RESUMEN

This corrects the article DOI: 10.1038/onc.2016.320.

RESUMEN

Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21Waf1/Cip1. The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21Waf1/Cip1 expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer.

Asunto(s)

Resistencia a Antineoplásicos/genética , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Lisina/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ciclo Celular/genética , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Cisplatino/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo

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Using the response to Mycobacterium butyricum as the test-immune response, the main goal of this study was to demonstrate the suitability of the growing feather (GF) as a dermal test site and window into in vivo cellular/tissue responses (US-Patent 8,216,551). Using M. butyricum immunized chickens, the specific objectives were to: 1) compare the leukocyte infiltration response to intra-dermally injected M. butyricum in GF, wattles, and wing webs; 2) use GF as the test site to monitor leukocyte response profiles to recall antigen in the same individuals; and 3) gain new knowledge regarding the local response to M. butyricum in chickens. For objective 1, chickens were euthanized for tissue collection at 4 to 6, 24, 48, and 72 h after intra-dermal antigen injection. Leukocyte infiltration profiles were determined using immunochemical and conventional histology. Data from this study established the similarities between the cellular response in GF, wattles, and wing webs and uncovered many advantages of working with GF. For objective 2, antigen was injected into multiple GF per individual. GF were collected before and at 0.25, 1, 2, 3, and 7 d post injection and processed for cell population analysis by flow cytometry. Advantages of the approach used in objective 2 included a technically easier, more comprehensive, and more objective leukocyte profile analysis; same-day data acquisition; and, most importantly, easy, minimally invasive sample collection from the same individual throughout the study. Both studies contributed new knowledge regarding the local cutaneous response to M. butyricum in M. butyricum immunized chickens and confirmed the cell-mediated nature of the immune response to M. butyricum (e.g., elevated levels [P < 0.05] of T cells [CD4+ and CD8+], macrophages and MHC class II+-cells on days one to 3 post injection in M. butyricum- compared to PBS-injected tissues). The use of GF as an "in vivo test tube" to monitor local innate and adaptive immune activities will find direct application in vaccine development, as well as in the assessment and optimization of immune system development and function in poultry.

Asunto(s)

Pollos , Cresta y Barbas/inmunología , Plumas/inmunología , Infecciones por Mycobacterium/veterinaria , Enfermedades de las Aves de Corral/inmunología , Alas de Animales/microbiología , Animales , Cresta y Barbas/microbiología , Plumas/microbiología , Inmunización/veterinaria , Recuento de Leucocitos/veterinaria , Leucocitos/inmunología , Masculino , Mycobacterium/fisiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/microbiología , Enfermedades de las Aves de Corral/microbiología , Alas de Animales/inmunología

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Hyperactivation of the Wingless-type (Wnt)/ß-catenin pathway promotes tumor initiation, tumor growth and metastasis in various tissues. Although there is evidence for the involvement of Wnt/ß-catenin pathway activation in salivary gland tumors, the precise mechanisms are unknown. Here we report for the first time that downregulation of the Wnt inhibitory factor 1 (WIF1) is a widespread event in salivary gland carcinoma ex-pleomorphic adenoma (CaExPA). We also show that WIF1 downregulation occurs in the CaExPA precursor lesion pleomorphic adenoma (PA) and indicates a higher risk of progression from benign to malignant tumor. Our results demonstrate that diverse mechanisms including WIF1 promoter hypermethylation and loss of heterozygosity contribute to WIF1 downregulation in human salivary gland tumors. In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21. Most importantly, WIF1 significantly diminished the number of salivary gland cancer stem cells and the anchorage-independent cell growth. Consistent with this observation, WIF1 caused a reduction in the expression of pluripotency and stemness markers (OCT4 and c-MYC), as well as adult stem cell self-renewal and multi-lineage differentiation markers, such as WNT3A, TCF4, c-KIT and MYB. Furthermore, WIF1 significantly increased the expression of microRNAs pri-let-7a and pri-miR-200c, negative regulators of stemness and cancer progression. In addition, we show that WIF1 functions as a positive regulator of miR-200c, leading to downregulation of BMI1, ZEB1 and ZEB2, with a consequent increase in downstream targets such as E-cadherin. Our study emphasizes the prognostic and therapeutic potential of WIF1 in human salivary gland CaExPA. Moreover, our findings demonstrate a novel mechanism by which WIF1 regulates cancer stemness and senescence, which might have major implications in the field of cancer biology.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenoma Pleomórfico/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Senescencia Celular , Células Madre Neoplásicas/metabolismo , Proteínas Represoras/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Vía de Señalización Wnt , Proteínas Adaptadoras Transductoras de Señales/genética , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/patología , Biomarcadores de Tumor/genética , Carcinoma/genética , Carcinoma/patología , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Progresión de la Enfermedad , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Pérdida de Heterocigocidad , MicroARNs/metabolismo , Células Madre Neoplásicas/patología , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Factores de Tiempo , Transfección

