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1.
Mod Pathol ; 29(6): 570-81, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26965583

RESUMEN

A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.


Asunto(s)
Biomarcadores de Tumor/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Linfoma Folicular/genética , Mutación , Receptores de IgE/análisis , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Factor de Transcripción STAT6/genética , Translocación Genética , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Deleción Cromosómica , Trastornos de los Cromosomas/inmunología , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/inmunología , Análisis Mutacional de ADN/métodos , Femenino , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma Folicular/química , Linfoma Folicular/inmunología , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Transcripción STAT6/análisis
2.
Fish Shellfish Immunol ; 26(5): 811-20, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19332135

RESUMEN

Channel catfish (Ictalurus punctatus) have proven to be an excellent model with which to study immune responses of lower vertebrates. Identification of anti-viral antibodies and cytotoxic cells, as well as both type I and II interferon (IFN), demonstrates that catfish likely mount a vigorous anti-viral immune response. In this report, we focus on other elements of the anti-viral response, and identify more than two dozen genes that are induced following treatment of catfish cells with poly [I:C]. We showed that poly [I:C] induced type I interferon within 2 h of treatment, and that characteristic interferon stimulated genes (ISGs) appeared 6-12 h after exposure. Among the ISGs detected by RT-PCR assay were homologs of ISG15, Mx1, IFN regulatory factor 1 (IRF-1), inhibitor of apoptosis protein-1 (IAP-1) and the chemokine CXCL10. Microarray analyses showed that 13 and 24 cellular genes, respectively, were upregulated in poly [I:C]-treated B cell and fibroblast cultures. Although many of these genes were novel and did not fit the profile of mammalian ISGs, there were several (ISG-15, ubiquitin-conjugating enzyme E2G1, integrin-linked kinase, and clathrin-associated protein 47) that were identified as ISGs in mammalian systems. Taken together, these results suggest that dsRNA, either directly or through the prior induction of IFN, upregulates catfish gene products that function individually and/or collectively to inhibit virus replication.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Ictaluridae/genética , Ictaluridae/inmunología , Poli I-C/farmacología , Animales , Línea Celular , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Genes/genética , Interferones/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
3.
PLoS One ; 14(1): e0210415, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30682039

RESUMEN

BACKGROUND: First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection. METHODS: From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed. RESULTS: Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner. CONCLUSION: In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Terapia Molecular Dirigida , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anciano , Carcinoma de Células Renales/secundario , Femenino , Genes p53 , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Modelos Genéticos , Mutación , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética
4.
BMC Bioinformatics ; 7 Suppl 2: S6, 2006 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-17118149

RESUMEN

BACKGROUND: Catalytic RNA molecules are called ribozymes. The aptamers are DNA or RNA molecules that have been selected from vast populations of random sequences, through a combinatorial approach known as SELEX. The selected oligo-nucleotide sequences (~200 bp in length) have the ability to recognize broad range of specific ligands by forming binding pockets. These novel aptamer sequences can bind to nucleic acids, proteins or small organic and inorganic chemical compounds and have many potential uses in medicine and technology. RESULTS: The comprehensive sequence information on aptamers and ribozymes that have been generated by in vitro selection methods are included in this RiboaptDB database. Such types of unnatural data generated by in vitro methods are not available in the public 'natural' sequence databases such as GenBank and EMBL. The amount of sequence data generated by in vitro selection experiments has been accumulating exponentially. There are 370 artificial ribozyme sequences and 3842 aptamer sequences in the total 4212 sequences from 423 citations in this RiboaptDB. We included general search feature, and individual feature wise search, user submission form for new data through online and also local BLAST search. CONCLUSION: This database, besides serving as a storehouse of sequences that may have diagnostic or therapeutic utility in medicine, provides valuable information for computational and theoretical biologists. The RiboaptDB is extremely useful for garnering information about in vitro selection experiments as a whole and for better understanding the distribution of functional nucleic acids in sequence space. The database is updated regularly and is publicly available at http://mfgn.usm.edu/ebl/riboapt/.


