Early Detection of Epidemic GII-4 Norovirus Strains in UK and Malawi: Role of Surveillance of Sporadic Acute Gastroenteritis in Anticipating Global Epidemics.

Noroviruses are endemic in the human population, and are recognised as a leading cause of acute gastroenteritis worldwide. Although they are a highly diverse group of viruses, genogroup-II genotype-4 (GII-4) noroviruses are the most frequently identified strains worldwide. The predominance of GII-4 norovirus strains is driven by the periodic emergence of antigenic variants capable of evading herd protection. The global molecular epidemiology of emerging GII-4 strains is largely based on data from outbreak surveillance programmes, but the epidemiology of GII-4 strains among sporadic or community cases is far less well studied. To understand the distribution of GII-4 norovirus strains associated with gastroenteritis in the wider population, we characterised the GII-4 norovirus strains detected during studies of sporadic cases of infectious gastroenteritis collected in the UK and Malawi between 1993 and 2009. Our data shows that GII-4 norovirus strains that have emerged as strains of global epidemic importance have circulated in the community up to 18 years before their recognition as pandemic strains associated with increases in outbreaks. These data may suggest that more comprehensive surveillance programmes that incorporate strains associated with sporadic cases may provide a way for early detection of emerging strains with pandemic potential. This may be of particular relevance as vaccines become available

Origin of norovirus positive samples analysed in this study.

<p>Origin of norovirus positive samples analysed in this study.</p

Alignment of the deduced amino acid sequencing obtained from sporadic strains detected in Malawi and the UK with prototype strains representative of the epidemic strain variants that emerged between 1987 and 2012.

<p>Successive variants are colour coded and prototype stains are listed chronologically with earliest variants at the top. Study sequences are identified according to origin as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0146972#pone.0146972.t001" target="_blank">Table 1</a>. Single amino acid identities of the study strains against prototype strains are colour coded using the colour assigned to each epidemic strain variant.</p

Numbers of GII-4 strains analysed and variant assignation according to phylogentic analysis.

<p>Strains that do not align chronologically with the GII-4 variant circulating during the study period study period are highlighted (bold, italic & underlined) in the table.</p

Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion

Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Abstract: Background: Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy. Methods: Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro. Results: Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT and showed downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway. Conclusions: Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathwa