RESUMEN
p140Cap is an adaptor protein that negatively controls tumor cell properties, by inhibiting in vivo tumor growth and metastasis formation. Our previous data demonstrated that p140Cap interferes with tumor growth and impairs invasive properties of cancer cells inactivating signaling pathways, such as the tyrosine kinase Src or E-cadherin/EGFR cross-talk. In breast cancer p140Cap expression inversely correlates with tumor malignancy. p140Cap is composed of several conserved domains that mediate association with specific partners. Here we focus our attention on two domains of p140Cap, the TER (Tyrosine Enriched Region) which includes several tyrosine residues, and the CT (Carboxy Terminal) which contains a proline rich sequence, involved in binding to SH2 and SH3 domains, respectively. By generating stable cell lines expressing these two proteins, we demonstrate that both TER and CT domains maintain the ability to associate the C-terminal Src kinase (Csk) and Src, to inhibit Src activation and Focal adhesion kinase (Fak) phosphorylation, and to impair in vitro and in vivo tumor cell features. In particular expression of TER and CT proteins in cancer cells inhibits in vitro and in vivo growth and directional migration at a similar extent of the full length p140Cap protein. Moreover, by selective point mutations and deletion we show that the ability of the modules to act as negative regulators of cell migration and proliferation mainly resides on the two tyrosines (Y) inserted in the EPLYA and EGLYA sequences in the TER module and in the second proline-rich stretch contained in the CT protein. Gene signature of cells expressing p140Cap, TER or CT lead to the identification of a common pattern of 105 down-regulated and 128 up-regulated genes, suggesting that the three proteins can act through shared pathways. Overall, this work highlights that the TER and CT regions of p140Cap can efficiently suppress tumor cell properties, opening the perspective that short, defined p140Cap regions can have therapeutic effects.
RESUMEN
BACKGROUND: Glycemic variability is an important parameter used to resolve potential clinical problems in diabetic patients. It is known that glycemic variability generates oxidative stress and potentially contributes to the development of macro- and microvascular complications in diabetes. By controlling glycemic variability, it is possible to reduce these complications and to set the therapy for all patients with diabetes. The aims of this study were to (1) propose a new standardized, objective, and flexible approach to measure glycemic variability by a continuous glucose monitoring system (CGMS)-the group of signs (GOS) method; (2) compare the correlation between mean amplitude of glucose excursion (MAGE), a well-known index of glycemic variability calculated by the physician and the MAGE defined with the GOS method, in order to validate the GOS; and (3) suggest new indexes of glycemic variability. METHODS: We tested the GOS algorithm on data collected by a CGMS every 5 minutes for 24 hours on 50 patients. Consequently, for 8 patients we calculated and compared the physician's MAGE in the standard way and by the GOS method. RESULTS: Comparison between the two methods has shown high correlations, from a minimum correlation of 86% to a maximum of 98%, with p values <0.01 (Pearson test). CONCLUSIONS: Preliminary data suggest that the proposed algorithm is a valid, efficient, and reliable method able to calculate the standard MAGE on CGMS data systematically and to create other alternative glycemic variability indexes.