Oncolytic adenoviral vectors are currently being developed as biologic anticancer agents. Coupling the lytic function of an oncolytic adenovirus (Ad) with its ability as a transgene delivery system represents a powerful extension of this methodology. A clear advantage is the amplification of a therapeutic gene, as replicating vectors would be able to infect and deliver the gene of interest to neighboring cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of the most potent stimulators of a specific and long-lasting antitumor immunity and its important role in the maturation of antigen-presenting cells to induce T-cell activation has been well documented. Similarly, the B7 family has also been shown to play an integral role in mediating an antitumor response. Most tumor cells, however, lack the expression of these costimulatory molecules on their surface, thus escaping immune system recognition. To increase the antitumor effect of an oncolytic Ad, we have generated an E1B 55 kDa-deleted oncolytic adenoviral vector, YKL-GB, that expresses both GM-CSF and B7-1. The therapeutic efficacy of YKL-GB Ad was evaluated in immunocompetent mice bearing murine melanoma B16-F10 tumors. Significant inhibition of tumor growth was seen in mice treated with YKL-GB compared to those treated with the analogous vector, YKL-1. Moreover, YKL-GB oncolytic Ad demonstrated enhanced antitumor activity and higher incidences of tumor regression compared to a replication-incompetent Ad, dl-GB, which coexpresses GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against a tumor re-challenge. To establish that the observed antitumor effect is associated with the generation of a tumorspecific immune response, we carried out interferon-g enzymelinked immune spot assay. We observed that YKL-GB induced significantly higher immune cell activation than YKL-1. Furthermore, immunohistochemical studies demonstrated robust dendritic cells and CD4 + /CD8 + T-cell infiltration in these mice compared to the YKL-1-treated groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of the costimulatory and activation molecules. These findings demonstrate the effectiveness of enhancing the immune response against tumors with an oncolytic Ad expressing both GM-CSF and B7-1 and provide a potential therapeutic strategy for the management of neoplasia.

RNA interference, due to its target specificity, may be highly effective as a novel therapeutic modality, but direct delivery of synthetic small interfering RNA still remains a major obstacle for this approach. To induce long-term expression and specific gene silencing, novel delivery vector system is also required. In this study, we have generated an efficient oncolytic adenovirus (Ad)-based short hairpin (shRNA) expression system (Ad-DeltaB7-U6shIL8) against IL-8, a potent proangiogenic factor. To demonstrate IL-8-specificity of this newly engineered Ad-based shRNA, we also manufactured replication-incompetent Ads (Ad-DeltaE1-CMVshIL8 and Ad-DeltaE1-U6shIL8) under the control of the cytomegalovirus (CMV) and U6 promoters, respectively. Ad-DeltaE1-U6shIL8 was highly effective in reducing IL-8 expression, and was much more effective in driving IL-8-specific shRNA than the CMV promoter-driven vector. The reduced IL-8 expression then translated into decreased angiogenesis in vitro as measured by migration, tube formation and rat aortic ring sprouting assays. In addition to its effect on endothelial cells, Ad-DeltaE1-U6shIL8 also effectively suppressed the migration and invasion of cancer cells. In vivo, intratumoral injection of Ad-DeltaB7-U6shIL8 significantly inhibited the growth of Hep3B and A549 human tumor xenografts. Histopathological analysis of Ad-DeltaB7-U6shIL8-treated tumors revealed an increase in apoptotic cells and a reduction in vessel density. Finally, Ad-DeltaB7-U6shIL8 was also shown to inhibit the growth of disseminated MDA-MB-231 breast cancer metastases. Taken together, these findings demonstrate the utility and antitumor effectiveness of oncolytic Ad expressing shRNA against IL-8.

BackgroundPostoperative pressure ulcers are important indicators of perioperative care quality, and are serious and expensive complications during critical care. This study aimed to identify perioperative risk factors for postoperative pressure ulcers.MethodsThis retrospective case-control study evaluated 2,498 patients who underwent major surgery. Forty-three patients developed postoperative pressure ulcers and were matched to 86 control patients based on age, sex, surgery, and comorbidities.ResultsThe pressure ulcer group had lower baseline hemoglobin and albumin levels, compared to the control group. The pressure ulcer group also had higher values for lactate levels, blood loss, and number of packed red blood cell (pRBC) units. Univariate analysis revealed that pressure ulcer development was associated with preoperative hemoglobin levels, albumin levels, lactate levels, intraoperative blood loss, number of pRBC units, Acute Physiologic and Chronic Health Evaluation II score, Braden scale score, postoperative ventilator care, and patient restraint. In the multiple logistic regression analysis, only preoperative low albumin levels (odds ratio [OR]: 0.21, 95% CI: 0.05–0.82; P < 0.05) and high lactate levels (OR: 1.70, 95% CI: 1.07–2.71; P < 0.05) were independently associated with pressure ulcer development. A receiver operating characteristic curve was used to assess the predictive power of the logistic regression model, and the area under the curve was 0.88 (95% CI: 0.79–0.97; P < 0.001).ConclusionsThe present study revealed that preoperative low albumin levels and high lactate levels were significantly associated with pressure ulcer development after surgery.

Arterial stiffness was independently associated with deep or infratentorial CMBs but not lobar CMBs. These findings suggest a pathophysiological association between arterial stiffness and CMBs in the deep or infratentorial region.