OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen

T cell costimulation via OX40 is known to increase CD4+ T cell expansion and effector function and enhances the development of T cell memory. OX40 costimulation can also prevent, and even reverse, CD4+ T cell anergy. However, the role of OX40 in CD8+ T cell function is less well defined, particularly in the setting of immune tolerance. To determine the effects of OX40 costimulation on the induction of the host CD8+ T cell repertoire to an endogenous tumor Ag, we examined the fate of CD8+ T cells specific for the immunodominant rat HER-2/neu epitope, RNEU420-429, in FVB MMTV-neu (neu-N) mice, which express rat HER-2/neu protein in a predominantly mammary-restricted fashion. We show that the RNEU420-429-specific T cell repertoire in neu-N mice expands transiently after vaccination with a neu-targeted GM-CSF-secreting whole-cell vaccine, but quickly declines to an undetectable level. However, OX40 costimulation, when combined with GM-CSF-secreting tumor-targeted vaccination, can break established CD8+ T cell tolerance in vivo by enhancing the expansion, and prolonging the survival and effector function of CD8+ T cells specific for RNEU420-429. Moreover, we demonstrate that OX40 expression is up-regulated on both CD4+ and CD8+ T cells shortly after administration of a GM-CSF expressing vaccine. These studies highlight the increased efficacy of OX40 costimulation when combined with a GM-CSF-secreting vaccine, and define a new role for OX40 costimulation of CD8+ T cells in overcoming tolerance and boosting antitumor immunity.     

Periodontal therapy increases neutrophil extracellular trap degradation

In periodontitis, polymorphonuclear leucocytes (PMNs) are activated. They entrap and eliminate pathogens by releasing neutrophil extracellular traps (NETs). Abnormal NET degradation is part of a pro-inflammatory status, affecting co-morbidities such as cardiovascular disease. We aimed to investigate the ex vivo NET degradation capacity of plasma from periodontitis patients compared to controls (part 1) and to quantify NET degradation before and after periodontal therapy (part 2). Fresh NETs were obtained by stimulating blood-derived PMNs with phorbol 12-myristate 13-acetate. Plasma samples from untreated periodontitis patients and controls were incubated for 3 h onto freshly generated NETs (part 1). Similarly, for part 2, NET degradation was studied for 91 patients before and 3, 6 and 12 mo after non-surgical periodontal therapy with and without adjunctive systemic antibiotics. Finally, NET degradation was fluorospectrometrically quantified. NET degradation levels did not differ between periodontitis patients and controls, irrespective of subject-related background characteristics. NET degradation significantly increased from 65.6 ± 1.7% before periodontal treatment to 75.7 ± 1.2% at 3 mo post periodontal therapy, and this improvement was maintained at 6 and 12 mo, irrespective of systemic usage of antibiotics. Improved NET degradation after periodontitis treatment is another systemic biomarker reflecting a decreased pro-inflammatory status, which also contributes to an improved cardiovascular condition.     

Multidimensional prognostic indices for use in COPD patient care. A systematic review

Background

A growing number of prognostic indices for chronic obstructive pulmonary disease (COPD) is developed for clinical use. Our aim is to identify, summarize and compare all published prognostic COPD indices, and to discuss their performance, usefulness and implementation in daily practice.

Methods

We performed a systematic literature search in both Pubmed and Embase up to September 2010. Selection criteria included primary publications of indices developed for stable COPD patients, that predict future outcome by a multidimensional scoring system, developed for and validated with COPD patients only. Two reviewers independently assessed the index quality using a structured screening form for systematically scoring prognostic studies.

Results

Of 7,028 articles screened, 13 studies comprising 15 indices were included. Only 1 index had been explored for its application in daily practice. We observed 21 different predictors and 7 prognostic outcomes, the latter reflecting mortality, hospitalization and exacerbation. Consistent strong predictors were FEV₁ percentage predicted, age and dyspnoea. The quality of the studies underlying the indices varied between fairly poor and good. Statistical methods to assess the predictive abilities of the indices were heterogenic. They generally revealed moderate to good discrimination, when measured. Limitations: We focused on prognostic indices for stable disease only and, inevitably, quality judgment was prone to subjectivity.

Conclusions

We identified 15 prognostic COPD indices. Although the prognostic performance of some of the indices has been validated, they all lack sufficient evidence for implementation. Whether or not the use of prognostic indices improves COPD disease management or patients'' health is currently unknown; impact studies are required to establish this.     

