Stable Integration of Transgenes Delivered by a Retrotransposon–Adenovirus Hybrid Vector

Helper-dependent adenoviruses show great promise as gene delivery vectors. However, because they do not integrate into the host chromosome, transgene expression cannot be maintained indefinitely. To overcome these limitations, we have inserted an L1 retrotransposon/transgene element into a helper-dependent adenovirus to create a novel chimeric gene delivery vector. Efficient adenovirus-mediated delivery of the L1 element into cultured human cells results in subsequent retrotransposition and stable integration of the transgene. L1 retrotransposition frequency was found to correlate with increasing multiplicity of infection by the chimeric vector, and further retrotransposition from newly integrated elements was not observed on prolonged culture. Therefore, this vector, which utilizes components of low immunogenic potential, represents a novel two-stage gene delivery system capable of achieving high titers via the initial helper-dependent adenovirus stage and permanent transgene integration via the retrotransposition stage.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63154/1/104303401750298571.pd

Can Social Policies Improve Health? A Systematic Review and Meta-Analysis of 38 Randomized Trials.

Policy Points Social policies might not only improve economic well-being, but also health. Health policy experts have therefore advocated for investments in social policies both to improve population health and potentially reduce health system costs. Since the 1960s, a large number of social policies have been experimentally evaluated in the United States. Some of these experiments include health outcomes, providing a unique opportunity to inform evidence-based policymaking. Our comprehensive review and meta-analysis of these experiments find suggestive evidence of health benefits associated with investments in early life, income support, and health insurance interventions. However, most studies were underpowered to detect health outcomes. CONTEXT: Insurers and health care providers are investing heavily in nonmedical social interventions in an effort to improve health and potentially reduce health care costs. METHODS: We performed a systematic review and meta-analysis of all known randomized social experiments in the United States that included health outcomes. We reviewed 5,880 papers, reports, and data sources, ultimately including 61 publications from 38 randomized social experiments. After synthesizing the main findings narratively, we conducted risk of bias analyses, power analyses, and random-effects meta-analyses where possible. Finally, we used multivariate regressions to determine which study characteristics were associated with statistically significant improvements in health outcomes. FINDINGS: The risk of bias was low in 17 studies, moderate in 11, and high in 33. Of the 451 parameter estimates reported, 77% were underpowered to detect health outcomes. Among adequately powered parameters, 49% demonstrated a significant health improvement, 44% had no effect on health, and 7% were associated with significant worsening of health. In meta-analyses, early life and education interventions were associated with a reduction in smoking (odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.86-0.99). Income maintenance and health insurance interventions were associated with significant improvements in self-rated health (OR = 1.20, 95% CI 1.06-1.36, and OR = 1.38, 95% CI 1.10-1.73, respectively), whereas some welfare-to-work interventions had a negative impact on self-rated health (OR = 0.77, 95% CI 0.66-0.90). Housing and neighborhood trials had no effect on the outcomes included in the meta-analyses. A positive effect of the trial on its primary socioeconomic outcome was associated with higher odds of reporting health improvements. We found evidence of publication bias for studies with null findings. CONCLUSIONS: Early life, income, and health insurance interventions have the potential to improve health. However, many of the included studies were underpowered to detect health effects and were at high or moderate risk of bias. Future social policy experiments should be better designed to measure the association between interventions and health outcomes

Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses.

In an effort to develop a safe and effective vaccine against respiratory syncytial virus (RSV), we used Escherichia coli heat-labile toxin (LT), and LTK63 (an LT mutant devoid of ADP-ribosyltransferase activity) to elicit murine CD8(+) CTL responses to an intranasally codelivered CTL peptide from the second matrix protein (M2) of RSV. M2(82-90)-specific CD8(+) T cells were detected by IFN-gamma enzyme-linked immunospot and (51)Cr release assay in local and systemic lymph nodes, and their induction was dependent on the use of a mucosal adjuvant. CTL elicited by peptide immunization afforded protection against RSV challenge, but also enhanced weight loss. CTL-mediated viral clearance was not dependent on IFN-gamma since depletion using specific mAb during RSV challenge did not affect cellular recruitment or viral clearance. Depletion of IFN-gamma did, however, reduce the concentration of TNF detected in lung homogenates of challenged mice and largely prevented the weight loss associated with CTL-mediated viral clearance. Mice primed with the attachment glycoprotein (G) develop lung eosinophilia after intranasal RSV challenge. Mucosal peptide vaccination reduced pulmonary eosinophilia in mice subsequently immunized with G and challenged with RSV. These studies emphasize that protective and immunoregulatory CD8(+) CTL responses can be mucosally elicited using enterotoxin-based mucosal adjuvants but that resistance against viral infection may be accompanied by enhanced disease