Function and regulation of TRPM7, as well as intracellular magnesium content, are altered in cells expressing ΔF508-CFTR and G551D-CFTR.

Cystic fibrosis (CF), one of the most common fatal hereditary disorders, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene product is a multidomain adenosine triphosphate-binding cassette (ABC) protein that functions as a chloride (Cl(-)) channel that is regulated by intracellular magnesium [Mg(2+)]i. The most common mutations in CFTR are a deletion of a phenylalanine residue at position 508 (ΔF508-CFTR, 70-80 % of CF phenotypes) and a Gly551Asp substitution (G551D-CFTR, 4-5 % of alleles), which lead to decreased or almost abolished Cl(-) channel function, respectively. Magnesium ions have to be finely regulated within cells for optimal expression and function of CFTR. Therefore, the melastatin-like transient receptor potential cation channel, subfamily M, member 7 (TRPM7), which is responsible for Mg(2+) entry, was studies and [Mg(2+)]i measured in cells stably expressing wildtype CFTR, and two mutant proteins (ΔF508-CFTR and G551D-CFTR). This study shows for the first time that [Mg(2+)]i is decreased in cells expressing ΔF508-CFTR and G551D-CFTR mutated proteins. It was also observed that the expression of the TRPM7 protein is increased; however, membrane localization was altered for both ΔF508del-CFTR and G551D-CFTR. Furthermore, both the function and regulation of the TRPM7 channel regarding Mg(2+) is decreased in the cells expressing the mutated CFTR. Ca(2+) influx via TRPM7 were also modified in cells expressing a mutated CFTR. Therefore, there appears to be a direct involvement of TRPM7 in CF physiopathology. Finally, we propose that the TRPM7 activator Naltriben is a new potentiator for G551D-CFTR as the function of this mutant increases upon activation of TRPM7 by Naltriben.

[Myelodysplastic syndromes. Clinico-pathologic analysis of 54 cases]. / Sindromi mielodisplastiche. Analisi clinico-patologica di 54 casi.

For myelodysplastic syndromes (MDS) many scoring systems were developed to improve the prognostic stratification of patients. METHODS AND AIM OF THE STUDY: We enrolled 54 primary MDS patients, having an advanced median age of 78.5 years, that discouraged the choice of aggressive treatments. Then, we employed only the Bournemouth score (without cytogenetic analysis), with the aim to identify the best predictor of death and of AML development. RESULTS: Both for overall and leukemia-free analysis, shorter survival and faster development of AML were found in MDS patients with severe peripheral cytopenia, RAEB-T, major proportion of bone marrow blasts (over 20%) and with the higher Bournemouth score (i.e. 3-4). The multivariate analysis by the Cox's regression model showed that a high percentage of bone marrow blasts presented the best statistical significance. CONCLUSIONS: In our survey we confirmed the value of Bournemouth score in identifying those MDS patients presenting a greater risk of death and AML development. Moreover, a high percentage of bone marrow blasts rose as the best predictor of death and leukemic evolution. The kariotypic analysis, with a stronger prognostic power but also complex and expensive, was not performed in our elderly MDS patients, who were unable to tolerate aggressive treatments.