Asunto(s)
Aptámeros de Nucleótidos/química , Bases de Datos de Ácidos Nucleicos , ARN Catalítico/química , Análisis de Secuencia de ADN/métodos , Biología Computacional , Internet , Diseño de Software
5.
BMC Genomics ; 7: 264, 2006 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-17052344

RESUMEN

BACKGROUND: Little is known about the genome sequences of lepidopteran insects, although this group of insects has been studied extensively in the fields of endocrinology, development, immunity, and pathogen-host interactions. In addition, cell lines derived from Spodoptera frugiperda and other lepidopteran insects are routinely used for baculovirus foreign gene expression. This study reports the results of an expressed sequence tag (EST) sequencing project in cells from the lepidopteran insect S. frugiperda, the fall armyworm. RESULTS: We have constructed an EST database using two cDNA libraries from the S. frugiperda-derived cell line, SF-21. The database consists of 2,367 ESTs which were assembled into 244 contigs and 951 singlets for a total of 1,195 unique sequences. CONCLUSION: S. frugiperda is an agriculturally important pest insect and genomic information will be instrumental for establishing initial transcriptional profiling and gene function studies, and for obtaining information about genes manipulated during infections by insect pathogens such as baculoviruses.


Asunto(s)
Etiquetas de Secuencia Expresada , Biblioteca de Genes , Spodoptera/genética , Animales , Secuencia de Bases , Biología Computacional , ADN Complementario/química , ADN Complementario/genética , Datos de Secuencia Molecular , Filogenia , Análisis de Secuencia de ADN
6.
Stem Cell Reports ; 6(5): 772-783, 2016 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-27132888

RESUMEN

Human male germ cell tumors (GCTs) are derived from primordial germ cells (PGCs). The master pluripotency regulator and neuroectodermal lineage effector transcription factor SOX2 is repressed in PGCs and the seminoma (SEM) subset of GCTs. The mechanism of SOX2 repression and its significance to GC and GCT development currently are not understood. Here, we show that SOX2 repression in SEM-derived TCam-2 cells is mediated by the Polycomb repressive complex (PcG) and the repressive H3K27me3 chromatin mark that are enriched at its promoter. Furthermore, SOX2 repression in TCam-2 cells can be abrogated by recruitment of the constitutively expressed H3K27 demethylase UTX to the SOX2 promoter through retinoid signaling, leading to expression of neuronal and other lineage genes. SOX17 has been shown to initiate human PGC specification, with its target PRDM1 suppressing mesendodermal genes. Our results are consistent with a role for SOX2 repression in normal germline development by suppressing neuroectodermal genes.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXF/genética , Seminoma/genética , Neoplasias Testiculares/genética , Linaje de la Célula/genética , Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Células Germinativas/patología , Histona Demetilasas/genética , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Proteínas Nucleares/genética , Proteínas del Grupo Polycomb/genética , Regiones Promotoras Genéticas , Seminoma/patología , Neoplasias Testiculares/patología
7.
Leuk Lymphoma ; 57(4): 899-908, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26294112

RESUMEN

Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis, but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses. Application of these criteria to independent datasets revealed novel candidate genes with coordinated expression, such as CNOT2, potentially with pathogenic roles. No one single aberration significantly associated with patient outcome across datasets, but genomic complexity, defined by imbalance in more than one MCR, significantly portended adverse outcome in two of three independent datasets. Thus, the standardized scoring of CNAs currently developed can be uniformly applied across platforms, affording robust validation of genomic imbalance and complexity in DLBCL and overall clinical utility as biomarkers of patient outcome.


Asunto(s)
Variación Genética , Genómica , Linfoma de Células B Grandes Difuso/genética , Sitios de Carácter Cuantitativo , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Ciclofosfamida/uso terapéutico , Variaciones en el Número de Copia de ADN , Doxorrubicina/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica , Pruebas Genéticas , Genómica/métodos , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Prednisona/uso terapéutico , Pronóstico , Rituximab , Transducción de Señal , Transcriptoma , Vincristina/uso terapéutico
8.
Stem Cells Dev ; 23(10): 1149-56, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24383669

