O Valor Prognóstico da Resposta Neutrofílica na Era da Reperfusão Mecânica do Enfarte Agudo do Miocárdico

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary angioplasty, neutrophil response and its prognostic significance are not entirely understood. METHODS: We retrospectively studied 305 consecutive and non-selected STEMI patients. They were divided into three groups according to the maximum neutrophil percentage in the first 48 hours. We compared baseline demographic characteristics, coronary disease risk factors, cardiac history, clinical presentation, therapeutics administered and clinical evolution. We then assessed survival in the three groups and determined predictors of 30-day mortality. Group 1 (G1) had a mean age of 57 +/- 14 years and showed mean neutrophilia of 73.3%, Group 2 (G2) 61 +/- 13 years and 79.9%, and Group 3 (G3) 66 +/- 13 years and 84.2%. We compared outcomes and 30-day mortality between the groups. RESULTS: Mean age rose with increased neutrophil response. There were no statistically significant baseline differences between the groups except for more smokers in Groups 1 and 2, and more patients presenting with Killip class > or = 2 and fewer with uncomplicated evolution in Group 3. During 30-day follow-up there were 19 deaths (G1=1, G2=3 and G3=15). In univariate analysis mortality predictors were age > or = 75 years, anterior STEMI, maximum creatinine kinase > or = 2500 UI/L, culprit lesion in proximal anterior descending artery, incomplete revascularization, Killip > or = 2 at presentation, and being in G3. After multivariate regression analysis independent predictors were age > or = 75 years, incomplete revascularization and being in G3. CONCLUSION: In myocardial infarction patients undergoing mechanical revascularization, an intense neutrophil response (routinely, easily and inexpensively assessed) is related to worse short-term prognosis.

Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.