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1.
Ecancermedicalscience ; 9: 498, 2015.
Article in English | MEDLINE | ID: mdl-25624879

ABSTRACT

Concerns about rising health care costs and the often incremental nature of improvements in health outcomes continue to fuel intense debates about 'progress' and 'value' in cancer research. In times of tightening fiscal constraints, it is increasingly important for patients and their representatives to define what constitutes 'value' to them. It is clear that diverse stakeholders have different priorities. Harmonisation of values may be neither possible nor desirable. Stakeholders lack tools to visualise or otherwise express these differences and to track progress in cancer treatments based on variable sets of values. The Patient Access to Cancer care Excellence (PACE) Continuous Innovation Indicators are novel, scientifically rigorous progress trackers that employ a three-step process to quantify progress in cancer treatments: 1) mine the literature to determine the strength of the evidence supporting each treatment; 2) allow users to weight the analysis according to their priorities and values; and 3) calculate Evidence Scores (E-Scores), a novel measure to track progress, based on the strength of the evidence weighted by the assigned value. We herein introduce a novel, flexible value model, show how the values from the model can be used to weight the evidence from the scientific literature to obtain E-Scores, and illustrate how assigning different values to new treatments influences the E-Scores. The Indicators allow users to learn how differing values lead to differing assessments of progress in cancer research and to check whether current incentives for innovation are aligned with their value model. By comparing E-Scores generated by this tool, users are able to visualise the relative pace of innovation across areas of cancer research and how stepwise innovation can contribute to substantial progress against cancer over time. Learning from experience and mapping current unmet needs will help to support a broad audience of stakeholders in their efforts to accelerate and maximise progress against cancer.

2.
Virology ; 315(2): 322-34, 2003 Oct 25.
Article in English | MEDLINE | ID: mdl-14585335

ABSTRACT

A documented consequence of poxvirus infections is global inhibition of host protein synthesis and reduction in mRNA levels. We examined this mRNA decrease by infecting A549 cells, derived from a human lung carcinoma, with rabbitpox virus (RPV), or RPV deleted for the serine protease inhibitor SPI-1 (RPVDeltaSPI-1), which exhibits a growth defect on A549 cells. At various times postinfection, mRNA profiles were analyzed using Affymetrix U95AV2 microarrays. There was a decline in overall cellular mRNA levels beginning at 2.5 hpi, and by 5 hpi, mRNA levels were drastically reduced for the majority of genes. However, several mRNAs increased, including those of heat-shock genes. Finally, a comparison of host mRNA profiles of RPV- to RPVDeltaSPI-1-infected cells revealed subtle differences in mRNA levels at 5 and 12 hpi. In summary, while there was a global decrease of host mRNA levels, the induction of selected mRNAs may be required for a successful poxvirus infection.


Subject(s)
Oligonucleotide Array Sequence Analysis , Peptides/genetics , Serine Proteinase Inhibitors/genetics , Vaccinia virus/genetics , Actins/genetics , Gene Expression Profiling , HSP70 Heat-Shock Proteins/genetics , Histones/genetics , Humans , Intercellular Signaling Peptides and Proteins , RNA, Messenger/analysis
3.
Virology ; 306(2): 289-302, 2003 Feb 15.
Article in English | MEDLINE | ID: mdl-12642102

ABSTRACT

The cowpox virus (CPV) glycoprotein serpin SPI-3, a functional protease inhibitor, and the viral hemagglutinin (HA) are required to prevent fusion of wt CPV infected cells. SPI-3 and HA from CPV infected cells co-localize to the plasma membrane and are found in extracellular enveloped virus (EEV). We also show that an N-terminal SPI-3 signal sequence, but not glycosylation, is required for membrane localization and fusion inhibition. In the absence of HA (CPVDeltaHA), no SPI-3 is found on the membrane and infected cells fuse. Conversely, HA from both wt CPV and CPVDeltaSPI-3 infections is on the membrane, indicating a requirement of HA for SPI-3 plasma membrane localization. In the absence of HA, secretion of SPI-3 or SPI-3 N-glyc(-) was markedly enhanced, suggesting HA serves to retain SPI-3 on the plasma membrane,thereby preventing cell fusion.


Subject(s)
Cowpox virus/physiology , Serpins/physiology , Viral Proteins/physiology , Animals , Base Sequence , Binding Sites , Cell Line , Cell Membrane/virology , Chlorocebus aethiops , Cowpox virus/genetics , DNA, Viral/genetics , Glycosylation , Hemagglutinins, Viral/chemistry , Hemagglutinins, Viral/genetics , Hemagglutinins, Viral/physiology , Membrane Fusion/genetics , Membrane Fusion/physiology , Mutagenesis, Site-Directed , Protein Sorting Signals/genetics , Protein Sorting Signals/physiology , Recombination, Genetic , Serpins/chemistry , Serpins/genetics , Viral Proteins/chemistry , Viral Proteins/genetics
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