Construction and evaluation of recombinant Lactobacillus plantarum NC8 delivering one single or two copies of G protein fused with a DC-targeting peptide (DCpep) as novel oral rabies vaccine.

Rabies remains an important public health threat in most developing countries. To develop a more effective and safe oral vaccine against rabies, we constructed recombinant Lactobacillus plantarum NC8 carrying one or two copies of the G gene with a dendritic cell-targeting peptide (DCpep) fused at the C-terminal designated NC8-pSIP409-sRVG or NC8-pSIP409-dRVG, respectively. The immunogenicity and protective efficacy of these recombinant Lactobacillus plantarum against RABV were evaluated by oral administration in a mouse model. The results showed that recombinant NC8-pSIP409-dRVG possessed more G protein, resulting in more functional maturation of DCs. After three cycle of oral immunization, NC8-pSIP409-dRVG induced significantly higher levels of specific IgG antibody and mixed Th1/Th2 with a strong Th1-biasd immune response in mice. Most importantly, although the titers of RABV neutralizing antibody (VNA) were below the threshold of 0.5 IU/mL, the NC8-pSIP409-dRVG could protect 60 % of inoculated mice against lethal RABV challenge. These data reveal that recombinant NC8-pSIP409-dRVG may be a novel and promising oral vaccine candidate to prevent and control of animal rabies.

A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the µ-Opioid Receptor.

TRV734 is an orally bioavailable G-protein-biased ligand at the µ-opioid receptor. In nonclinical studies it was potently analgesic while causing less gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A 2-part, first-in-human study was conducted with ascending doses of TRV734 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV734 was well tolerated over the dose range 2 to 250 mg when administered orally. Plasma TRV734 maximum concentration and area under the plasma concentration-time curve generally increased with dose, while time to maximum concentration was similar across doses (0.5-1.3 h). The half-life increased with dose from 10 mg through 150 mg (0.75-2.28 h) but was similar from 150 mg through 250 mg. Pupil constriction, confirming central nervous system µ-opioid receptor engagement, correlated with higher plasma TRV734 concentrations; the greatest reductions in pupil diameter occurring between 0 and 4 hours after dosing (-2.9 mm/h, with reduction peaking at 1 hour, and returning to baseline by 8 hours). Following administration of TRV734 125 mg under fasted or fed conditions, there was no significant difference in bioavailability when given as a solution or drug in capsule to fasted subjects. When drug in capsule was given to subjects following a high-fat meal, absorption was slowed, resulting in decreased peak concentrations, but area under the plasma concentration-time curve was not affected.

Co-immunization of BALB/c mice with recombinant immunogens containing G protein fragment and chimeric CTL epitope of respiratory syncytial virus induces enhanced cellular immunity and high level of antibody response.

With the goal to develop effective immunogens against infection of respiratory syncytial virus (RSV), vectors co-expressing chimeric CTL epitope or G protein fragment of RSV with carrier protein DsbA (disulfide bond isomerase) were constructed. The capacity of the expressed recombinant immunogens to induce cellular and humoral immunities were evaluated. It was demonstrated that the presence of G protein fragment was able to enhance the CTL activities induced by the chimeric CTL epitope, though G protein fragment alone had no effect on induction of CTL response. In contrast, the level of antibody response to RSV and neutralization titer in co-immunization with G protein fragment plus chimeric CTL epitope was lower than that in immunization with G protein fragment alone. The challenge experiments indicated that co-immunization further reduced RSV titers both in lung tissue and nasal track, indicating the combination of humoral and cellular immunities is more effective. This data imply that the combination of the two protein immunogens would be a viable strategy for a RSV vaccine.

beta-adrenoceptor blockers as agonists: coupling of beta2-adrenoceptors to multiple G-proteins in the failing human heart.

Beta blockers have been shown in clinical trials to improve cardiac function and reduce mortality of heart failure patients. However, these agents require careful titration since they can produce an initial decrease in cardiac output. The authors have recently shown that beta blockers, including some used clinically, can directly depress contraction of myocardium from the failing (but not nonfailing) human heart. This occurs on single ventricular myocytes and is therefore completely independent of any inhibition of endogenous catecholamines. The effect appears to be mediated primarily by the beta2-adrenoceptor (AR) and is dependent on the inhibitory guanine nucleotide binding protein, Gi. Using a transgenic mouse model, as well as adenoviral vectors to overexpress Gi or the human beta2AR in adult myocytes of various species, the authors demonstrate that agents that are blockers for bAR/Gs coupling can be agonists at a beta2AR/Gi-coupled form of the receptor. The negative effect of beta blockers could contribute to the initial cardiodepression that is observed when introducing these agents in heart failure patients. However, in the long term, beta2AR/Gi coupling may enhance the ability of beta blockers to protect and improve the function of the failing heart.

Relación de nm23-H1 con las metástasis en el cáncer de recto / Relationship between nm23-H1 and metastasis in cancer of the rectum

Introducción y objetivos. El gen nm23-H1 es un supresor de metástasis estudiado en distintos tipos de tumores humanos. El objeto de este estudio es determinar su prevalencia en el cáncer de recto y su relación con los parámetros clinicopatológicos clásicos y con la supervivencia. Pacientes y métodos. Estudio retrospectivo inmunohistoquímico y clínico con un anticuerpo monoclonal de ratón sobre 54 pacientes con tumores de recto resecados consecutivamente con una mediana de seguimiento de 37 meses. Resultados. La positividad fue de 42 casos (77,8 por ciento) en el tumor primario frente a 6 casos (26,1 por ciento) en los ganglios metastatizados (p = 0,03). La expresión de nm23-H1 se correlaciona de forma inversa con la existencia de diseminación ganglionar (p = 0,05) y de metástasis (p = 0,03). No hubo influencia sobre la supervivencia. Conclusiones. Existe una pérdida de la expresión de nm23-H1 en las metástasis ganglionares de los tumores rectales. La determinación inmunohistoquímica de nm23-H1 en el tejido tumoral primario puede predecir la existencia de diseminación ganglionar o metástasis a distancia en el cáncer de recto (AU)