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1.  Absence of Oncogenic Canonical Pathway Mutations in Aggressive Pediatric Rhabdoid Tumors 
Pediatric blood & cancer  2012;59(7):1155-1157.
Rhabdoid tumors (also called atypical teratoid/rhabdoid tumor (AT/RT) in the brain), are highly malignant, poor prognosis lesions arising in the kidneys, soft tissues and central nervous system. Targeted therapy in this disease would benefit from advanced technologies detecting relevant actionable mutations.
Here we report on the evaluation of twenty-five tumors, all with known SMARCB1/INI1 alterations, for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection.
Other than mutations in SMARCB1, our results identified a single activating mutation in NRAS and complete absence of oncogenic mutations in all other genes tested.
The absence of mutations in canonical pathways critical for development and progression of adult cancers suggests that distinct mechanisms drive these highly malignant pediatric tumors. This may limit the therapeutic utility of available targeted therapies and require a refocusing toward developmental and epigenetic pathways.
PMCID: PMC3538080  PMID: 22997201
Rhabdoid; AT/RT; targeted therapy; OncoMap
2.  Interleukin-7 induces recruitment of monocytes/macrophages to endothelium 
European Heart Journal  2011;33(24):3114-3123.
Interleukin-7 (IL-7) is a master regulator of T-cell development and homoeostasis. Increased IL-7 levels are associated with inflammatory diseases. The aims of this study were to determine whether IL-7 is a biomarker for inflammatory conditions or an active participant in atherogenesis.
Methods and results
Advanced atherosclerotic lesions in Apoe−/− mice were regressed by long-term cholesterol lowering through treatment with a helper-dependent adenovirus expressing apolipoprotein E (n= 6–10). Using this model, gene expression patterns in the aorta were analysed at an early phase of regression by microarray. After stringent statistical analysis, we found that IL-7 expression is significantly reduced in response to lowering of cholesterol (n= 6). To understand the importance of IL-7 down-regulation for atherosclerotic regression, we studied the effects and mechanisms of action of IL-7 on endothelial cells (ECs) in vitro as well as in vivo. Our major findings are: (i) IL-7 up-regulates cell adhesion molecules and monocyte chemoattractant protein-1 in ECs and promotes monocyte adhesion to ECs; (ii) this regulation is mediated by phosphatidylinositol 3-kinase (PI3K)/AKT-dependent and -independent activation of NF-κB; (iii) elevation of plasma IL-7 induces recruitment of monocytes/macrophages to endothelium without affecting plasma cholesterol (n= 5, 6); and (4) lack of IL-7 in bone marrow-derived cells reduces migration of monocytes/macrophages to the lesions (n= 5, 6).
These results suggest that IL-7 inflames endothelium via PI3K/AKT-dependent and -independent activation of NF-κB and recruits monocytes/macrophages to the endothelium, thus playing an active role in atherogenesis.
PMCID: PMC3598429  PMID: 21804111
Atherosclerosis; Cell adhesion molecules; Chemokine; Endothelium
3.  Maintenance of peripheral tolerance through controlled tissue homing of antigen-specific T cells in K14-mOVA mice 
Immunological tolerance is crucial to avoid autoimmune and inflammatory diseases, however the mechanisms involved are incompletely understood. To study peripheral tolerance to skin-associated antigens, we generated new transgenic mice expressing a membrane-bound form of ovalbumin in skin under the human K14-promoter (K14mOVA mice). In contrast to other transgenic mice expressing similar self-antigens in skin, adoptive transfer of antigen-specific T cells does not induce inflammatory skin disease in our K14-mOVA mice. OVA-specific T cells transferred into K14-mOVA mice are activated in lymphoid tissues, undergo clonal expansion and eventually acquire effector function. Importantly, these antigen-specific T cells selectively up-regulate expression of E-selectin ligand (ESL) in cutaneous lymph nodes but not in mesenteric lymph nodes and spleen, demonstrating that expression of endogenous self-antigens in skin dictates imprinting of skin tissue homing in vivo. However, an additional inflammatory signal, here induced by tape stripping, is required in K14-mOVA mice to induce T cell migration to skin and development of inflammatory skin disease. Depletion of regulatory CD4+ CD25+ T cells did not provoke homing of transferred T cells to skin under steady-state conditions, indicating that these cells are not the key regulators for inhibiting T cell homing in K14-mOVA mice. Both skin-derived and LN-resident CD8α+ DCs are responsible for antigen presentation in vivo and induce tolerance to skin antigens, as we show by selective depletion of Langerin+ and CD11c+ DCs. Taken together, controlled skin homing of T cells is critical for the maintenance of peripheral immune tolerance to epidermal self-antigens.
PMCID: PMC2843920  PMID: 19342642
T cells; dendritic cells; cell trafficking; tolerance; skin
4.  Langerhans cells are not required for the CD8 T cell response to epidermal self antigens1 
Langerhans cells (LC) are antigen presenting cells (APC) that reside at the barrier surfaces. Mice expressing an ovalbumin peptide in the epidermis (K14-OVAp) were used to study CD8+ T cell responses to an epidermal self-antigen. Earlier results suggested that LC were the predominant APC, inducing a robust T cell response and autoimmunity. In this study we employed a whole protein model system, the K14-mOVA mouse, in which a transmembrane form of ovalbumin was expressed in keratinocytes. In contrast to K14-OVAp mice, T cells in K14-mOVA mice were activated, but did not expand and instead died by apoptosis. Furthermore, in double transgenic mice expressing both mOVA and OVAp, robust OT-I expansion occurred, indicating that tolerance to this antigen is not dominant and was due to lack of activating signals. We sought to identify the relevant APC in K14 mice using bone marrow chimeras, and found that radioresistant cells (presumably LC) were able to cross-present the OVA antigen from keratinocytes to naïve T cells in the lymph node. However, use of LC deficient mice indicated that LC were not required for the expansion of OT-I in K14-OVAp, or the deletion of OT-I in K14-mOVA mice. These data suggest that radioresistant non-Langerhans cells present self-antigen in K14-OVAp mice, and drive a robust CD8 T cell response.
PMCID: PMC2722807  PMID: 19342641
Dendritic cells; Langerhans cells; skin; peripheral tolerance
5.  Visualization and Identification of IL-7 Producing Cells in Reporter Mice 
PLoS ONE  2009;4(11):e7637.
Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein ) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging.
PMCID: PMC2770321  PMID: 19907640

Results 1-5 (5)