Yersinia enterocolitica Targets Cells of the Innate and Adaptive Immune System by Injection of Yops in a Mouse Infection Model

Yersinia enterocolitica (Ye) evades the immune system of the host by injection of Yersinia outer proteins (Yops) via a type three secretion system into host cells. In this study, a reporter system comprising a YopE-β-lactamase hybrid protein and a fluorescent staining sensitive to β-lactamase cleavage was used to track Yop injection in cell culture and in an experimental Ye mouse infection model. Experiments with GD25, GD25-β1A, and HeLa cells demonstrated that β1-integrins and RhoGTPases play a role for Yop injection. As demonstrated by infection of splenocyte suspensions in vitro, injection of Yops appears to occur randomly into all types of leukocytes. In contrast, upon infection of mice, Yop injection was detected in 13% of F4/80+, 11% of CD11c+, 7% of CD49b+, 5% of Gr1+ cells, 2.3% of CD19+, and 2.6% of CD3+ cells. Taking the different abundance of these cell types in the spleen into account, the highest total number of Yop-injected cells represents B cells, particularly CD19+CD21+CD23+ follicular B cells, followed by neutrophils, dendritic cells, and macrophages, suggesting a distinct cellular tropism of Ye. Yop-injected B cells displayed a significantly increased expression of CD69 compared to non-Yop-injected B cells, indicating activation of these cells by Ye. Infection of IFN-γR (receptor)- and TNFRp55-deficient mice resulted in increased numbers of Yop-injected spleen cells for yet unknown reasons. The YopE-β-lactamase hybrid protein reporter system provides new insights into the modulation of host cell and immune responses by Ye Yops

Rituximab for the First-Line Maintenance Treatment of Follicular Non-Hodgkin’s Lymphoma

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of rituximab (RTX) [Roche] to submit evidence for the clinical and cost effectiveness of RTX as first-line maintenance treatment for patients with follicular non-Hodgkin’s lymphoma (fNHL) whose disease has responded to induction therapy with RTX plus cytotoxic chemotherapy (R-CTX) in accordance with the Institute’s Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG’s review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee’s (AC) decision. The clinical evidence was derived from a multi-centred, open-label, randomized phase III study (PRIMA) comparing first-line maintenance treatment with RTX with observation only in 1,018 patients with previously untreated advanced fNHL. Median time to event (MTE) for the primary endpoint of progression-free survival (PFS) in the RTX arm was not estimable due to data immaturity; median PFS in the observation arm was 48.36 months. A statistically significant benefit of RTX maintenance therapy for PFS was reported (hazard ratio [HR] 0.55, 95 % CI 0.44–0.68; p < 0.0001). Statistically significant differences in favour of RTX were also reported for a range of secondary endpoints. Assessment of overall survival benefit could be not made due to insufficient events. The ERG’s main concern with the clinical-effectiveness data presented was their lack of maturity. The submitted incremental cost-effectiveness ratio was within the NICE threshold. The ERG questioned the model on a number of grounds, particularly the use of Markov methodology rather than patient simulations, the impact of patient age on the outcome and the projective PFS modelling. The ERG considered it impossible to draw firm conclusions regarding the clinical or cost effectiveness of the intervention as the dataset was as yet too immature. At a third meeting, the AC concluded that RTX could be recommended as first-line maintenance treatment for patients with fNHL whose disease has responded to induction R-CTX

The Maine tourism industry has more jobs than it can fill, leading to the hiring

The Maine tourism industry has more jobs than it can fill, leading to the hiring of foreign workers. Related profile of Carol Martin of Jamaica at the Lodge at Moosehead Lake. Lengthy, detailed story. Related essays by an 18-year-old employee of Funtown USA-Splashdown in Saco and by the owner of Havana and Rupununi restaurants and Carmen Verandah and Joe\u27s Smoke Shop bars in Bar Harbor

Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy

The UK National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of erlotinib (Roche) to submit evidence for the clinical and cost effectiveness of erlotinib as monotherapy for the maintenance treatment of patients with non-small cell lung cancer (NSCLC) and stable disease following previous treatment with four cycles of platinumcontaining therapy. The Liverpool Reviews and Implementation Group(LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG) for this appraisal. The ERG reviewed the clinical- and cost-effectiveness evidence in two stages and in accordance with the decision problem defined by NICE. The analysis of the submitted models assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem. Analysis also included reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to have substantial impact on the base-case cost-effectiveness results. Clinical evidence was derived from a multi-centre, double-blind, randomized, phase III study designed to address the overall population of NSCLC patients. Outcomes included progression-free survival (PFS) and overall survival (OS). The recruited population was mainly from outside of Western Europe and no patients in the pivotal trial had received pemetrexed as a firstline therapy, which is now accepted clinical practice in the UK. The evidence considered in this article includes only the population for whom marketing authorizations has been received–that is, patients with stable disease following first-line therapy. The trial reported a small but statistically significant increase in both PFS and OS in patients with stable disease receiving erlotinib compared with placebo. However, no significant difference was identified in OS when patients with non-squamous disease and stable disease were considered as a subgroup. The economic evidence was focussed on the ERG’s assessment of three economic models that related to patients with stable disease and compared erlotinib with placebo in the squamous and non-squamous populations and erlotinib with pemetrexed in the non-squamous population. The incremental cost-effectiveness ratios (ICERs) reported by the manufacturer were £39 936 per QALY gained (stable disease, all); £35 491 per QALY gained (stable disease, squamous); and £40 020 per QALY gained (stable disease, nonsquamous). In comparison with pemetrexed, in the cases where erlotinib was considered to be superior or equivalent, erlotinib dominated. In the cases where erlotinib was considered to be slightly inferior, then the ICERs ranged between £91 789 and £511 351 per QALY gained; these ICERs appear in the south-west corner of a cost-effectiveness plane, i.e. erlotinib is cheaper but less effective than pemetrexed. The ERG recalculated the base-case cost-effectiveness results in the manufacturer’s submission, considering nine key areas where corrections and/or adjustments were required, related to time horizon, discounting logic, costs of erlotinib and pemetrexed, cost of second-line chemotherapy, unit costs, utility values, PFS and OS. This resulted in ERG-revised ICERs for the stable disease squamous population of £44 812 per QALY gained, in the stable disease non-squamous population of £68 120 per QALY gained, and, when erlotinib was compared with pemetrexed, the result was £84 029 per QALY gained. All values were above NICE’s perceived willingness-to-pay threshold. After the second Appraisal Committee meeting, the Committee did not recommend the use of erlotinib in this patient population