Plasma copeptin, a possible prognostic marker in cirrhosis.

BACKGROUND & AIM: Copeptin, secreted stoichiometrically with vasopressin, demonstrated its prognostic role in various diseases other than cirrhosis. METHODS: We investigated the association between severity of cirrhosis and plasma concentrations of copeptin, and the prognostic value of copeptin in 95 non-septic cirrhotic patients (34 Child-Pugh A, 29 CP-B, 32 CP-C), 30 septic patients with a Child-Pugh >8 ('group D'), and 16 healthy volunteers. Patients were followed for at least 12 months to assess the composite endpoint death/liver transplantation. RESULTS: Median copeptin concentrations (interquartile range) increased through healthy volunteers group [5.95 (3.76-9.43) pmol/L] and 'group D' patients [18.81 (8.96-36.66) pmol/L; P < 0.001)]. During a median follow-up of 11.0 ± 6.1 months, 28 non-transplanted patients died and eight were transplanted. In receiver operated characteristic curves analysis, the area under the curve values were as follows: Child-Pugh score 0.80 (95% CI: 0.71-0.86), model of end-stage liver disease (MELD) score 0.80 (0.70-0.86), C-reactive protein (CRP) 0.71 (0.60-0.80) and copeptin 0.70 (0.57-0.79). By stratifying the values of these variables into tertiles, the risk of death/liver transplantation for patients belonging to the highest tertile of copeptin (>13 pmol/L) was high (Log-rank test: P = 0.0002) and 2.3-fold higher than for patients with lower concentrations after adjusting for MELD score (>21) and CRP (>24 mg/L) in a Cox model. Other potential predictors (age, total cholesterol, natraemia and serum free cortisol) did not reach a significant level. CONCLUSION: In cirrhotic patients, copeptin concentrations increased along with the severity of liver disease. In our cohort, the 1-year mortality or liver transplantation was predicted by high MELD score and high concentrations of CRP and copeptin.

Replicative retroviral vectors for cancer gene therapy.

Poor efficiency of gene transfer into cancer cells constitutes the major bottleneck of current cancer gene therapy. We reasoned that because tumors are masses of rapidly dividing cells, they would be most efficiently transduced with vector systems allowing transgene propagation. We thus designed two replicative retrovirus-derived vector systems: one inherently replicative vector, and one defective vector propagated by a helper retrovirus. In vitro, both systems achieved very efficient transgene propagation. In immunocompetent mice, replicative vectors transduced >85% tumor cells, whereas defective vectors transduced <1% under similar conditions. It is noteworthy that viral propagation could be efficiently blocked by azido-thymidine, in vitro and in vivo. In a model of established brain tumors treated with suicide genes, replicative retroviral vectors (RRVs) were approximately 1000 times more efficient than defective adenoviral vectors. These results demonstrate the advantage and potential of RRVs and strongly support their development for cancer gene therapy.

DNA vaccines encoding retrovirus-based virus-like particles induce efficient immune responses without adjuvant.

Virus-like particle (VLP)-based vaccines have provided highly encouraging results in clinical trials while, in contrast, DNA vaccines expressing non-particulate proteins have proven less successful. Seeking to combine the immunogenicity of VLPs and the ease of production of plasmid DNA, we designed DNA vaccines expressing VLPs consisting of the MLV Gag and modified MLV Env proteins displaying T cell epitopes. We show here that such DNA vaccines are remarkably efficient immunogens for inducing cellular immune responses. In contrast to similar plasmids harboring a point mutation preventing VLP formation, they induce protection against a lethal viral challenge in mice. Thus, these "plasmo-retroVLPs" represent a promising second-generation DNA vaccine.