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1.
Gut ; 72(4): 654-662, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36191961

RESUMO

OBJECTIVE: Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined. DESIGN: ROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury. RESULTS: TNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation. CONCLUSIONS: NOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Humanos , Animais , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Células M , NADPH Oxidase 1/genética , NADPH Oxidase 1/metabolismo , Peróxido de Hidrogênio/efeitos adversos , Colite/induzido quimicamente
3.
Am J Clin Pathol ; 140(1): 103-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23765540

RESUMO

OBJECTIVES: To identify, describe, and investigate the clinical, radiologic, and pathologic features of 8 cases of telangiectatic oncocytoma. METHODS: Fifty-three consecutive renal oncocytomas were reviewed for the telangiectatic pathologic features that were subsequently correlated with the demographic, clinical, and radiographic findings. RESULTS: Telangiectatic oncocytoma accounted for 15% of the 53 renal oncocytomas collected in the past 7 years in our institution. On radiology, almost all presented as an enhancing mass and were suspicious for or consistent with a renal malignant tumor. Grossly, the tumors ranged from 2.4 to 6.0 cm (mean, 3.5 cm) and macroscopically were hemorrhagic spongy or multicystic masses without a central stellate scar. Microscopically, they were characterized by variably sized blood-distended spaces (<0.1-mm to 2- to 3-mm blood lakes) lined by typical oncocytoma cells and without evidence of degenerative changes. CONCLUSIONS: With its unique radiologic and pathologic presentations in comparison with classic renal oncocytoma, it is important to recognize this new variant of renal oncocytoma.


Assuntos
Adenoma Oxífilo/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Renais/patologia , Telangiectasia/patologia , Adenoma Oxífilo/irrigação sanguínea , Adenoma Oxífilo/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Demografia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Telangiectasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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