Tumor Vascular Morphology Undergoes Dramatic Changes during Outgrowth of B16 Melanoma While Proangiogenic Gene Expression Remains Unchanged

In established tumors, angiogenic endothelial cells (ECs) coexist next to “quiescent” EC in matured vessels. We hypothesized that angio-gene expression of B16.F10 melanoma would differ depending on the growth stage. Unraveling the spatiotemporal nature thereof is essential for drug regimen design aimed to affect multiple neovascularization stages. We determined the angiogenic phenotype—represented by 52 angio-genes—and vascular morphology of small, intermediate, and large s.c. growing mouse B16.F10 tumors and demonstrated that expression of these genes did not differ between the different growth stages. Yet vascular morphology changed dramatically from small vessels without lumen in small to larger vessels with increased lumen size in intermediate/large tumors. Separate analysis of these vascular morphologies revealed a significant difference in αSMA expression in relation to vessel morphology, while no relation with VEGF, HIF-1α, nor Dll4 expression levels was observed. We conclude that the tumor vasculature remains actively engaged in angiogenesis during B16.F10 melanoma outgrowth and that the major change in tumor vascular morphology does not follow molecular concepts generated in other angiogenesis models

Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination

Vierboom et al. demonstrate the induction of trained immunity in blood and bone marrow monocytes after vaccination with live attenuated TB vaccines in nonhuman primates. Mucosal respiratory delivery of BCG or MTBVAC induces trained immunity more efficiently compared to standard intradermal vaccination

Thyrotrophin and thyroxine support immune homeostasis in humans

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease

Exploring the effects of shale gas development on natural gas markets: A multi-method approach

Now that conventional gas resources are rapidly declining in many industrialised regions, national governments are considering the exploration and production of unconventional resources, with shale gas in particular. Large-scale development of these resources could significantly lower import dependency of the gas supply of many countries. The complexity of gas markets and the uncertainties affecting it make that simulation modelling is required to assess these economic implications of global shale gas development. In this study, System Dynamics and Agent-based Modelling are deployed in parallel to discover scenarios for the effects of shale gas development on regional gas markets, while accounting for method uncertainty. It is shown that the gas market is mainly demand-driven, hence economic growth is likely to have a larger impact on gas import dependency than the actual size of shale gas resources. The use of a multi-method approach provided additional insights in the behaviour of gas markets. Future work should focus on the inclusion of additional structural uncertainties in order to obtain a more complete view on plausible economic implications of global shale gas development.Multi Actor SystemsTechnology, Policy and Managemen

Vascular endothelial growth factor receptor 2 inhibition in-vivo affects tumor vasculature in a tumor type-dependent way and downregulates vascular endothelial growth factor receptor 2 protein without a prominent role for miR-296.

Item does not contain fulltextThe precise molecular effects that antiangiogenic drugs exert on tumor vasculature remain to be poorly understood. We therefore set out to investigate the molecular and architectural changes that occur in the vasculature of two different tumor types that both respond to vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor therapy. Mice bearing Lewis lung carcinoma (LLC) or B16.F10 melanoma were treated with vandetanib (ZD6474), a VEGFR2/epidermal growth factor receptor (EGFR)/REarranged during Transfection (RET) kinase inhibitor, resulting in a significant 80% reduction in tumor outgrowth. Although in LLC the vascular density was not affected by vandetanib treatment, it was significantly decreased in B16.F10. In LLC, vandetanib treatment induced a shift in vascular gene expression toward stabilization, as demonstrated by upregulation of Tie2 and N-cadherin and downregulation of Ang2 and integrin beta3. In contrast, only eNOS and P-selectin responded to vandetanib treatment in B16.F10 vasculature. Strikingly, vandetanib reduced protein expression of VEGFR2 in both models, whereas mRNA remained unaffected. Analysis of miR-296 expression allowed us to exclude a role for the recently proposed microRNA-296 in VEGFR2 posttranslational control in LLC and B16.F10 in vivo. Our data demonstrate that VEGFR2/EGFR inhibition through vandetanib slows down both LLC and B16.F10 tumor growth. Yet, the underlying molecular changes in the vasculature that orchestrate the antitumor effect differ between tumor types. Importantly, in both models, vandetanib treatment induced loss of its pharmacological target, which was not directly related to miR-296 expression. Validation of our observations in tumor biopsies from VEGFR2 inhibitor-treated patients will be essential to unravel the effects of VEGFR2 inhibitor therapy on tumor vasculature in relation to therapeutic efficacy.1 februari 201

Detachment of Human Endothelial Cells Under Flow From Wettability Gradient Surfaces with Different Functional Groups

In this study, the position bound adhesion, spreading and detachment under flow of human umbilical cord endothelial cells (HUVEC) was studied on a dichlorodimethylsilane (DDS), dimethylocta-decylchlorosilane (DOCS) and tridecafluor-1,1,2,2-tetrahydrooctyl-1-dimethylchlorosilane (TFCS) wettability gradient on glass. Gradient surfaces were prepared by the diffusion method and characterized by the Wilhelmy plate technique for their wettability and by X-ray photoelectron spectroscopy (XPS) for their chemical composition. Quantitative analysis of the cellular response on the wettability gradient surfaces showed that the position bound cellular response was influenced by wettability for each type of gradient in a different way. On DDS-wettability gradients, cells withstood flow best on hydrophilic regions of the gradient with advancing water contact angles below 25 degrees while on TFCS-wettability gradients this inversal point was located on regions of the gradient with advancing water contact angles around 65 degrees. After the onset of flow, cells detached from the DOCS surface, but remained adhering in low numbers irrespective of the position bound wettability. This paper confirms that cells have unfavourable interactions with hydrophobic, immobile surfaces, like adsorbed DDS on glass. However, if the hydrophobicity is created by more mobile, relatively long chain groups, possibly yielding incomplete surface coverage due to their mobility, favourable interactions may also occur on more hydrophobic surfaces

Spatiotemporal distribution of <i>S.</i><i>pneumoniae</i> in the different compartments of the brain.

<p>A. Visualization of <i>S. pneumoniae</i> co-localized with the vasculature in the brain during the entire course of infection, same images as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068408#pone-0068408-g002" target="_blank">Figure 2B</a>; total magnification 50X. Pneumococci that co-localized with the vascular endothelium appear as white, pneumococci not co-localized appear as green. B. Brain slides of mice challenged with <i>S. pneumoniae</i> were stained for vasculature using tomato lectin (red), bacteria (green), and nuclei (blue) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068408#s2" target="_blank">Material and Methods</a>. Total magnification of subarachnoid space, septum, choroid plexus 630X; total magnification of cerebral cortex 1000X. At 14 hours post infection the white arrow indicates the pneumococci forming clusters in the subarachnoid vessels. For each time point of infection, brains from 3 mice were analyzed, and of each mouse 4 brain sections were used for the immunofluorescent detection. These images are representative of the situation in i) each brain compartment during all the time course of infection and ii) each mouse that was analyzed.</p