RESUMEN

MicroRNAs (miRNAs) regulate myriad biological processes; however, their role in cell fate choice is relatively unexplored. Pluripotent NT2/D1 embryonal carcinoma cells differentiate into an epithelial/smooth muscle phenotype when treated with bone morphogenetic protein-2 (BMP-2). To identify miRNAs involved in epithelial cell development, we performed miRNA profiling of NT2/D1 cells treated with BMP-2 at 6, 12, and 24 h, and on days 6 and 10. Integration of the miRNA profiling data with previously obtained gene expression profiling (GEP) data of NT2/D1 cells treated with BMP-2 at the same time points identified miR-18b and miR-518b as the top two miRNAs with the highest number of up-regulated predicted targets with known functions in epithelial lineage development. Silencing of miR-18b and miR-518b in NT2/D1 cells revealed several up-regulated TFs with functions in epithelial lineage development; among these, target prediction programs identified FOXN1 as the only direct target of both miRNAs. FOXN1 has previously been shown to play an important role in keratinocyte differentiation and epithelial cell proliferation. NT2/D1 and H9 human embryonic stem cells with silenced miR-18b and miR-518b showed up-regulation of FOXN1 and the epithelial markers CDH1, EPCAM, KRT19, and KRT7. A 3'UTR luciferase assay confirmed FOXN1 to be a target of the two miRNAs, and up-regulation of FOXN1 in NT2/D1 cells led to the expression of epithelial markers. Overexpression of the two miRNAs in BMP-2-treated NT2/D1 cells led to down-regulation of FOXN1 and epithelial lineage markers. These results show that miR-18b and miR-518b are upstream controllers of FOXN1-directed epithelial lineage development.


Asunto(s)
Diferenciación Celular/fisiología , Células Epiteliales/metabolismo , Factores de Transcripción Forkhead/biosíntesis , MicroARNs/metabolismo , Células Madre Pluripotentes/metabolismo , Línea Celular , Proliferación Celular/fisiología , Regulación hacia Abajo/fisiología , Células Epiteliales/citología , Factores de Transcripción Forkhead/genética , Humanos , MicroARNs/genética , Células Madre Pluripotentes/citología , Regulación hacia Arriba/fisiología
9.
Leuk Lymphoma ; 55(4): 920-8, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24047479

RESUMEN

Array comparative genomic hybridization (aCGH) has yet to be fully leveraged in a prognostic setting in chronic lymphocytic leukemia (CLL). Genomic imbalance was assessed in 288 CLL specimens using a targeted array. Based on 20 aberrations in a hierarchical manner, all 228 treatment-naive specimens were classified into a group with poor outcome (20.6%) exhibiting at least one aberration that was univariately associated with adverse outcome (gain: 2p, 3q, 8q, 17q, loss: 7q, 8p, 11q, 17p, 18p), good outcome (32.5%) showing 13q14 loss without any of the other 10 aberrations (gain: 1p, 7p, 12, 18p, 18q, 19, loss: 4p, 5p, 6q, 7p) or intermediate outcome (remainder). The three groups were significantly separated with respect to time to first treatment and overall survival (p < 0.001), and validation of the stratification scheme was performed in two independent datasets. Gain of 3q and 8q, and 17p loss were determined to be independent unfavorable prognostic biomarkers. TP53, NOTCH1 and SF3B1 mutations correlated with the presence of one poor outcome aCGH marker, at a considerably higher frequency than when only considering poor risk aberrations routinely detected by fluorescence in situ hybridization (FISH). These data support genomic imbalance evaluation in CLL by aCGH to assist in risk stratification.


Asunto(s)
Aberraciones Cromosómicas , Genómica , Leucemia Linfocítica Crónica de Células B/genética , Biomarcadores de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Par 13 , Hibridación Genómica Comparativa , Conjuntos de Datos como Asunto , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Mutación , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Pronóstico
10.
Cancer Res ; 70(23): 9682-92, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20952505

RESUMEN

Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast-like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well-characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell.


Asunto(s)
Carcinoma de Células Renales/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/genética , Miofibroblastos/metabolismo , Adulto , Animales , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Metilación de ADN , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Mesodermo/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Metástasis de la Neoplasia , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Trasplante Heterólogo , Células Tumorales Cultivadas
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