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Noman M.Z.,French Institute of Health and Medical Research | Buart S.,French Institute of Health and Medical Research | Romero P.,University of Lausanne | Ketari S.,French Institute of Health and Medical Research | And 4 more authors.
Cancer Research | Year: 2012

Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve. ©2012 AACR. Source

Navarro A.G.,University of Bergen | Kmiecik J.,University of Bergen | Leiss L.,University of Bergen | Zelkowski M.,University of Bergen | And 5 more authors.
Journal of Immunology | Year: 2014

Glioblastomas (GBMs) are lethal brain cancers that are resistant to current therapies. We investigated the cytotoxicity of human allogeneic NK cells against patient-derived GBM in vitro and in vivo, as well as mechanisms mediating their efficacy. We demonstrate that KIR2DS2 immunogenotype NK cells were more potent killers, notwithstanding the absence of inhibitory killer Ig-like receptor (KIR)-HLA ligand mismatch. FACS-sorted and enriched KIR2DS2+ NK cell subpopulations retained significantly high levels of CD69 and CD16 when in contact with GBM cells at a 1:1 ratio and highly expressed CD107a and secreted more soluble CD137 and granzyme A. In contrast, KIR2DS2- immunogenotype donor NK cells were less cytotoxic against GBM and K562, and, similar to FACS-sorted or gated KIR2DS2- NK cells, significantly diminished CD16, CD107a, granzyme A, and CD69 when in contact with GBM cells. Furthermore, NK cell-mediated GBM killing in vitro depended upon the expression of ligands for the activating receptor NKG2D and was partially abrogated by Ab blockade. Treatment of GBM xenografts in NOD/SCID mice with NK cells from a KIR2DS2+ donor lacking inhibitory KIR-HLA ligand mismatch significantly prolonged the median survival to 163 d compared with vehicle controls (log-rank test, p = 0.0001), in contrast to 117.5 d (log-rank test, p = 0.0005) for NK cells with several inhibitory KIR-HLA ligand mismatches but lacking KIR2DS2 genotype. Significantly more CD56+CD16+ NK cells from a KIR2DS2+ donor survived in non-tumor-bearing brains 3 wk after infusion compared with KIR2DS2- NK cells, independent of their proliferative capacity. In conclusion, KIR2DS2 identifies potent alloreactive NK cells against GBM that are mediated by commensurate, but dominant, activating signals. Copyright © 2014 by The American Association of Immunologists, Inc. Source

Philipsen A.,Steno Diabetes Center | Hansen A.-L.S.,University of Aarhus | JOrgensen M.E.,Steno Diabetes Center | Brage SO.,University of Cambridge | And 7 more authors.
Medicine and Science in Sports and Exercise | Year: 2015

Introduction/Purpose: Visceral adipose tissue (VAT) and physical activity are both independent predictors of Type 2 diabetes. Physical activity and overall obesity are inversely associated with each other. Yet the nature of the association between objectively measured dimensions of physical activity and abdominal fat distribution has not been well characterized. We aimed to do so in a middle-age to elderly population at high risk of diabetes. Methods: A crosssectional analysis of 1134 participants of the ADDITION-PRO study. VAT and subcutaneous adipose tissue (SAT) were assessed onedimensionally by ultrasonography and physical activity with combined accelerometry and HR monitoring. Linear regression of physical activity energy expenditure (PAEE) and time spent in different physical activity intensity levels on VAT and SAT was performed. Results: Median body mass index (BMI) was 26.6 kg.m2 and PAEE was 28.1 kJIkgj1Idj1, with 18.9 hIdj1 spent sedentary, 4.5 hIdj1 in light-intensity physical activity, and 0.4 hIdj1 in moderate-intensity physical activity. PAEE was significantly negatively associated with VAT, and in women, PAEE was also significantly negatively associated with SAT. The difference in VAT was j1.1 mm (95% confidence interval [CI] = j1.8 to j0.3) per 10-kJIkgj1Idj1 increment, and the corresponding difference in SAT for women was j0.6 mm (95% CI = j1.2 to j0.04) in models adjusted for age, sex, and waist circumference. Exchanging 1 h of light physical activity withmoderate physical activity was significantly associated with VAT (j4.5 mm, 95%CI =j7.6 toj1.5). Exchanging one sedentary hour with light physical activity was significantly associated with both VAT (j0.9 mm, 95% CI = j0.1 to j1.8) and SAT (j0.4 mm, 95% CI = j0.0 to j0.7). Conclusions: In this population with low physical activity levels, cross-sectional findings indicate that increasing overall physical activity and decreasing time spent sedentary is important to avoid the accumulation of metabolically deleterious VAT. © 2014 by the American College of Sports Medicine. Source

