CXCR4 Antagonists: A Screening Strategy for Identification of Functionally Selective Ligands.

The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein-coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gα(i)-mediated cyclic adenosine monophosphate modulation, ß-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gα(i)-dependent pathway; antagonists on both the ß-arrestin and Gα(i)-dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling.

Internationally adopted children: a new challenge for pediatricians.

Children adopted from abroad by Italian families have increased during the last years. Since 2001 to 2004 they have been more than 10,000, mainly from Eastern Europe, and all indications suggest that they will continue to increase. Most of the internationally adopted children reside in orphanage before adoption where they may experience malnutrition, exposure to infectious diseases, environmental deprivation, neglect. Moreover, their pre-adoptive records are scarcely reliable and their immunization status is not always adequate. The most common long-term problems of internationally adopted children concern developmental and scholastic delay especially if they come from a long and severely deprived institutional setting, precocious puberty and, during adolescence, depressive disorders as well as antisocial behaviours. Inter-country adopted children are at increased risk for health and social problems and have to be recognized as a group of subjects requiring special medical attentions. Specialized centres for internationally adopted children where they could receive medical evaluations upon arrival and a prolonged health follow-up should be set up.