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1.
PLoS Pathog ; 11(10): e1005158, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26468873

RESUMEN

Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.


Asunto(s)
Linfoma de Burkitt/genética , Linfoma de Burkitt/virología , Infecciones por Virus de Epstein-Barr/virología , Citomegalovirus/aislamiento & purificación , Análisis Mutacional de ADN , Enfermedades Endémicas , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Inmunohistoquímica , Reacción en Cadena de la Polimerasa , ARN Viral/análisis , ARN Viral/genética , Uganda
2.
Blood ; 125(20): e14-22, 2015 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-25827832

RESUMEN

Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.


Asunto(s)
Transformación Celular Viral , Linfoma Relacionado con SIDA/etiología , Virus Oncogénicos , Infecciones Tumorales por Virus/complicaciones , Análisis por Conglomerados , Estudios de Cohortes , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Regulación Viral de la Expresión Génica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Linfoma Relacionado con SIDA/patología , Virus Oncogénicos/genética , Virus Oncogénicos/inmunología
3.
BMC Cancer ; 15: 668, 2015 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-26453442

RESUMEN

BACKGROUND: The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. METHODS: We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. CONCLUSIONS: Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer.


Asunto(s)
Linfoma de Burkitt/genética , Metilasas de Modificación del ADN/genética , Regulación Neoplásica de la Expresión Génica , Genes myc , Translocación Genética , Linfoma de Burkitt/metabolismo , Análisis por Conglomerados , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , Amplificación de Genes , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , Familia de Multigenes , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Transcriptoma
4.
Blood ; 117(13): 3596-608, 2011 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-21245480

RESUMEN

Burkitt lymphoma (BL) is classified into 3 clinical subsets: endemic, sporadic, and immunodeficiency-associated BL. So far, possible differences in their gene expression profiles (GEPs) have not been investigated. We studied GEPs of BL subtypes, other B-cell lymphomas, and B lymphocytes; first, we found that BL is a unique molecular entity, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. Second, we found that BL subtypes presented slight differences in GEPs. Particularly, they differed for genes involved in cell cycle control, B-cell receptor signaling, and tumor necrosis factor/nuclear factor κB pathways. Notably, by reverse engineering, we found that endemic and sporadic BLs diverged for genes dependent on RBL2 activity. Furthermore, we found that all BLs were intimately related to germinal center cells, differing from them for molecules involved in cell proliferation, immune response, and signal transduction. Finally, to validate GEP, we applied immunohistochemistry to a large panel of cases and showed that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In conclusion, our study provided substantial insights on the pathobiology of BLs, by offering novel evidences that may be relevant for its classification and possibly future treatment.


Asunto(s)
Linfoma de Burkitt/clasificación , Linfoma de Burkitt/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Animales , Linfoma de Burkitt/metabolismo , Línea Celular Tumoral , Análisis por Conglomerados , Humanos , Ratones , Ratones Desnudos , Análisis por Micromatrices , Trasplante de Neoplasias , Fenotipo , Trasplante Heterólogo
5.
Blood ; 115(18): 3726-36, 2010 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-20061561

RESUMEN

Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.


Asunto(s)
Apoptosis , Linfocitos B/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas Adaptadoras de la Señalización Shc/metabolismo , Animales , Western Blotting , Estudios de Casos y Controles , Supervivencia Celular , Metilación de ADN , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcr/genética , Proteínas Proto-Oncogénicas c-bcr/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src
6.
Hematol Oncol ; 29(3): 111-5, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21922507

RESUMEN

Lymphomas represent one of the most frequent cancer types in Africa. In particular, approximately 30,000 non-Hodgkin lymphomas occur in the equatorial belt of Africa each year and these tumours are in among the top-ten cancers in this geographical region. Several pathogens and environmental factors have been detected in association with these tumours, suggesting that they may contribute to lymphomagenesis. Unfortunately, there are still striking differences between developed and African countries in terms of early detection, diagnosis and treatment of lymphomas. Of note, the disease burden appears to be increasing in Africa. In addition, a much lower cure rate in the low-income countries suggests that the difference in mortality will even become more pronounced in future. Therefore, improving diagnosis is crucial as without it, neither meaningful research projects nor effective patient management can be instituted. In this review, we will summarize the state-of-the-art of lymphoma epidemiology, pathobiology and therapy, and will highlight the still existing gaps between developed and African countries.


