Involvement of DNA-dependent protein kinase in down-regulation of cell cycle progression.

The catalytic polypeptide of DNA-dependent protein kinase (p470) is encoded by the gene responsible for murine severe combined immunodeficiency (SCID) devoid of DNA double-strand break repair and V(D)J recombination. Here, we have characterized the role of p470 in cell proliferation using SCID mice and the cell lines. In accord with DNA histogram patterns, SCID cell lines (SD/SD-eA and SC3VA2) expressing extremely low level of DNA-PK activity grew faster than a normal mouse cell line (CB/CB-eB) and SC3VA2 complemented with human p470 gene (RD13B2). In regenerating liver after partial hepatectomy, de novo DNA synthesis determined by [(3)H]thymidine incorporation started at 30h in C.B-17/Icr-SCID (SCID) mice and at around 36h in C.B-17/Icr (C.B-17) mice. Compared with normal cells, SCID cells contained slightly higher levels of transcripts of cyclin A, cyclin E, B-Myb and dihydrofolate reductase, which are regulated by E2F-1. E2F-1 playing a key role in G1- to S-phase progression was phosphorylated in vitro by DNA-PK. Importantly, the E2F-1 promoter transcriptional activity in SCID cell lines (SD/SD-eA and SC3VA2) was 4-5-fold higher than that in CB/CB-eB and RD13B2. These results suggest that p470 is involved in down-regulation of cell cycle progression through E2F-1-responsible genes

Relation between frequency of activated partial prothrombin time measurements and clinical outcomes in patients after initiation of dabigatran: A two-center cooperative study

Background: Although activated partial prothrombin time (aPTT) has often been used as a biomarker for evaluating the safety of dabigatran use in patients with non-valvular atrial fibrillation (NVAF), the optimal frequency of aPTT measurements is unclear. This study aimed to identify the frequency distribution of aPTT measurements in clinical practice and its clinical significance. Methods: This was a retrospective cooperative study conducted in 2 sites. All NVAF patients who underwent aPTT measurements before and after dabigatran treatment were included (n=380). The patients were divided into 2 groups according to the frequency of aPTT measurements during the first 3 months after drug prescription: Group A: infrequent group with only 1 measurement; and Group B: frequent group with ≥2 measurements. The clinical characteristics and outcomes were compared between the groups. Results: The frequency of aPTT measurements in the 3 months after dabigatran initiation varied: 240 patients underwent 1 measurement (Group A), and the remaining 140 patients underwent repeated measurements (Group B). There were significant differences in age and creatinine clearance (Ccr) between the groups (Group A vs. Group B: age 64.0±11.7 vs. 67.0±11.1 years, p=0.01; Ccr 83.8±30.3 vs.76.7±31.1 mL/min, p=0.03). During the mean follow-up period of 310 days, there were no significant differences in the discontinuation rate and incidence of bleeding (17% vs. 15% and 5% vs. 3%, respectively; both not significant). In Group B, the aPTT rarely increased beyond twice the upper normal limit within the 3 months (2.1%), although the correlation between the initial and subsequent aPTT measurements was low (r=0.366). Conclusions: In this retrospective study, the frequency of aPTT measurements after dabigatran initiation might have been dependent on patient characteristics. However, frequent aPTT measurements did not lead to a reduction in adverse clinical events

Detection of regional low myocardial perfusion helps predict a response to cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy: Results of the Find Index by Nuclear Imaging for Dyssynchrony (FIND) study

Background: The aim of this study was to investigate the use of imaging techniques to predict the response to cardiac resynchronization therapy (CRT) in patients with non-ischemic cardiomyopathy (NICM) by simultaneous assessment of left ventricular (LV) dyssynchrony and myocardial perfusion in a single nuclear scan of the heart. Methods: Patients indicated for CRT device implantation underwent a resting myocardial perfusion assessment with single photon emission computed tomography (MP-SPECT) examination using technetium-99 m methoxyisobutylisonitrile prior to device implantation. CardioGRAF and cardioBull software (FUJIFILM RI Pharma, Tokyo, Japan) were used to analyze the LV mechanical dyssynchrony and myocardial viability, respectively. Patient follow-ups were performed at 6 months after device implantation. CRT response was defined as a ≥10% decrease in the LV end systolic volume. Results: A total of 43 patients with NICM were analyzed. Using the cutoff points of 6.2 for the dyssynchrony index and 66% for LV myocardial perfusion, the combined indices predicted CRT response with a sensitivity of 77.8% and specificity of 91.2%. Conclusion: Combined assessment of MP-SPECT and a measure of LV mechanical dyssynchrony showed good predictive ability in patients with non-ischemic heart failure