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AIM: To determine the accuracy of high-resolution magnetic resonance enterography (HR-MRE) against surgical and histopathology standards in Crohn's disease, and to determine quantitative MRE findings that can differentiate minor from advanced bowel inflammation. MATERIALS AND METHODS: Forty-nine consecutive patients who underwent 51 surgical procedures underwent standard MRE and HR-MRE prior to surgery. MRE images were assessed for superficial ulcers, deep ulcers, abscesses, fistulae, and strictures. Quantitative MRE parameters, such as mural thickness, enhancement ratios (ER) of the abnormal bowel, mesentery (ME), and normal bowel (controls), were recorded. MRE findings were compared with surgical and histological results to obtain sensitivity, specificity, and accuracy. Grading of inflammation was compared with MRE parameters for correlation and discriminating power. RESULTS: The sensitivities and specificities of MRE and HR-MRE enterography in the detection of abnormal segments were 0.82 and 0.95 versus 0.86 and 0.95 respectively. HR-MRE was significantly more sensitive than MRE and HR-MRE in the detection of superficial and deep ulcers, fistulae, and abscesses (0.5 versus 0.69; 0.69 versus 0.94; 0.76 versus 0.95; 0.77 versus 1.0, respectively). Mural thickness, ER, and ME had positive correlation with higher grades of inflammation(r = 0.8, 0.66, 0.42, respectively). Regression analysis showed deep and superficial ulcers, ER > 1.85 and mural thickness >4.5 mm were independent predictors of advanced inflammation. CONCLUSION: HR-MRE has significantly greater diagnostic accuracy as compared to MRE in the diagnosis of bowel ulceration, fistulae and abscesses. Bowel ulcers, mural enhancement ratio >1.85 are strong predictors of advanced inflammation.

Asunto(s)

Enfermedad de Crohn/patología , Adulto , Anciano , Enfermedad de Crohn/cirugía , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Sensibilidad y Especificidad

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The purpose of this article is to review the imaging findings of various infections affecting the gastrointestinal tract. Barium examinations, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography all play an important role in the diagnostic workup of gastrointestinal tract infections. Knowledge of differential diagnosis, sites of involvement, and typical imaging features of different infections can help in accurate diagnosis and guide treatment.

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Infecciones Bacterianas/diagnóstico , Enfermedades Gastrointestinales/diagnóstico , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/virología , Micosis/diagnóstico , Virosis/diagnóstico , Adulto , Sulfato de Bario , Medios de Contraste , Diagnóstico Diferencial , Femenino , Enfermedades Gastrointestinales/microbiología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos

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The purpose of this article is to provide a comprehensive review of the imaging findings of various parasitic infestations and other miscellaneous infections affecting the gastrointestinal tract. Barium examinations play an important role in the diagnostic workup of parasitic intestinal infections. Knowledge of differential diagnosis, sites of involvement, and imaging features of different infections and infestations can help in accurate diagnosis and guide treatment.

