ABSTRACT
Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology, and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-Seq of patient-matched colon and ileum biopsies from treatment-naive pediatric patients with CD (n = 169) and a control cohort (n = 108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we found that pediatric patients with CD with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 upregulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
Subject(s)
Crohn Disease , MicroRNAs , Adult , Animals , Mice , Humans , Child , Crohn Disease/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Phenotype , InflammationABSTRACT
Objetivos: Evaluar nuestra experiencia en citología en medio líquido (Thin Prep Pap Test) durante un año, evaluando el seguimiento de las pacientes diagnosticadas. Comparar estos datos con nuestros resultados obtenidos previamente con citología convencional. Sujetos y métodos: Se realizaron 11.150 citologías cervicovaginales, 8.086 convencionales y 3.064 en medio líquido (Thin Prep Pap Test) y se evaluaron los resultados. Se efectuó un seguimiento de las pacientes y una evaluación de éste en los casos diagnosticados como células escamosas atípicas de significado incierto y como lesión escamosa intraepitelial de bajo grado. Resultados: Los resultados obtenidos demuestran un incremento de los diagnósticos en todas las categorías, si bien sólo de forma estadísticamente significativa si evaluamos los resultados en conjunto, no por separado. En cuanto al seguimiento, los resultados son similares en la citología convencional y en el Thin Prep. Conclusiones: La citología en medio líquido incrementa de forma más o menos significativa la detección de las lesiones cervicales preneoplásicas y, por tanto, mejora el rendimiento de la citología cervicovaginal
Objectives: To describe our experience of liquid-based cytology (Thin Prep Pap Test) over a 1-year period by evaluating the follow-up of patients with an abnormal result and to compare the results obtained with the Thin Prep Pap Test with those previously obtained with conventional cytology. Subjects and methods: The results of 11,150 cervico-vaginal pap tests (8,086 conventional tests and 3,064 liquid-based tests [Thin Prep]) were evaluated. The follow-up of patients with a diagnosis of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) was evaluated. Results: Diagnosis of abnormal results in all categories increased, although this increase was only statistically significant when the results were evaluated as a whole. The results of follow-up were similar with both methods. Conclusions: Liquid-based cytology (Thin Prep Pap Test) substantially increases the detection of preneoplastic cervical lesions and consequently improves the yield of cervico-vaginal cytology
Subject(s)
Female , Humans , Cytodiagnosis/methods , Vaginal Smears/methods , Mass Screening , Uterine Cervical Neoplasms/pathologyABSTRACT
In a genome-wide screen for putative tumor suppressor genes, the EBF3 locus on the human chromosome 10q26.3 was found to be deleted or methylated in 73% of the examined cases of brain tumors. EBF3 is expressed in normal brain but is silenced in brain tumors. Therefore, it is suggested that EBF3 is a tumor suppressor. However, it remains unknown whether inactivation of EBF3 locus also occurs in other types of tumors and what functions of EBF3 underlie EBF3-mediated tumor suppression. We show here that expression of EBF3 resulted in cell cycle arrest and apoptosis. The expression of cyclin-dependent kinase inhibitors was profoundly affected with early activation and then repression of p21(cip1/waf1) and persistent activation of both p27(kip1) and p57(kip2), whereas genes involved in cell survival and proliferation were suppressed. EBF3 bound directly to p21(cip1/waf1) promoter and regulated transcription from both p21(cip1/waf1) and p27(kip1) promoters in reporter assays. Apoptosis occurred 48 hours after EBF3 expression with caspase-3 activation. Silencing of the EBF3 locus was observed in brain, colorectal, breast, liver, and bone tumor cell lines and its reactivation was achieved on treatment with 5-aza-2'-deoxycytidine and trichostatin A in a significant portion of these tumor cells. Therefore, EBF3 regulates a transcriptional program underlying a putative tumor suppression pathway.
Subject(s)
Apoptosis/genetics , Cell Cycle/genetics , Genes, Tumor Suppressor , Microtubule-Associated Proteins/physiology , Neoplasms/genetics , Transcription, Genetic/genetics , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Chromosomes, Human, Pair 10/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p27 , DNA Methylation , Decitabine , Epigenesis, Genetic , Female , Gene Deletion , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydroxamic Acids/pharmacology , Intracellular Signaling Peptides and Proteins/genetics , Male , Neoplasm Proteins/genetics , Neoplasms/pathology , Promoter Regions, Genetic/genetics , Recombinant Fusion Proteins/biosynthesis , Transcription, Genetic/drug effectsABSTRACT
La predicción de la evolución del ASCUS sigue siendo un tema controvertido. En un intento de hallar aspectos citológicos que permitan predecir dicha evolución hemos evaluado 5 detalles citológicos en células escamosas inmaduras con características de ASCUS sugestivo de lesión escamosa de alto grado. Ninguno de los detalles evaluados ha mostrado valor predictivo respecto a la evolución de la lesión
Follow-up of patients diagnosed as having ASCUS have no predictable morphological data. We have evaluated 5 aspects of ASCUS affecting immature squamous cells to find out whether these details have predictive value. None of these data have statistical significance related to follow-up of the patients examined
Subject(s)
Female , Humans , Homeopathic Clinical-Dynamic Prognosis/methods , Carcinoma, Squamous Cell/pathology , Cytological Techniques/methods , Predictive Value of Tests , Prognosis , Chromatin/pathology , Cell Biology/trends , 31574/diagnosis , 31574/pathology , Uterine Cervical Neoplasms/diagnosisABSTRACT
La predicción de la evolución del ASCUS sigue siendo un tema controvertido. En un intentode hallar aspectos citológicos que permitan predecir dicha evolución hemos evaluado 5 detallescitológicos en células escamosas inmaduras con características de ASCUS sugestivo de lesiónescamosa de alto grado. Ninguno de los detalles evaluados ha mostrado valor predictivo respectoa la evolución de la lesión
Follow-up of patients diagnosed as having ASCUS have no predictable morphological data.We have evaluated 5 aspects of ASCUS affecting immature squamous cells to find out whetherthese details have predictive value. None of these data have statistical significance related tofollow-up of the patients examined
Subject(s)
Female , Adult , Middle Aged , Humans , Carcinoma, Squamous Cell/pathology , Neoplasms, Squamous Cell/pathology , Carcinoma, Squamous Cell/classification , Metaplasia/pathology , 31574/pathology , Prognosis , Neoplasms, Squamous Cell/classificationABSTRACT
Objetivo: Establecer un mecanismo de control de calidad lo más efectivo posible para las citologías diagnosticadas como ASCUS. Material y método: Revisión de las citologías cérvico-vaginales diagnosticadas como ASCUS durante los años 1995 a 1999 ambos inclusive. Reevaluación por dos citotécnicas diferentes al azar, sin datos clínicos. Reevaluación de las discrepancias por el citopatólogo. Estudio estadístico. Revisión de la Literatura. Resultados: Índice de concordancia entre citotécnicas: 80 por ciento. Índice de concordancia del citopatólogo: 84,5 por ciento. Todos los casos considerados como negativos mostraron desaparición de la lesión en el seguimiento. Los cambios asentados sobre células metaplásicas y en mujeres peri y post-menopáusicas son los casos con mayores discrepancias. Discusión: Nuestros resultados muestran una concordancia para el diagnóstico de ASCUS mayor que la reportada en la Literatura. Creemos que este método, si bien es más laborioso que otros publicados en la Literatura, es mejor por cuanto unifica criterios entre el personal que trabaja en un Laboratorio de Citopatología, y permite evaluar los casos en relación al seguimiento de las pacientes (AU)