Assuntos
Angiopatia Amiloide Cerebral/diagnóstico , Encefalite/diagnóstico , Febre/etiologia , Cefaleia/etiologia , Adulto , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/patologia , Diagnóstico Diferencial , Encefalite/complicações , Encefalite/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/patologiaRESUMO
KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR.
Assuntos
Neoplasias Encefálicas/patologia , Carcinogênese/metabolismo , Glioblastoma/patologia , Histona Acetiltransferases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Adulto , Idoso , Animais , Biomarcadores Tumorais/análise , Western Blotting , Separação Celular , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaRESUMO
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a dominantly inherited disorder belonging to the group of transmissible human spongiform encephalopathies or prion diseases. Several families affected by GSS with patients carrying mutations in the prion protein gene have been described worldwide. We report clinical, genealogical, neuropathology and molecular study results from two members of the first Argentine kindred affected by GSS. Both family members presented a frontotemporal-like syndrome, one with and the other without ataxia, with different lesions on neuropathology. A Pro to Leu point mutation at codon 102 (P102L) of the prion protein gene was detected in one of the subjects studied. The pathogenic basis of phenotypic variability observed in this family remains unclear, but resembles that observed in other P102L GSS patients from the same family.
Assuntos
Doença de Gerstmann-Straussler-Scheinker/diagnóstico , Doença de Gerstmann-Straussler-Scheinker/genética , Príons/genética , Adulto , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Proteínas PriônicasRESUMO
Most of the mutations in the presenilin-1 gene (PS-1) are associated with familial Alzheimer's disease (AD). However, certain examples can be associated with frontotemporal dementia (FTD). We performed a clinical evaluation of individuals belonging to a family with the FTD phenotype, and additional molecular studies and neuropathological assessment of the proband. The PS-1 M146V mutation was found in the 50-year-old subject (the proband) with family history of early-onset FTD. Neuropathological examination showed abundant amyloid plaques, widespread neurofibrillary pathology, Pick bodies in the hippocampus and cortex, cortical globose tangles and ubiquitin-positive nuclear inclusions in white matter oligodendrocytes. We report a kindred with clinical features of FTD, whose proband bore the PS-1 M146V mutation and showed diffuse Alzheimer's type pathology and Pick bodies on post-mortem neuropathological examination. As with other mutations within the same codon, this substitution may predispose to both diseases by affecting APP and/or tau processing.