Asunto(s)

Tracto Gastrointestinal/parasitología , Parasitosis Intestinales/diagnóstico , Infecciones por Protozoos/diagnóstico , Adulto , Anciano , Sulfato de Bario , Niño , Medios de Contraste , Diagnóstico Diferencial , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/parasitología , Humanos , Parasitosis Intestinales/parasitología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Infecciones por Protozoos/parasitología , Tomografía Computarizada por Rayos X/métodos

RESUMEN

Aberrant activation of Wingless-type (Wnt)/ß-catenin signaling is widespread in human cervical cancer. However, the underlying mechanisms of Wnt activation and the therapeutic potential of Wnt inhibition remain largely unknown. Here, we demonstrate that the Wnt inhibitory factor 1 (WIF1), a secreted Wnt antagonist, is downregulated in all human primary cervical tumors and cell lines analyzed. Our data reveal that WIF1 downregulation occurs due to promoter hypermethylation and is an early event in cervical oncogenesis. WIF1 re-expression upon 5-aza-2'-deoxycytidine treatment or WIF1 gene transfer induces significant apoptosis and G(2)/M arrest, and inhibits cervical cancer cell proliferation in vitro. Consistent with this, treatment of established mice tumor xenografts with peritumoral WIF1 gene transfer results in a significant inhibition of cancer growth and invasion. WIF1 treatment causes a significant decrease in intracellular WNT1 and TCF-4 proteins revealing novel Wnt-regulatory mechanisms. Thus, WIF1 causes a major cellular re-distribution of ß-catenin and a significant inhibition of the Wnt/ß-catenin pathway in tumor cells, as documented by a remarkable reversion in the expression of Wnt/ß-catenin transcriptional target genes (E-cadherin, c-Myc, cyclin D1, CD44 and VEGF). Consequently, multiple critical events in tumor progression and metastasis such as cell proliferation, angiogenesis and invasion were inhibited by WIF1. In addition, WIF1 modulated the expression of specific anti-apoptotic and apoptotic proteins, thereby inducing significant apoptosis in vivo. Our findings demonstrate for the first time that WIF1 downregulation by epigenetic gene silencing is an important mechanism of Wnt activation in cervical oncogenesis. Of major clinical relevance, we show that peritumoral WIF1 gene transfer reduces not only cancer growth but also invasion in well-established tumors. Therefore, our data provide novel mechanistic insights into the role of WIF1 in cervical cancer progression, and the important preclinical validation of WIF1 as a potent drug target in cervical cancer treatment.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica , Proteínas Represoras/metabolismo , Neoplasias del Cuello Uterino/irrigación sanguínea , Neoplasias del Cuello Uterino/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Azacitidina/análogos & derivados , Azacitidina/farmacología , Western Blotting , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Cuello del Útero/metabolismo , Cuello del Útero/patología , Metilación de ADN , Decitabina , Regulación hacia Abajo , Epigénesis Genética , Femenino , Silenciador del Gen , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Desnudos , Invasividad Neoplásica , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Neoplasias del Cuello Uterino/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo

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Computed tomography is being increasingly used for the evaluation of patients with vague abdominal symptoms, and may provide the initial opportunity to detect and characterize tumours of the small bowel. The recognition of imaging features on CT allows distinction to be made between benign and malignant neoplasms. Multidetector row CT (MDCT) provides high-resolution imaging and helps in precise localization and characterization of lesions. This article illustrates the imaging appearances of small bowel tumours on MDCT and demonstrates the usefulness of multiplanar reformatting (MPR) in the diagnosis and categorization of these tumours.

Asunto(s)

Neoplasias Gastrointestinales/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Neoplasias Gastrointestinales/cirugía , Humanos , Intestino Delgado/diagnóstico por imagen , Intestino Delgado/cirugía , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/instrumentación

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In recent years there has been a marked increase in the incidence of pseudomembranous colitis (PMC). PMC is more common in patients over 65 years of age and can cause significant morbidity. The purpose of this article is to review the imaging features of PMC on plain radiography, sonography, computed tomography (CT), scintigraphy and magnetic resonance imaging (MRI). It is important to recognize the imaging findings of PMC using different imaging methods and encourage urgent confirmation of the diagnosis serologically, as the differential includes other fulminant colitides for which colectomy may be the required. Awareness of the spectrum of imaging findings of PMC can help radiologists make the primary or incidental diagnosis of PMC.

Asunto(s)

Enterocolitis Seudomembranosa/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X