Clinical endpoints to inform vaccine policy: A systematic review of outcome measures from pediatric influenza vaccine efficacy trials.

INTRODUCTION: We conducted a systematic review of pediatric influenza vaccine efficacy trials to assess clinical outcome measures and whether the trials defined important public health endpoints. MATERIAL AND METHODS: We systematically identified phase 3 or 4 influenza vaccine randomized controlled trials among children ≤18 years of age with laboratory-confirmed influenza outcomes since 1980. We recorded countries, age groups, vaccine formulations, specimen collection criteria, laboratory diagnostics, primary and secondary outcome measures, and funders, and we determined income category for study countries. We used descriptive statistics to summarize study characteristics. We analyzed the studies overall and a subset of studies conducted in at least one low- and middle-income country (LMIC). RESULTS: From 6455 potentially relevant articles, we identified 41 eligible studies. Twenty-one studies (51%) were conducted in at least one LMIC, while the remaining studies (49%) were conducted in high-income countries only. Thirty-one studies (76%) included children younger than six years. We found 40 different primary outcome measures among the 41 eligible studies. Thirty-three studies (80%) reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. One study defined a primary outcome which captured more severe illness; however, cases were mostly due to high body temperature without other severity criteria. Of the 21 studies from at least one LMIC, 15 (71%) were published since 2010 and 17 (81%) enrolled children younger than six years. Eighteen (86%) studies from at least one LMIC reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. CONCLUSIONS: Among pediatric influenza vaccine efficacy trials, primary outcome measures and clinical specimen collection criteria were highly variable and, with one exception, focused on capturing any influenza illness. As most LMICs do not have influenza vaccination programs, our study highlights a potential data limitation affecting policy and implementation decisions in these settings.

Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer.

PURPOSE: COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer. EXPERIMENTAL DESIGN: Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib ± standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined. RESULTS: COX-2 inhibition reduced the IC(50) of gemcitabine ± erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression. CONCLUSIONS: Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer.

CO2-formatics: how do proteins bind carbon dioxide?

The rising atmospheric concentration of CO(2) has motivated researchers to seek routes for improved utilization, increased mitigation, and enhanced sequestration of this greenhouse gas. Through a combination of bioinformatics, molecular modeling, and first-principles quantum mechanics the binding of carbon dioxide to proteins is analyzed. It is concluded that acid/base interactions are the principal chemical force by which CO(2) is bound inside proteins. With respect to regular secondary structural elements, beta-sheets show a marked preference for CO(2) binding compared to alpha-helices. The data also support the inference that while either or both oxygens of CO(2) are generally tightly bound in the protein environment, the carbon is much less "sequestered." First principles and more approximate modeling techniques are assessed for quantifying CO(2) binding thermodynamics.