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1.
Toxicol Pathol ; 42(5): 923-35, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24292388

RESUMO

Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy.


Assuntos
Inflamação/patologia , Nefropatias/patologia , Glomérulos Renais/efeitos dos fármacos , Oligonucleotídeos Antissenso/efeitos adversos , Animais , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Nefropatias/induzido quimicamente , Glomérulos Renais/patologia , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Oligonucleotídeos Antissenso/administração & dosagem , Medição de Risco , Especificidade da Espécie
2.
Am J Surg Pathol ; 31(9): 1337-43, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17721188

RESUMO

BACKGROUND: Malignant struma ovarii (MSO) are rare tumors that arise from ectopic thyroid tissue in the ovary, benign struma ovarii (BSO). Most MSO are histologically classified as papillary thyroid carcinomas (PTC). Oncogenic activation of BRAF (35% to 69%), RAS (10%), or RET (5% to 30%) is common in PTC, and the mutations correlate with tumor subtype, patient age, and clinical behavior. In this study, we explored the possible role of these genes in the development of BSO and MSO. DESIGN: Six paraffin-embedded cases of MSO with histopathologic features of PTC (4 follicular variants, 1 classic, and 1 metastasis of a classic) and 9 BSO were identified. BRAF, NRAS, and KRAS mutations were evaluated using a combination of polymerase chain reaction, denaturing high performance liquid chromatography, and automated sequencing. RET alterations were screened by fluorescence in situ hybridization with multicolor probes. Corresponding benign tissues were evaluated when available. RESULTS: BRAF mutations were present in 4 of 6 MSO and none of 9 BSO. The BRAF mutations included V600E (2 cases), K601E, and a novel deletion/substitution TV599-600M. Neither MSO nor BSO contained alterations in NRAS, KRAS, or RET. CONCLUSIONS: The development of MSOs with PTC features is associated with BRAF mutations of the type commonly observed in PTC, suggesting a common pathogenesis for all PTCs regardless of location. In contrast, mutations in the RET/RAS/RAF pathway are not found in BSO. The prognostic significance of BRAF mutation status in MSO remains to be determined.


Assuntos
Carcinoma Papilar/genética , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estruma Ovariano/genética , Adulto , Idoso , Carcinoma Papilar/patologia , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Feminino , Genes ras , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-ret/genética , Estruma Ovariano/patologia
3.
Am J Pathol ; 165(5): 1773-80, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15509545

RESUMO

Aneurysmal bone cyst (ABC) is a locally recurrent bone lesion that has been regarded as a reactive process. Recently, a neoplastic basis in primary ABC was evidenced by demonstration of clonal chromosome band 17p13 translocations that place the USP6 (TRE2 or TRE17) oncogene under the regulatory influence of the highly active CDH11 promoter. Herein, we report CDH11 and/or USP6 rearrangements in 36 of 52 primary ABCs (69%), of which 10 had CDH11-USP6 fusion, 23 had variant USP6 rearrangements without CDH11 rearrangement, and three had variant CDH11 rearrangements without USP6 rearrangement. USP6 and CDH11 rearrangements were restricted to spindle cells in the ABC and were not found in multinucleated giant cells, inflammatory cells, endothelial cells, or osteoblasts. CDH11 and USP6 rearrangements did not correlate with recurrence-free survival, or with other clinicopathological features. CDH11 and USP6 rearrangements were not found in any of 17 secondary ABC associated with giant cell tumor, chondroblastoma, osteoblastoma, and fibrous dysplasia. These findings demonstrate that primary ABC are mesenchymal neoplasms exhibiting USP6 and/or CDH11 oncogenic rearrangements. By contrast, secondary ABC lack CDH11 and USP6 rearrangements, and although morphological mimics of primary ABC, appear to represent a non-specific morphological pattern of a diverse group of non-ABC neoplasms.


Assuntos
Cistos Ósseos Aneurismáticos/genética , Neoplasias Ósseas/genética , Caderinas/genética , Caderinas/fisiologia , Endopeptidases/genética , Endopeptidases/fisiologia , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/fisiologia , Adolescente , Adulto , Cistos Ósseos Aneurismáticos/metabolismo , Cistos Ósseos Aneurismáticos/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Inflamação , Masculino , Mutação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Ubiquitina Tiolesterase
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