The Interplay of Tumor Vessels and Immune Cells Affects Immunotherapy of Glioblastoma.

Immunotherapies with immune checkpoint inhibitors or adoptive cell transfer have become powerful tools to treat cancer. These treatments act via overcoming or alleviating tumor-induced immunosuppression, thereby enabling effective tumor clearance. Glioblastoma (GBM) represents the most aggressive, primary brain tumor that remains refractory to the benefits of immunotherapy.

Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM.

Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium.

The compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function.

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2 oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB).

Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3. Therefore, we hypothesize that these cells may play a role in the pathogenesis of CADASIL.

Dysfunction of mouse cerebral arteries during early aging.

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice.

Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia.

Rationale And Objective: Arginase-1 is an important component of the intricate mechanism regulating arginine availability during immune responses and nitric oxide synthase (NOS) activity. In this study Arg1(fl/fl)/Tie2-Cre(tg/-) mice were developed to investigate the effect of arginase-1 related arginine depletion on NOS2- and NOS3-dependent NO production and jejunal microcirculation under resting and endotoxemic conditions, in mice lacking arginase-1 in endothelial and hematopoietic cells.

Methods And Results: Arginase-1-deficient mice as compared with control mice exhibited higher plasma arginine concentration concomitant with enhanced NO production in endothelial cells and jejunal tissue during endotoxemia.

The flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside is able to protect endothelial cells by a direct antioxidant effect.

The flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) is an effective protector against doxorubicin induced toxicity which has been related to the antioxidant activity of monoHER. The present study examines the potential relevance of the direct scavenging activity of the flavonoid. The potency of the direct antioxidant effect was confirmed by its instantaneous protection against intracellular oxidative stress in human umbilical vein endothelial cells at therapeutically achievable concentrations (EC50=60 nM) underpinning the involvement of a direct scavenging activity.

Specific visualization of nitric oxide in the vasculature with two-photon microscopy using a copper based fluorescent probe.

To study the role and (sub) cellular nitric oxide (NO) constitution in various disease processes, its direct and specific detection in living cells and tissues is a major requirement. Several methods are available to measure the oxidation products of NO, but the detection of NO itself has proved challenging. We visualized NO production using a NO-sensitive copper-based fluorescent probe (Cu 2FL2E) and two-photon laser scanning microscopy (TPLSM).

Carbon nano-onions for imaging the life cycle of Drosophila melanogaster.

Real-time X-ray or magnetic resonance imaging are known methods used for biomedical diagnosis. By the oral administration of barium meal, X-ray imaging can be extended for use in soft tissue imaging. The oral ingestion of a fluorescent probe is a new approach to imaging a living species.