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1.
Leuk Res ; 65: 5-13, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29227812

RESUMO

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.


Assuntos
Arginase/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Leucemia Mielomonocítica Crônica/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Proto-Oncogênicas/genética , Biomarcadores Tumorais/metabolismo , Medula Óssea/enzimologia , Estudos de Casos e Controles , Estudos de Coortes , DNA Metiltransferase 3A , Dioxigenases , Epigênese Genética , Feminino , Humanos , Leucemia Mielomonocítica Crônica/imunologia , Leucemia Mielomonocítica Crônica/patologia , Masculino , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Gradação de Tumores , Microambiente Tumoral
2.
Proc Inst Mech Eng H ; 221(7): 801-12, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18019466

RESUMO

The general framework and experimental validation of a novel navigation system designed for shoulder arthroscopy are presented. The system was designed to improve the surgeon's perception of the three-dimensional space within the human shoulder. Prior to surgery, a surface model of the shoulder was created from computed tomography images. Intraoperatively, optically tracked arthroscopic instruments were calibrated. The surface model was then registered to the patient using tracked freehand ultrasound images taken from predefined landmark regions on the scapula. Three-dimensional models of the surgical instruments were displayed, in real time, relative to the surface model in a user interface. Laboratory experiments revealed only small registration and calibration errors, with minimal time needed to complete the intraoperative tasks.


Assuntos
Artroscopia/métodos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Robótica/métodos , Ombro/diagnóstico por imagem , Ombro/cirurgia , Cirurgia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Gráficos por Computador , Simulação por Computador , Humanos , Modelos Biológicos , Ombro/fisiopatologia , Software , Interface Usuário-Computador
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