An update on oral cavity cancer: epidemiological trends, prevention strategies and novel approaches in diagnosis and prognosis.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

Cost-based optimization of the stopping threshold for local disease surveillance during progressive eradication of tuberculosis from New Zealand wildlife.

Bovine tuberculosis (TB) is managed in New Zealand largely via population reduction of the major wildlife disease reservoir of Mycobacterium bovis, the introduced brushtail possum Trichosurus vulpecula. New Zealand aims to eradicate M. bovis infection from its livestock and wildlife within 40 years, as the culmination of progressive regional eradication programmes. Declarations of regional eradication are decided after extensive possum population control and post-control surveillance; hence, we developed a modelling framework, based on eco-epidemiological simulation data, to provide cost-evaluated options for deciding when to make these declarations. A decision-support framework evaluated potential costs of wildlife surveillance (and recontrol, if required) with respect to the calculated probability of successful eradication of M. bovis from wildlife. This enabled expected costs to be predicted in terms of stopping thresholds, allowing selection of optimal stopping rules based on minimizing costs. We identified factors that could influence optimal stopping values applied during regional eradication. Where vector/disease surveillance was inexpensive (for example, using low-cost detection devices or sentinel wildlife hosts) optimization involved setting a higher rather than lower stopping value, as it would be cheaper to minimize the risk of making a false declaration of eradication than to remedy any such failure. In addition, any cost of recontrol would largely depend on the time to rediscovery of residual M. bovis infection in wildlife, which would in turn be linked to the level of ongoing passive surveillance (with more rapid detection of re-emergent infection among wildlife in farmland situations than in remote forested regions). These two scenarios would favour different optimal stopping rules, as would the consideration of stakeholder confidence and socio-political issues, which are discussed. The framework presented here provides guidance to assess the economics underlying eradication of bovine TB from New Zealand farming; this eliminates reliance upon a pre-determined and uniform stopping rule for ceasing active management.

Livestock as sentinels for an infectious disease in a sympatric or adjacent-living wildlife reservoir host.

A central question to address in managing wildlife diseases is how much effort and resources are required to reduce infection prevalence to below a requisite threshold? This requires surveillance for infection in at least one species involved in the infection cycle, a process that is often expensive and time-consuming but one which could be enhanced using additional sources of readily-obtainable surveillance data. We demonstrate how surveillance data from ruminant livestock monitored for bovine tuberculosis (bTB) in New Zealand can be employed in spatially-explicit modelling to help predict the probability of freedom from Mycobacterium bovis infection in a sympatric wildlife reservoir species, the brushtail possum (Trichosurus vulpecula). We apply the model to a case study and compare resulting probabilities of freedom when utilizing (1) livestock data only, (2) wildlife data only, and (3) combined livestock-plus-wildlife surveillance data. Results indicated that the greatest probability of M. bovis eradication was achieved using wildlife monitoring data supplemented with livestock surveillance data. This combined approach lessened the time required for a confident (95% probability) declaration of regional eradication. However, the combined model was sensitive to the precision of the input parameters, and we describe ways to account for this. In a broad sense, this modelling approach is flexible in that any spatial arrangement of wildlife habitat and farms can be analysed, provided infection is readily detectable in both the wild and domestic animal(s) of interest. It is applicable to monitoring any communicable wildlife disease that affects regularly-tested livestock. The potential benefits to wildlife disease management include reduced surveillance costs and more rapid achievement of targeted reductions in disease prevalence.

Elevated mercury concentrations in the feathers of grey-faced petrels (Pterodroma gouldi) in New Zealand.

Our objective was to measure the concentrations of Hg, As, Cd, Co, Cr, Cu, Pb, Sb, V and Zn in the body feathers of grey-faced petrel (Pterodroma gouldi), fluttering shearwater (Puffinus gavia), little shearwater (Puffinus assimilis) and common diving petrel (Pelecanoides urinatrix) from breeding colonies in New Zealand between 2006 and 2013. The mean Hg concentration (36.48ppm; SD=9.59) in grey-faced petrel feathers was approximately 8.5 to 14 times that detected in the other three species sampled. We detected no trend or differences in Hg concentrations in grey-faced petrels over the 8years of this study, but Hg concentrations varied between breeding colonies although there was no strong relationship with latitude. The elevated Hg concentrations detected in grey-faced petrels could pose a risk to the breeding performance of grey-faced petrels and the customary harvest of chicks by Maori (New Zealand's indigenous peoples).

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth.

Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis.

A novel approach to assess the probability of disease eradication from a wild-animal reservoir host.

Surveying and declaring disease freedom in wildlife is difficult because information on population size and spatial distribution is often inadequate. We describe and demonstrate a novel spatial model of wildlife disease-surveillance data for predicting the probability of freedom of bovine tuberculosis (caused by Mycobacterium bovis) in New Zealand, in which the introduced brushtail possum (Trichosurus vulpecula) is the primary wildlife reservoir. Using parameters governing home-range size, probability of capture, probability of infection and spatial relative risks of infection we employed survey data on reservoir hosts and spillover sentinels to make inference on the probability of eradication. Our analysis revealed high sensitivity of model predictions to parameter values, which demonstrated important differences in the information contained in survey data of host-reservoir and spillover-sentinel species. The modelling can increase cost efficiency by reducing the likelihood of prematurely declaring success due to insufficient control, and avoiding unnecessary costs due to excessive control and monitoring.

Selective inhibition of neurite outgrowth on mature astrocytes by Thy-1 glycoprotein.

THY-1, the smallest member of the immunoglobulin superfamily, is a major cell-surface component expressed by several tissues. The protein, carbohydrate and gene structures of this molecule are known, yet its function is not. It is highly expressed in nervous tissue, where it appears on virtually all neurons after the cessation of axonal growth. Here we show that expression of Thy-1 by a neural cell line inhibits neurite outgrowth on mature astrocytes, but not on other cellular substrata which include Schwann cells and embryonic glia. This inhibition of neurite extension on astrocytes can be reversed by low concentrations (nanomolar) of soluble Thy-1. If a similar interaction between neuronal Thy-1 and astrocytes occurs in vivo, it could stabilize neuronal connections and suppress axonal regrowth after injury in the astrocyte-rich areas of adult central nervous system.

Activation of T lymphocytes by cross-linking of glycophospholipid-anchored Thy-1 mobilizes separate pools of intracellular second messengers to those induced by the antigen-receptor/CD3 complex.

T cells can be activated, not only by the conventional (antigen-receptor/CD3 complex) route, but also by cross-linking any one of their lipid-anchored surface glycoproteins. We have compared early transmembrane signalling events mediated through CD3 with those mediated through Thy-1, a lipid-linked surface glycoprotein, on the human lymphoid cell line Jurkat and transfectants expressing higher levels of Thy-1. Cross-linking of Thy-1 causes immediate phosphatidylinositol (PI) turnover and an influx of extracellular Ca2+, while releasing very little Ca2+ from intracellular stores. CD3 activation, on the other hand, causes PI turnover which releases intracellular Ca2+, and only secondarily induces an influx of extracellular ions. The Thy-1 response is detectable at very low levels of surface Thy-1, and is not mimicked by enzymatic removal of lipid-linked proteins from the cell surface. The Thy-1-induced Ca2+ influx is more sensitive to L channel blockers than the CD3-mediated flux. These results indicate that the initial stages of Thy-1-mediated activation involve the rapid and extensive mobilization of the intracellular second messengers, PI and Ca2+, by mechanisms separate to those activated by the antigen-receptor/CD3 complex.