10 research outputs found
Conserved expression and functions of PDE4 in rodent and human heart
PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
Niraparib for Advanced Breast Cancer with Germline <i>BRCA1</i> and <i>BRCA2</i> Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study.
Purpose To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (g BRCA m) advanced breast cancer. Patients and methods BRAVO was a randomized, open-label phase III trial. Eligible patients had g BRCA m and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor-positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm ( n = 141) versus 3.1 months in the PC arm [ n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65-1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63-1.42) and 0.65 (95% CI, 0.46-0.93), respectively. ORR was 35% (95% CI, 26-45) with niraparib and 31% (95% CI, 19-46) in the PC arm. Conclusions Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population
Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)
Glucagon Increases Beating Rate but Not Contractility in Rat Right Atrium. Comparison with Isoproterenol
Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project.
Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass
215 spectrometry through a worldwide collaboration. Methods: Cumulative percentiles of amino
216 acids and acylcarnitines in dried blood spots of approximately 30 million normal newborns and
217 10,615 true positive cases are compared to assign clinical significance, which is achieved when
218 the median of a disease range is either >99%ile or <1%ile of the normal population. The cutoff
219 target ranges of analytes and ratios are then defined as the interval between the limits of the two
220 populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity
221 taking in consideration all available factors. Results: As of December 1, 2010, 129 sites in 45
222 countries have uploaded to the project website a total of 23,970 percentile data points, 558,168
223 analyte results of 10,615 true positive cases with 64 conditions, and 5,088 cutoff values. The
224 average rate of submission of true positive cases between December 1, 2008 and December 1,
225 2010 was 4.7 cases per day (3,418 cases). This cumulative evidence generated 91 and 23 high
226 and low target cutoff ranges, respectively. The overall proportion of cutoff values within the
227 respective target range was 43% (2,176/5,088). Conclusions: An unprecedented level of
228 cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114
229 markers applied to newborn screening of rare metabolic disorders. This set of data could be used
230 as baseline for monitoring of future performance