Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report,part I

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D₂ receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.     

The effect of ambient temperature on gross-efficiency in cycling

Time-trial performance deteriorates in the heat. This might potentially be the result of a temperature-induced decrease in gross-efficiency (GE). The effect of high ambient temperature on GE during cycling will be studied, with the intent of determining if a heat-induced change in GE could account for the performance decrements in time trial exercise found in literature. Ten well-trained male cyclists performed 20-min cycle ergometer exercise at 60% (power output at which VO_2max was attained) in a thermo-neutral climate (N) of 15.6 ± 0.3°C, 20.0 ± 10.3% RH and a hot climate (H) of 35.5 ± 0.5°C, 15.5 ± 3.2% RH. GE was calculated based on VO₂ and RER. Skin temperature (T _sk), rectal temperature (T _re) and muscle temperature (T _m) (only in H) were measured. GE was 0.9% lower in H compared to N (19.6 ± 1.1% vs. 20.5 ± 1.4%) (P < 0.05). T _sk (33.4 ± 0.6°C vs. 27.7 ± 0.7°C) and T _re (37.4 ± 0.6°C vs. 37.0 ± 0.6°C) were significantly higher in H. T _m was 38.7 ± 1.1°C in H. GE was lower in heat. T _m was not high enough to make mitochondrial leakage a likely explanation for the observed reduced GE. Neither was the increased T _re. Increased skin blood flow might have had a stealing effect on muscular blood flow, and thus impacted GE. Cycling model simulations showed, that the decrease in GE could account for half of the performance decrement. GE decreased in heat to a degree that could explain at least part of the well-established performance decrements in the heat.     

Lymphatic Transport and Lymph Node Location of Microspheres Subcutaneously Injected in the Vicinity of Tumors in a Rabbit Model of Breast Cancer

Purpose

To assess the lymphatic transport of microparticles of 100 nm, 1 μm and 10 μm subcutaneously injected into the breast area of healthy and tumor-bearing rabbits, and to analyze their location in lymph node (LN) in relation to malignant cells.

Methods

Female rabbits (n?=?9) bearing a VX2 tumor in one thoracic mammary gland were subcutaneously injected at D15 with polystyrene fluorescent particles around the nipple, on the tumor and on the healthy sides. The tumor and the LN measured by ultrasound at D9, D15 and D20 were explanted at D20. The LN metastases were evaluated by cytokeratin staining. LN uptake of the particles was measured by quantifying the green fluorescence surface in hot spot regions of healthy and pathologic LN.

Results

All animals developed mammary tumors. Metastases were found in 39% of LN from the tumor side. LN invasion was significantly lower for the 10 μm group versus the 100 nm group (p?<?0.0348). The fully invaded area of metastatic LN contained significantly less 100 nm and 1 μm particles compared to the low and non-invaded regions and to the healthy LN. In the invaded LN, the 1 μm MS occupied more surface than the 100 nm particles.

Conclusions

1 μm MS arrived numerously into the areas low-invaded and non-invaded by the tumoral cells of the pathologic LN, but they were very rare in the fully invaded regions. Compared to the 100 nm nanospheres, the 1 μm were better retained (20 times) into the sentinel LN, showing the advantage of micrometric particles for lymph-targeted chemotherapy when injected before complete invasion by metastases.

     

Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8⁺ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies.     

Penalized least squares regression methods and applications to neuroimaging

The goals of this paper are to review the most popular methods of predictor selection in regression models, to explain why some fail when the number P of explanatory variables exceeds the number N of participants, and to discuss alternative statistical methods that can be employed in this case. We focus on penalized least squares methods in regression models, and discuss in detail two such methods that are well established in the statistical literature, the LASSO and Elastic Net. We introduce bootstrap enhancements of these methods, the BE-LASSO and BE-Enet, that allow the user to attach a measure of uncertainty to each variable selected. Our work is motivated by a multimodal neuroimaging dataset that consists of morphometric measures (volumes at several anatomical regions of interest), white matter integrity measures from diffusion weighted data (fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity) and clinical and demographic variables (age, education, alcohol and drug history). In this dataset, the number P of explanatory variables exceeds the number N of participants. We use the BE-LASSO and BE-Enet to provide the first statistical analysis that allows the assessment of neurocognitive performance from high dimensional neuroimaging and clinical predictors, including their interactions. The major novelty of this analysis is that biomarker selection and dimension reduction are accomplished with a view towards obtaining good predictions for the outcome of interest (i.e., the neurocognitive indices), unlike principal component analysis that are performed only on the predictors' space independently of the outcome of interest.