Schuster C.,French Institute of Health and Medical Research | Schuster C.,Hopitaux Universitaires Of Strasbourg | Schuller A.M.,Public Research Center for Health | Namer I.,Hopitaux Universitaires Of Strasbourg | And 8 more authors.
Schizophrenia Bulletin | Year: 2012

Background: Aged patients (>50 years old) with residual schizophrenic symptoms differ from young patients. They represent a subpopulation with a more unfavorable Kraepelinian course and have an increased risk (up to 30%) for dementia of unknown origin. However, our current understanding of age-related brain changes in schizophrenia is derived from studies that included less than 17% of patients who were older than 50 years of age. This study investigated the anatomical distribution of gray matter (GM) brain deficits in aged patients with ongoing schizophrenia. Methods: Voxel-based morphometry was applied to 3D-T1 magnetic resonance images obtained from 27 aged patients with schizophrenia (mean age of 60 years) and 40 age-matched normal controls. Results: Older patients with schizophrenia showed a bilateral reduction of GM volume in the thalamus, the prefrontal cortex, and in a large posterior region centered on the occipito-temporo-parietal junction. Only the latter region showed accelerated GM volume loss with increasing age. None of these results could be accounted for by institutionalization, antipsychotic medication, or cognitive scores. Conclusions: This study replicated most common findings in patients with schizophrenia with regard to thalamic and frontal GM deficits. However, it uncovered an unexpected large region of GM atrophy in the posterior tertiary cortices. The latter observation may be specific to this aged and chronically symptomatic subpopulation, as atrophy in this region is rarely reported in younger patients and is accelerated with age. © 2012 The Author. Source

Gole B.,Slovenian National Institute of Biology | Huszthy P.C.,University of Bergen | Popovic M.,Institute of Pathology | Jeruc J.,Institute of Pathology | And 4 more authors.
International Journal of Cancer | Year: 2012

Cysteine cathepsins play an important role in shaping the highly infiltrative growth pattern of human gliomas. We have previously demonstrated that the activity of cysteine cathepsins is elevated in invasive glioblastoma (GBM) cells in vitro, in part due to attenuation of their endogenous inhibitors, the cystatins. To investigate this relationship in vivo, we established U87-MG xenografts in non-obese diabetic (NOD)/severe combined immunodeficiency (SCID)-enhanced green fluorescent protein (eGFP) mice. Here, tumor growth correlated with an elevated enzymatic activity of CatB both in the tumor core and at the periphery, whereas CatS and CatL levels were higher at the xenograft edge compared to the core. Reversely, StefB expression was detected in the tumor core, but it was generally absent in the tumor periphery, suggesting that down-regulation of this inhibitor correlates with in vivo invasion. In human GBM samples, all cathepsins were elevated at the tumor periphery compared to brain parenchyma. CatB was also typically associated with angiogenic endothelia and necrotic areas. StefB was mainly detected in the tumor core, whereas CysC and StefA were evenly distributed, reflecting the observations in the xenografts. However, at the mRNA level, no differences in cathepsins and cystatins were observed between the tumor center and the periphery in both human biopsies and xenografts. Interestingly, in human tumors, cathepsin and stefin transcript levels correlated with CD68 and CXCR4 levels, but not with epidermal growth factor receptor (EGFR). Moreover, we reveal for the first time that an elevated StefA mRNA level is a highly significant prognostic factor for patient survival. © 2011 UICC. Source

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