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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(1), pp.4-5
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: BBA - Reviews on Cancer, December 2014, Vol.1846(2), pp.560-575
    Description: Glioma-associated microglia and macrophages (GAMs) and myeloid-derived suppressor cells (MDSCs) condition the glioma microenvironment to generate an immunosuppressed niche for tumour expansion. This immunosuppressive microenvironment is considered to be shaped through a complex multi-step interactive process between glioma cells, GAMs and MDSCs. Glioma cells recruit GAMs and MDSCs to the tumour site and block their maturation. Glioma cell-derived factors subsequently skew these cells towards an immunosuppressive, tumour-promoting phenotype. Finally, GAMs and MDSCs enhance immune suppression in the glioma microenvironment and promote glioma growth, invasiveness, and neovascularization. The local and distant cross-talk between glioma cells and GAMs and MDSCs is regulated by a plethora of soluble proteins and cell surface-bound factors, and possibly via extracellular vesicles and platelets. Importantly, GAMs and MDSCs have been reported to impair the efficacy of glioma therapy, in particular immunotherapeutic approaches. Therefore, advancing our understanding of the function of GAMs and MDSCs in brain tumours and targeted intervention of their immunosuppressive function may benefit the treatment of glioma.
    Keywords: Glioblastoma ; Cross-Talk ; Immune Response ; Monocytes ; Glioma-Associated Macrophages and Microglia ; Myeloid-Derived Suppressor Cells ; Biology ; Chemistry
    ISSN: 0304-419X
    E-ISSN: 1879-2561
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Nov 15, 2016, Vol.113(46), p.13227(6)
    Description: Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P 〈 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P 〈 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.
    Keywords: Multiple Sclerosis – Physiological Aspects ; Cell Interactions – Health Aspects
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 4
    In: Journal of Neurochemistry, March 2016, Vol.136(6), pp.1142-1154
    Description: We proposed that in malignant gliomas prostaglandin E (PGE) produced by cyclooxygenases (COX) up‐regulates tryptophan‐2,3‐dioxygenase (TDO) expression and enzyme activity through binding to its Gs‐coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.
    Keywords: Tryptophan‐2 ; 3‐Dioxygenase ; Glioma ; Immunosuppression ; Prostaglandin
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 5
    Language: English
    In: Radiology, 04 December 2018, pp.181051
    Description: Purpose To investigate the association of inflammation and brain edema in a cerebral malaria (CM) mouse model with a combination of bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium, referred to as MPO-Gd, and cross-linked iron oxide nanoparticle (CLIO-NP) imaging. Materials and Methods Female wild-type (n = 23) and myeloperoxidase (MPO) knock-out (n = 5) mice were infected with the Plasmodium berghei ANKA strain from May 2016 to July 2018. Seven healthy mice served as control animals. At a Rapid Murine Coma and Behavioral Scale (RMCBS) score of less than 15, mice underwent MRI at 9.4 T and received gadodiamide, MPO-Gd, or CLIO-NPs. T1-weighted MRI was used to assess MPO activity, and T2*-weighted MRI was used to track CLIO-NPs. Immunofluorescent staining and flow cytometric analyses characterized CLIO-NPs, MPO, endothelial cells, and leukocytes. An unpaired, two-tailed Student t test was used to compare groups; Spearman correlation analysis was used to determine the relationship of imaging parameters to clinical severity. Results MPO-Gd enhancement occurred in inflammatory CM hotspots (olfactory bulb 〉 rostral migratory stream 〉 brainstem 〉 cortex, P 〈 .05 for all regions compared with control mice; mean olfactory bulb signal intensity ratio: 1.40 ± 0.07 vs 0.96 ± 0.01, P 〈 .01). The enhancement was reduced in MPO knockout mice (mean signal intensity ratio at 60 minutes: 1.13 ± 0.04 vs 1.40 ± 0.07 in CM, P 〈 .05). Blood-brain barrier compromise was suggested by parenchymal gadolinium enhancement, leukocyte recruitment, and endothelial activation. CLIO-NPs accumulated mainly intravascularly and at the vascular endothelium. CLIO-NPs were also found in the choroid plexus, indicating inflammation of the ventricular system. Blood-cerebrospinal fluid barrier breakdown showed correlation with brain swelling (r: 0.55, P 〈 .01) and RMCBS score (r: 0.75, P 〈 .001). Conclusion Iron oxide nanoparticle imaging showed strong inflammatory involvement of the microvasculature in a murine model of cerebral malaria. Furthermore, bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium imaging depicted parenchymal and intraventricular inflammation. This combined molecular imaging approach links vascular inflammation to breakdown of the blood-brain barrier and blood-cerebrospinal fluid barrier that correlate with global brain edema and disease severity. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.
    Keywords: Animals–Diagnostic Imaging ; Brain–Enzymology ; Brain Edema–Pathology ; Disease Models, Animal–Diagnostic Imaging ; Encephalitis–Enzymology ; Female–Parasitology ; Magnetic Resonance Imaging–Pathology ; Magnetite Nanoparticles–Diagnostic Imaging ; Malaria, Cerebral–Enzymology ; Mice–Parasitology ; Mice, Inbred C57bl–Pathology ; Mice, Knockout–Methods ; Peroxidase–Chemistry ; Peroxidase–Complications ; Peroxidase–Diagnostic Imaging ; Peroxidase–Enzymology ; Peroxidase–Pathology ; Peroxidase–Metabolism ; Abridged ; Magnetite Nanoparticles;
    ISSN: 00338419
    E-ISSN: 1527-1315
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  • 6
    Language: English
    In: The Journal of neuroscience : the official journal of the Society for Neuroscience, 19 July 2017, Vol.37(29), pp.6837-6850
    Description: Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (〉10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was (), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients. In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.
    Keywords: Ttyh1 ; Glioblastoma ; Glioma ; Invasion ; Migration ; Tumor Microtubes ; Brain Neoplasms -- Metabolism ; Glioblastoma -- Metabolism ; Membrane Proteins -- Metabolism
    ISSN: 02706474
    E-ISSN: 1529-2401
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  • 7
    Language: English
    In: Journal of Clinical Oncology, 05/20/2016, Vol.34(15_suppl), pp.11587-11587
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: CrossRef
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  • 8
    Language: English
    In: Nature medicine, August 2018, Vol.24(8), pp.1192-1203
    Description: The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
    Keywords: Immunity ; Glutarates -- Metabolism ; T-Lymphocytes -- Immunology
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 9
    Language: English
    In: OncoImmunology, 03 July 2017, Vol.6(7)
    Description: Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical...
    Keywords: Glioma ; K27m-Mutant Histone H3 ; Neoepitope ; Vaccination ; Biology
    ISSN: 21624011
    E-ISSN: 2162-402X
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 November 2016, Vol.113(46), pp.13227-13232
    Description: Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P 〈 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P 〈 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.
    Keywords: Eae ; Mri ; Uspio ; Multiple Sclerosis ; Nanoparticle Imaging ; Encephalomyelitis, Autoimmune, Experimental -- Diagnostic Imaging ; Magnetite Nanoparticles -- Administration & Dosage ; Multiple Sclerosis -- Diagnostic Imaging
    E-ISSN: 1091-6490
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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