Habitat utilisation by pike Esox lucius L. during winter floods in a southern English chalk river

Seven pike Esox lucius L., implanted with radio-transmitters, were tracked throughout autumn and winter in the River Frome, a southern English chalk river. During the first flood events of the year, pike remained within the main river channel but during subsequent flood events, pike could also be found in flooded fields, in drainage ditches or in a millstream. Eighty percent of the fixes over flooded land occurred within 10 m of the riverbank, although distances of up to 89 m from the bank were recorded. In ditches, pike could be found over 250 m from the main river. For pike in ditches and flooded fields, distance from the main river channel was positively correlated with discharge. There was individual variation amongst pike for the habitat types selected, with some pike utilising flooded field or ditch habitat more often than others. The proportion of time spent out of the main river channel does not appear to be related to the size of the pike. It is hypothesised that pike are leaving the main river channel to exploit feeding opportunities in the flooded fields and drainage ditches, rather than using these areas as refugia from high flow conditions.     

Tyrosine phosphorylation of myosin heavy chain during skeletal muscle differentiation: an integrated bioinformatics approach

Background  

Previously it has been shown that insulin-mediated tyrosine phosphorylation of myosin heavy chain is concomitant with enhanced association of C-terminal SRC kinase during skeletal muscle differentiation. We sought to identify putative site(s) for this phosphorylation event.     

Conservation Biogeography: assessment and prospect

There is general agreement among scientists that biodiversity is under assault on a global basis and that species are being lost at a greatly enhanced rate. This article examines the role played by biogeographical science in the emergence of conservation guidance and makes the case for the recognition of Conservation Biogeography as a key subfield of conservation biology delimited as: the application of biogeographical principles, theories, and analyses, being those concerned with the distributional dynamics of taxa individually and collectively, to problems concerning the conservation of biodiversity. Conservation biogeography thus encompasses both a substantial body of theory and analysis, and some of the most prominent planning frameworks used in conservation. Considerable advances in conservation guidelines have been made over the last few decades by applying biogeographical methods and principles. Herein we provide a critical review focussed on the sensitivity to assumptions inherent in the applications we examine. In particular, we focus on four inter‐related factors: (i) scale dependency (both spatial and temporal); (ii) inadequacies in taxonomic and distributional data (the so‐called Linnean and Wallacean shortfalls); (iii) effects of model structure and parameterisation; and (iv) inadequacies of theory. These generic problems are illustrated by reference to studies ranging from the application of historical biogeography, through island biogeography, and complementarity analyses to bioclimatic envelope modelling. There is a great deal of uncertainty inherent in predictive analyses in conservation biogeography and this area in particular presents considerable challenges. Protected area planning frameworks and their resulting map outputs are amongst the most powerful and influential applications within conservation biogeography, and at the global scale are characterised by the production, by a small number of prominent NGOs, of bespoke schemes, which serve both to mobilise funds and channel efforts in a highly targeted fashion. We provide a simple typology of protected area planning frameworks, with particular reference to the global scale, and provide a brief critique of some of their strengths and weaknesses. Finally, we discuss the importance, especially at regional scales, of developing more responsive analyses and models that integrate pattern (the compositionalist approach) and processes (the functionalist approach) such as range collapse and climate change, again noting the sensitivity of outcomes to starting assumptions. We make the case for the greater engagement of the biogeographical community in a programme of evaluation and refinement of all such schemes to test their robustness and their sensitivity to alternative conservation priorities and goals.     

Effect of Anionic Salt and Highly Fermentable Carbohydrate Supplementations on Urine pH and on Experimentally Induced Hypocalcaemia in Cows

The objective of this experiment was to determine the effect of dietary grain on calcium homeostasis. Six rumen-fistulated dairy cows with 3 or more previous lactations and no history of parturient paresis were randomly assigned to a sequence of diets in a crossover study with 4 periods of 10 days each. Dietary treatments were: A control ration consisting of wrap grass silage alone (1), the control ration supplemented with ammonium chloride and ammonium sulphate salt solution (2), control ration following a period with supplementation (3) and control ration supplemented with increasing amounts of barley from 4 to 10 kg/cow per day, expected to produce subclinical rumen acidosis (4). Daily intake of the diets was adjusted to 14 kg DM/cow per day. On day 11, the calcium-regulating mechanisms in cows were challenged until recumbency by a standardized intravenous EDTA infusion and cows were left to recover spontaneously. Anion supplementation and the feeding of highly fermentable carbohydrate lowered urine pH below 7.0 due to subclinical acidosis. During spontaneous recovery from EDTA induced hypocalcaemia, the cows more quickly regained a whole blood free calcium concentration of 1.00 mmol/L if they had most recently been supplemented with either anionic salts or with increasing amounts of barley, as compared to the basic ration. It is concluded that so-called slug-feeding or 'steaming up' with highly fermentable carbohydrates before parturition in milk fever susceptible cows enhanced calcium homeostasis similar to the effect seen in cows on anionic diets.