PS-341 (Bortezomib) inhibits proliferation and induces apoptosis of megakaryoblastic MO7-e cells.

PS-341 (Bortezomib) is a dipeptide boronic acid proteasome inhibitor with antitumor activity that induces apoptosis in different human cancer cell lines. We investigated effects of PS-341 (Bortezomib) on cell proliferation, cell cycle progression, induction of apoptosis and differentiation in a megakaryoblastic (MO7-e) cell line. PS-341 was able to retain NF-kappaB in the cytoplasm and inhibit cell growth (IC(50)=22.5 nM), in a dose/time-dependent way. This anti-proliferative activity resulted to be lineage-specific, because other leukemic cell lines (KG1a, K562/R7, HL60/DNR) were unaffected by the PS-341 treatment. Moreover, PS-341 in MO7-e induced a significant pro-apoptotic effect from 10 nM concentration (40% versus 12% in the control, p<0.05). On the other hand, at lower concentration (5 nM), Bortezomib blocked cell cycle in the G2 phase. Finally, this compound was able to down-regulate WT1 expression. No significant effects on cell differentiation were found. Because a spontaneous NF-kappaB activation has been reported in megakaryocytes from patients affected by myeloproliferative disorders, Bortezomib would so be an attractive therapeutic tool for these malignancies, including essential thrombocythemia or idiopathic myelofibrosis. Preliminary data show an inhibiting activity of Bortezomib in the megakaryocytic colonies formation. Finally, also down-regulation of the WT1 gene Bortezomib-driven could be relevant, because of the role that this gene would play in the pathogenesis of acute and chronic myeloproliferative disorders.

KDIGO 2012 Clinical Practice Guideline CKD classification rules out creatinine clearance 24 hour urine collection?

OBJECTIVES: The recent guideline for the evaluation and management of Chronic Kidney Disease recommends assessing GFR employing equations based on serum creatinine; despite this, creatinine clearance 24-hour urine collection is used routinely in many settings. In this study we compared the classification assessed from CrCl (creatinine clearance 24h urine collection) and e-GFR calculated with CKD-EPI or MDRD formulas. DESIGN AND METHODS: In this retrospective study we analyze consecutive laboratory data: creatinine clearance 24h urine collection, serum creatinine and demographic data such as sex and age from 15,777 patients >18 years of age collected from 2011 to 2013 in our laboratory at Careggi Hospital. The results were then compared to the estimated GFR calculated with the equations according to the recent treatment guidelines. Consecutive and retrospective laboratory data (creatinine clearance 24h urine collection, serum creatinine and, demographic data such as sex and age) from 15,777 patients >18 years of age seen at Careggi Hospital were collected. RESULTS: Comparison between e-GFR calculated with CKD-EPI or MDRD formulas and GFR according CrCl determinations and bias [95% CI] were 11.34 [-47,4/70.1] and 11.4 [-50.2/73] respectively. The concordance for 18/65 years aged group when compared with e-GFR classification between MDRD vs CKDEPI, MDRD vs CrCl and CKD-EPI vs CrCl were 0.78, 0.34, and 0.41 respectively, while in the 65/110years aged group the concordance Kappas were 0.84, 0.38, and 0.36 respectively. CONCLUSIONS: The use of CrCl provides a different classification than the estimation of GFR using a prediction equation. The CrCl is unreliable when it is necessary to identify CKD subjects with decrease of GFR of 5ml/min/1.73m(2)/year.