Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT0120183

Molecular test of Paget's disease of bone in families not linked to SQSTM1 gene mutations

Purpose: Paget's disease of bone (PDB) is a focal metabolic bone disorder characterized by an increased bone remodeling. Fifteen to 40 % of PDB patients have a familial form with an autosomal dominant inheritance. Disease-causing mutations of the SQSTM1 gene have been linked to PDB in about 40 % of families whereas genes linked to the remaining families are unknown. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in unrelated patient non-carriers of a SQSTM1 mutation. The current clinical practice guidelines still recommend the measure of serum total alkaline phosphatase (sALP) for PDB screening. In unrelated individual non-carriers of SQSTM1 mutations, we previously developed a genetic test combining male sex with five genetic markers (rs499345, rs5742915, rs2458413, rs3018362, rs2234968), giving rise to an area under the curve (AUC) for PDB phenotype of 0.73 (0.69; 0.77). A combination of male sex with total calcium corrected for albumin and Procollagen type I N-terminal propeptide (P1NP), had an AUC of 0.82 (0.73; 0.92). Combining both genetic and biochemical tests increased the AUC to 0.89 (0.83; 0.95). Objective: This study aimed at estimating the performance of our previous test of PDB, in families not linked to SQSTM1 mutations with disease-causing genes yet unknown, and at developing a new algorithm if the performance is not satisfactory. Methods: We genotyped the five SNPs cited above, and measured calcium corrected for albumin and P1NP in 181 relatives, with PDB or not, from 19 PDB families not linked to SQSTM1 mutations. Bivariate and multivariate logistic regression models including male sex were fitted to search for a molecular test that could best detect PDB in these families. A receiving operating characteristics analysis was done to establish a cut-off point for continuous variables. Results: Logistic regression estimates of our previous molecular test gave rise to a high sensitivity of 78 %, 97 % and 88 % for the genetic, biochemical, and combined test but the specificity was very low, 35 %, 11 % and 21 %, respectively. This poor specificity persisted even when the cut-off point was changed. We then generated in these families, new logistic regression estimates but on the same parameters as mentioned above, giving rise to an AUC of 0.65 (0.55; 0.75) for the genetic test, of 0.84 (0.74; 0.94) for the biochemical test, and 0.89 (0.82; 0.96) for the combination test, the latter having a sensitivity of 96 % and specificity of 57 %. By comparison serum P1NP alone gave rise to an AUC of 0.84 (0.73; 0.94), with a sensitivity of 71 % and a specificity of 79 %. Conclusion: In PDB families not linked to SQSTM1 mutations, the estimates of our previous molecular test gave rise to a poor specificity. Using new estimates, the biochemical and combined tests have similar predictive abilities than our former test. Serum P1NP is a bone marker of interest for the screening for PDB in families not linked to SQSTM1 mutations

cAMP-Dependent Activation of Mammalian Target of Rapamycin (mTOR) in Thyroid Cells. Implication in Mitogenesis and Activation of CDK4.

How cAMP-dependent protein kinases [protein kinase A (PKA)] transduce the mitogenic stimulus elicited by TSH in thyroid cells to late activation of cyclin D3-cyclin-dependent kinase 4 (CDK4) remains enigmatic. Here we show in PC Cl3 rat thyroid cells that TSH/cAMP, like insulin, activates the mammalian target of rapamycin (mTOR)-raptor complex (mTORC1) leading to phosphorylation of S6K1 and 4E-BP1. mTORC1-dependent S6K1 phosphorylation in response to both insulin and cAMP required amino acids, whereas inhibition of AMP-activated protein kinase and glycogen synthase kinase 3 enhanced insulin but not cAMP effects. Unlike insulin, TSH/cAMP did not activate protein kinase B or induce tuberous sclerosis complex 2 phosphorylation at T1462 and Y1571. However, like insulin, TSH/cAMP produced a stable increase in mTORC1 kinase activity that was associated with augmented 4E-BP1 binding to raptor. This could be caused in part by T246 phosphorylation of PRAS40, which was found as an in vitro substrate of PKA. Both in PC Cl3 cells and primary dog thyrocytes, rapamycin inhibited DNA synthesis and retinoblastoma protein phosphorylation induced by TSH and insulin. Although rapamycin reduced cyclin D3 accumulation, the abundance of cyclin D3-CDK4 complexes was not affected. However, rapamycin inhibited the activity of these complexes by decreasing the TSH and insulin-mediated stimulation of activating T172 phosphorylation of CDK4. We propose that mTORC1 activation by TSH, at least in part through PKA-dependent phosphorylation of PRAS40, crucially contributes to mediate cAMP-dependent mitogenesis by regulating CDK4 T172-phosphorylation.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe