Reforming the cancer drug fund focus on drugs that might be shown to be cost effective

The Cancer Drug Fund was originally conceived as a temporary measure, until value based pricing for drugs was introduced, to give NHS cancer patients access to drugs not approved by NICE. Spending on these drugs rose from less than the £50m (€63m; $79m) budgeted for the first year in 2010-11 to well over £200m in 2013-14, and the budget for the scheme—now extended for a further two years—will reach £280m by 2016.1 The recent changes to the fund recognise the impossibility, within any sensible budget limit, of providing all the new cancer drugs that offer possible benefit to patients. More radical changes are needed to the working of the fund, given the failure to introduce value based pricing, so that it deals with the underlying problem of inadequate information on the effectiveness and cost effectiveness of new cancer drugs when used in the NHS

Disease activity and cognition in rheumatoid arthritis : an open label pilot study

Acknowledgements This work was supported in part by NIHR Newcastle Biomedical Research Centre. Funding for this study was provided by Abbott Laboratories. Abbott Laboratories were not involved in study design; in the collection, analysis and interpretation of data; or in the writing of the report.Peer reviewedPublisher PD

Effects of human and porcine bile on the proteome of Helicobacter hepaticus

<p>Abstract</p> <p>Background</p> <p><it>Helicobacter hepaticus </it>colonizes the intestine and liver of mice causing hepatobiliary disorders such as hepatitis and hepatocellular carcinoma, and has also been associated with inflammatory bowel disease in children. In its habitat, <it>H. hepaticus </it>must encounter bile which has potent antibacterial properties. To elucidate virulence and host-specific adaptation mechanisms of <it>H. hepaticus </it>modulated by human or porcine bile, a proteomic study of its response to the two types of bile was performed employing two-dimensional gel electrophoresis (2-DE) and mass spectrometry.</p> <p>Results</p> <p>The 2-DE and mass spectrometry analyses of the proteome revealed that 46 proteins of <it>H. hepaticus </it>were differentially expressed in human bile, 18 up-regulated and 28 down-regulated. In the case of porcine bile, 32 proteins were differentially expressed of which 19 were up-regulated, and 13 were down-regulated. Functional classifications revealed that identified proteins participated in various biological functions including stress response, energy metabolism, membrane stability, motility, virulence and colonization. Selected genes were analyzed by RT-PCR to provide internal validation for the proteomic data as well as provide insight into specific expressions of motility, colonization and virulence genes of <it>H. hepaticus </it>in response to human or porcine bile.</p> <p>Conclusions</p> <p>Overall, the data suggested that bile is an important factor that determines virulence, host adaptation, localization and colonization of specific niches within host environment.</p

Latent class analysis variable selection

We propose a method for selecting variables in latent class analysis, which is the most common model-based clustering method for discrete data. The method assesses a variable's usefulness for clustering by comparing two models, given the clustering variables already selected. In one model the variable contributes information about cluster allocation beyond that contained in the already selected variables, and in the other model it does not. A headlong search algorithm is used to explore the model space and select clustering variables. In simulated datasets we found that the method selected the correct clustering variables, and also led to improvements in classification performance and in accuracy of the choice of the number of classes. In two real datasets, our method discovered the same group structure with fewer variables. In a dataset from the International HapMap Project consisting of 639 single nucleotide polymorphisms (SNPs) from 210 members of different groups, our method discovered the same group structure with a much smaller number of SNP

Comparative Phosphoproteomics of Classical Bordetellae Elucidates the Potential Role of Serine, Threonine and Tyrosine Phosphorylation in Bordetella Biology and Virulence.

The Bordetella genus is divided into two groups: classical and non-classical. Bordetella pertussis, Bordetella bronchiseptica and Bordetella parapertussis are known as classical bordetellae, a group of important human pathogens causing whooping cough or whooping cough-like disease and hypothesized to have evolved from environmental non-classical bordetellae. Bordetella infections have increased globally driving the need to better understand these pathogens for the development of new treatments and vaccines. One unexplored component in Bordetella is the role of serine, threonine and tyrosine phosphorylation. Therefore, this study characterized the phosphoproteome of classical bordetellae and examined its potential role in Bordetella biology and virulence. Applying strict identification of localization criteria, this study identified 70 unique phosphorylated proteins in the classical bordetellae group with a high degree of conservation. Phosphorylation was a key regulator of Bordetella metabolism with proteins involved in gluconeogenesis, TCA cycle, amino acid and nucleotide synthesis significantly enriched. Three key virulence pathways were also phosphorylated including type III secretion system, alcaligin synthesis and the BvgAS master transcriptional regulatory system for virulence genes in Bordetella. Seven new phosphosites were identified in BvgA with 6 located in the DNA binding domain. Of the 7, 4 were not present in non-classical bordetellae. This suggests that serine/threonine phosphorylation may play an important role in stabilizing/destabilizing BvgA binding to DNA for fine-tuning of virulence gene expression and that BvgA phosphorylation may be an important factor separating classical from non-classical bordetellae. This study provides the first insight into the phosphoproteome of classical Bordetella species and the role that Ser/Thr/Tyr phosphorylation may play in Bordetella biology and virulence

Comparison of the Whole Cell Proteome and Secretome of Epidemic Bordetella pertussis Strains From the 2008-2012 Australian Epidemic Under Sulfate-Modulating Conditions.

Sulfate is an important modulator for virulence factor expression in Bordetella pertussis, the causative organism for whooping cough. During infection, sulfate is released when respiratory epithelial cells are damaged which can affect gene expression. The current predominant strains in Australia are found in single nucleotide polymorphism (SNP) cluster I (ptxP3/prn2). It has been reported that ptxP3 strains have higher mRNA expression of virulence genes than ptxP1 strains under intermediate sulfate-modulating conditions (5 mM MgSO4). Our previous proteomic study compared L1423 (cluster I, ptxP3) and L1191 (cluster II, ptxP1) in Thalen-IJssel (THIJS) media without sulfate modulation and identified an upregulation of transport proteins and a downregulation of immunogenic proteins. To determine whether proteomic differences exist between cluster I and cluster II strains in intermediate modulating conditions, this study compared the whole cell proteome and secretome between L1423 and L1191 grown in THIJS media with 5 mM MgSO4 using iTRAQ and high-resolution multiple reaction monitoring (MRM-hr). Two proteins (BP0200 and BP1175) in the whole cell were upregulated in L1423 [fold change (FC) >1.2, false discovery rate (FDR) <0.05]. In the secretome, four proteins from the type III secretion system (T3SS) effectors were downregulated (FC < 0.8, FDR < 0.05) while six proteins, including two adhesins, pertactin (Prn) and tracheal colonization factor A (TcfA), were upregulated which were consistent with our previous proteomic study. The upregulation of Prn and TcfA in SNP cluster I may result in improved adhesion while the downregulation of the T3SS and other immunogenic proteins may reduce immune recognition, which may contribute to the increased fitness of cluster I B. pertussis strains