis Block Micronucleus/CBMN assay and SMART test in human lymphocytes and fruit flies respectively). LC-MS-TOF analysis was also performed for elucidating [omim][BF4] mode of action in the presence of the carrier solvent. The results showed the toxic potential of [omim][BF4], as well as acetone's ability to attenuate [omim][BF4]-mediated toxicity in almost all cases, probably due to the significant effect of acetone on the hydrophilic-lipophilic character and the viscosity of [omim][BF4], as well as its interaction and permeability on the cell membranes. The slight involvement of acetone in the attenuation of [omim][BF4]-mediated genotoxic effects on D. melanogaster could be due to species feeding experimental conditions, thus favoring the induction of antioxidant defense system against the [omim][BF4]-mediated effects in all cases.