ABSTRACT
BACKGROUND: Chronic lymphocytic leukemia has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms that are poorly understood. In particular it remains unclear whether the prognostic subgroups of chronic lymphocytic leukemia are characterized by different levels of leukemogenic proteins. DESIGN AND METHODS: Expression of 23 proteins involved in apoptosis, proliferation, DNA damage, and signaling or whose genes map to chromosomal regions known to be critical in chronic lymphocytic leukemia was quantified in 185 cytogenetically well characterized cases of chronic lymphocytic leukemia using immunoblotting. Cases were categorized hierarchically into deletion(17p), deletion(11q), trisomy 12, deletion(13q) as sole abnormality or normal karyotype. Statistical analysis was performed for expression differences between these subgroups. In addition, the expression levels of CDK4, P27 and P53 were quantified over the clinical course and compared to levels in immunopurified B cells from healthy individuals. RESULTS: In subgroups with a good prognosis, differential expression was mainly seen for proteins that regulate apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, differential expression was mostly detected for proteins that control DNA damage and proliferation. Expression levels of CDK4, P27 and P53 were higher compared to those in B cells from healthy individuals and significantly correlated with increasing hierarchical risk. In addition, no significant longitudinal changes of expression levels of CDK4, P27 and P53 could be detected in chronic lymphocytic leukemia patients. CONCLUSIONS: Differences in expression levels of apoptosis- and proliferation-controlling proteins define distinct prognostic subgroups of chronic lymphocytic leukemia and uncover a correlation of levels of CDK4, P27 and P53 proteins with higher hierarchical risk.
Subject(s)
Chromosome Aberrations , Cyclin-Dependent Kinase 4/biosynthesis , Gene Expression Regulation, Leukemic , Intracellular Signaling Peptides and Proteins/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Tumor Suppressor Protein p53/biosynthesis , Apoptosis/genetics , B-Lymphocytes/metabolism , Cell Line, Transformed , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase Inhibitor p27 , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Risk Factors , Tumor Suppressor Protein p53/geneticsABSTRACT
INTRODUCTION: Since data regarding new-onset atrial fibrillation (AF) in septic shock patients are scarce, the purpose of the present study was to evaluate the incidence and prognostic impact of new-onset AF in this patient group. METHODS: We prospectively studied all patients with new-onset AF and all patients suffering from septic shock in a non-cardiac surgical intensive care unit (ICU) during a 13 month period. RESULTS: During the study period, 687 patients were admitted to the ICU, of which 58 patients were excluded from further analysis due to pre-existing chronic or intermittent AF. In 49 out of the remaining 629 patients (7.8%) new-onset AF occurred and 50 out of the 629 patients suffered from septic shock. 23 out of the 50 patients with septic shock (46%) developed new-onset AF. There was a steady, significant increase in C-reactive protein (CRP) levels before onset of AF in septic shock patients. ICU mortality in septic shock patients with new-onset AF was 10/23 (44%) compared with 6/27 (22%) in septic shock patients with maintained sinus rhythm (SR) (P = 0.14). During a 2-year follow-up there was a trend towards an increased mortality in septic shock patients with new-onset AF, but the difference did not reach statistical significance (P = 0.075). The median length of ICU stay among surviving patients was longer in patients with new-onset AF compared to those with maintained SR (30 versus 17 days, P = 0.017). The success rate to restore SR was 86%. Failure to restore SR was associated with increased ICU mortality (71.4% versus 21.4%, P = 0.015). CONCLUSIONS: AF is a common complication in septic shock patients and is associated with an increased length of ICU stay among surviving patients. The increase in CRP levels before onset of AF may support the hypothesis that systemic inflammation is an important trigger for AF.
