Public health is what we do together as a society to ensure the conditions in which everyone can be healthy. Although many sectors play key roles, governmental public health is an essential component. Recent stressors on public health are driving many local governments to pioneer a new Public Health 3.0 model in which leaders serve as Chief Health Strategists, partnering across multiple sectors and leveraging data and resources to address social, environmental, and economic conditions that affect health and health equity. In 2016, the US Department of Health and Human Services launched the Public Health 3.0 initiative and hosted listening sessions across the country. Local leaders and community members shared successes and provided insight on actions that would ensure a more supportive policy and resource environment to spread and scale this model. This article summarizes the key findings from those listening sessions and recommendations to achieve Public Health 3.0.
Compared to 2011, WB and RBC collections declined significantly in 2013 and disproportionately to the significant reductions in WB and RBC transfusions. Distributions of PLTs and plasma for transfusion declined in 2013, as did transfusions of plasma, while transfusion of PLTs increased significantly. Decreases in outdated and wasted components by hospitals suggest improvements in product and inventory management. Ongoing national surveys allow for trend analysis and are important for future planning.
Purpose: To evaluate the therapeutic and biological effects of CHIR-258, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases, in colon cancer models. Experimental Design: The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models. Results: CHIR-258 inhibits vascular endothelial growth factor receptor1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor B (PDGFRB) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1and PDGFRB phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm 3 ). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRB and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRB and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity. Conclusion:These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.
Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.
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