The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the T2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.

Abstract-Nitric oxide (NO) is a powerful angiogenic mediator acting downstream of vascular endothelial growth factor (VEGF). Both the endothelial NO synthase (eNOS) and the VEGFR-2 receptor colocalize in caveolae. Because the structural protein of these signaling platforms, caveolin, also represses eNOS activity, changes in its abundance are likely to influence the angiogenic process in various ways. In this study, we used mice deficient for the caveolin-1 gene (Cav Ϫ/Ϫ ) to examine the impact of caveolae suppression in a model of adaptive angiogenesis obtained after femoral artery resection. Evaluation of the ischemic tissue perfusion and histochemical analyses revealed that contrary to Cav ϩ/ϩ mice, Cav Ϫ/Ϫ mice failed to recover a functional vasculature and actually lost part of the ligated limbs, thereby recapitulating the effects of the NOS inhibitor L-NAME administered to operated Cav ϩ/ϩ mice. We also isolated endothelial cells (ECs) from Cav Ϫ/Ϫ aorta and showed that on VEGF stimulation, NO production and endothelial tube formation were dramatically abrogated when compared with Cav ϩ/ϩ ECs. The Ser1177 eNOS phosphorylation and Thr495 dephosphorylation but also the ERK phosphorylation were similarly altered in VEGF-treated Cav Ϫ/Ϫ ECs. Interestingly, caveolin transfection in Cav Ϫ/Ϫ ECs redirected the VEGFR-2 in caveolar membranes and restored the VEGF-induced ERK and eNOS activation. However, when high levels of recombinant caveolin were reached, VEGF exposure failed to activate ERK and eNOS. These results emphasize the critical role of caveolae in ensuring the coupling between VEGFR-2 stimulation and downstream mediators of angiogenesis. This study also provides new insights to understand the paradoxical roles of caveolin (eg, repressing basal enzyme activity but facilitating activation on agonist stimulation) in cardiovascular pathophysiology. Key Words: caveolin-1 Ⅲ nitric oxide Ⅲ vascular endothelial growth factor Ⅲ angiogenesis Ⅲ ischemia C aveolae are 50-to 100-nm cell surface invaginations playing key roles in vesicular transport and signal transduction. 1 The structural protein of these plasmalemmal microdomains, caveolin, acts as a scaffold for many caveolar residents. 2 The caveolin-1 isoform is particularly abundant in endothelial cells (ECs) where it regulates various functions including transcytosis, permeability, vascular tone, and angiogenesis. 3 Recently, Woodman et al 4 documented that in a model of tumor cell injection in caveolin-deficient mice (Cav Ϫ/Ϫ ), angiogenesis was markedly reduced in comparison with wild-type (WT) animals. Although the same authors showed that the reduction in vessel density could be reproduced in a model of Matrigel plugs supplemented with bFGF, 4 the mechanisms supporting the role of caveolin in the angiogenic response to exogenous stimuli remain poorly understood and, based on previous publications, 5-9 a matter of debate.For instance, the well-established inhibitory interaction between caveolin and the endothelial nitric oxide (NO) synthase (eNOS) 10,11 le...

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O 2 diffusion-limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO 2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxyge-

Textural analysis of baseline F-FDG PET/CT provides strong independent predictors of survival in patients with LARC, with better predictive power than intensity- and volume-based parameters. The utility of such features, especially coarseness, should be confirmed by larger clinical studies before considering their potential integration into decisional algorithms aimed at personalized medicine.

). † These authors contributed equally to the present work. AbstractBackground. Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. Method. While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure.Results. Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. Conclusion. Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse. Key wordsCXCL12 | glioblastoma | mesenchymal activation | radioresistance | subventricular zone Primary brain tumors are considered as one of the nastiest scourges faced in oncology. Their most aggressive form, glioblastoma (GBM, WHO grade IV), is also regarded as the most common and lethal subtype. 1 Patients' poor survival rates are typically correlated with unsatisfactory therapeutic strategies leading to systematic GBM relapses. 2 Trying to better