EBV latent membrane protein 1 (LMP1) is an oncoprotein frequently expressed in nasopharyngeal carcinoma. We have generated transgenic mice expressing the nasopharyngeal carcinoma-derived CAO strain of LMP1 and LMP1 of the B95-8 strain, using the viral ED-L2 promoter for epithelial expression. LMP1(CAO) and LMP1(B95-8) induce transforming growth factor alpha expression and epidermal hyperplasia. However, levels of total epidermal growth factor receptor (EGFR) decline with the appearance of phosphorylated EGFR products, suggesting that the negative feedback loop upon EGFR expression is intact or that there is faster turnover at these early stages of carcinogenesis. In the L2LMP1(CAO) mice, increased levels of vascular endothelial growth factor are also seen at an early stage in the skin. As the phenotype worsens, with increasing hyperplasia and vascularization leading to keratoacanthoma, p16(INK4a) and matrix metalloproteinase 9 expression is induced. The lesions can progress spontaneously to carcinoma. Carcinoma cell lines developed from these mice show high levels of total and phosphorylated EGFR. These data show that the induction of signaling through EGFR by LMP1 is an early event in carcinogenesis and that any inhibition upon EGFR expression is lifted during progression. Furthermore, expression of LMP1 is not sufficient to inhibit induction of p16(INK4a) in response to abnormal proliferation. These data are consistent with the cooperative effects seen between LMP1 and loss of the INK4a locus in transgenic mice and with the frequency of loss of this locus in EBV-associated nasopharyngeal carcinoma.

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is an oncoprotein expressed in several EBV-associated malignancies. We have utilised mice expressing the Cao strain of LMP1 in epithelia to explore the consequences of expression in vivo, specifically the changes that occur prior to neoplasia, in the hyperplastic but degenerating tissue. Epidermal growth factor receptor (EGFR) ligands (transforming growth factor alpha (TGFalpha), heparin-binding EGF-like growth factor and epiregulin) are constitutively induced by LMP1, leading to EGFR phosphorylation but also down-regulation, degradation or turn-over, with the appearance of cleaved EGFR fragments. This is accompanied by down-regulation of Akt and activation of caspase-3 and p38 mitogen-activated protein kinase (MAPK). Surprisingly, removal of TGFalpha (using the null strain) does not ameliorate the LMP1-induced phenotype, but instead accelerates the deterioration. Consistent with this, EGFR is reduced less rapidly and MAPK/ERK kinase (MEK) and extracellular-signal-regulated kinase (ERK) are initially activated in the null background, suggesting that TGFalpha or excess of the ligands together act to divert phosphorylated EGFR into a cleavage pathway. In addition, LMP1 leads to the activation of c-Jun N-terminal kinase 2 (JNK2) followed by JNK1 in the effected tissue. Specific AP1 family members FosB, Fra-1 and JunB are constitutively induced and serum response factor, AP1 and nuclear factor kappaB (incorporating p65) are activated in the transgenic tissue compared with wild-type. This system allows the analysis of early events resulting from the expression of a viral oncogene with broad impact in the signalling milieu and the attempts at homeostasis in the responding tissue. It reveals what regulatory circuits are in place in a normal tissue, thus facilitating further prediction of causative events in carcinogenic progression.

No abstract

No abstract

BackgroundCurrently there is a dual system of oral healthcare delivery in Cyprus: the public dental system (PDS) run by the Government and the private system provided by private dental practitioners. Although 83% of the population is entitled to free treatment by the PDS only 10% of the population make use of them. As Cyprus faces now the challenges of the introduction of a new health care system and rising healthcare costs in general, surveys that examine, among other things, the efficiency of the PDS become very important as tools to make important cost savings. The aims of this study are to assess trends regarding the number of visits and the age distribution of patients using PDS from 2004 to 2007, to measure the technical efficiency of the PDS and to investigate various factors that may affect it.MethodsNon-parametric Data Envelopment Analysis (DEA) was employed to assess technical efficiency. Two separate cases were examined. Efficiency was calculated, firstly using as inputs the wages and the working hours of the personnel, and secondly the working hours of the personnel and the cost of the materials. As outputs, in both cases, the treatment offered (divided into primary, secondary and tertiary care) and the numbers of visits were used. In the second stage Tobit analysis was used to explore various predictors of efficiency (time per patient, location, age of dentists, age of patients and age of assistants).ResultsThe study showed that whilst there was an increase in the number of patients using the PDS from 2004 to 2007, only a small proportion of the population (10%) make use of them. Women, middle and older aged patients, make more use of the PDS. Regarding efficiency, there were large differences between the units. The average Technical Efficiency score was 68% in the first model and 81% in the second. Urban areas and low time per patient are predictors of increased efficiency.ConclusionThe results suggest that many of the rural PDS are underperforming. Given that the option of shutting them down is undesirable, measures should be taken to reduce inputs (e.g. by reducing the personnel’s working hours) and to increase outputs (remove barriers, make PDS more accessible and increase the number of patients).