Asunto(s)
Linfoma/epidemiología , África/epidemiología , Femenino , Humanos , Linfoma/patología , Masculino , Resultado del Tratamiento
7.
Semin Diagn Pathol ; 28(2): 178-87, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21842703

RESUMEN

In the past 25 years revelations on the genesis of human cancer have come at an increasing pace. Research on oncogenic infectious agents, especially viruses, has helped us to understand the process of malignant transformation of cells because the cellular events in viral-driven transformation mirror, often brilliantly, basic cellular processes that culminate in cancer, even those not associated with viruses. Infectious agents, especially viruses, account for several of the most common malignancies-up to 20% of all cancers. Some of these cancers are endemic, with a high incidence in certain geographic locations, but sporadic/lower incidence in other parts of the world. Lymphomas arise frequently in association with infectious agents such as Epstein-Barr virus, human immunodeficiency virus, human herpes virus 8, Helicobacter pylori, and hepatitis C virus. In this review, we will focus on the association between infectious agents and lymphomas, with a look at the molecular mechanisms they use to disturb cell regulation and eventually result in cancer.


Asunto(s)
Infecciones Bacterianas/complicaciones , Linfoma/microbiología , Virosis/complicaciones , Humanos
8.
Semin Cancer Biol ; 19(6): 401-6, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19619656

RESUMEN

Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, the first being Burkitt lymphoma. However, the exact mechanism by which EBV promotes oncogenesis is still matter of discussion. A role in EBV-mediated transformation has been proposed for a novel described class of small non-coding RNAs, the microRNAs (miRNAs). EBV encodes viral miRNAs, through which it may interfere with the physiological regulation exterted by cellular miRNAs. In addition, EBV-coded proteins may also disturb the well-orchestrated mechanisms of regulation of cellular function. In this review, we will focus on the role of EBV in malignant transformation of Burkitt lymphoma, with a particular insight in the interplay between the virus and cellular miRNAs.


Asunto(s)
Linfoma de Burkitt/virología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/fisiología , MicroARNs/metabolismo , Animales , Humanos
9.
J Cell Physiol ; 223(1): 143-50, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20039270

RESUMEN

RB loss has long been recognized as the causative genetic alteration underlying retinoblastoma but it is increasingly evident that other alterations are required for the tumor to develop. Therefore, we set out to identify additional inheritable susceptibility markers and new potential preventive and therapeutic targets for retinoblastoma. We focused on the p16INK4A tumor suppressor gene because of its possible role in retinoblastoma pathogenesis and its involvement in predisposition to familial cancer. p16INK4A expression was analyzed in tumor samples from retinoblastoma patients by immunohistochemistry and in peripheral blood cells from both patients and their parents by real-time quantitative reverse transcription-PCR (qRT-PCR). Since promoter methylation is a common mechanism regulating p16INK4A expression, the methylation status of its promoter was also analyzed in blood samples from patients and their parents by methylation-specific PCR. A downregulation of p16INK4A was observed in 55% of retinoblastoma patients. Interestingly, in 56% of the cases showing p16INK4A downregulation at least one of the patients' parents bore the same alteration in blood cells. Analysis of p16INK4A promoter methylation showed hypermethylation in most patients with p16INK4A downregulation and in the parents with the same alteration in p16INK4A expression. The finding that p16INK4A was downregulated both in patients and their parents suggests that this alteration could be a novel inheritable susceptibility marker to retinoblastoma. The observation that p16INK4A downregulation seems to be due to its promoter hypermethylation opens the way for the development of new preventive and therapeutic strategies using demethylating agents.


Asunto(s)
Biomarcadores de Tumor/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas , Neoplasias de la Retina/genética , Retinoblastoma/genética , Biomarcadores de Tumor/análisis , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Regulación hacia Abajo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Lactante , Masculino , Linaje , Fosforilación , ARN/análisis , Neoplasias de la Retina/química , Neoplasias de la Retina/patología , Retinoblastoma/química , Retinoblastoma/patología , Proteína de Retinoblastoma/análisis , Proteína p130 Similar a la del Retinoblastoma/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo
10.
Int J Cancer ; 126(6): 1316-26, 2010 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19530237

RESUMEN

Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.


Asunto(s)
Linfocitos B/metabolismo , Linfoma de Burkitt/genética , Diferenciación Celular , MicroARNs/genética , Procesamiento Postranscripcional del ARN , Adolescente , Adulto , Linfocitos B/patología , Linfocitos B/virología , Western Blotting , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Línea Celular Tumoral , Niño , Preescolar , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Masculino , Persona de Mediana Edad , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción del Factor Regulador X , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box , Adulto Joven
11.
Hematol Oncol ; 28(1): 20-6, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19728399

RESUMEN

A particular extra-nodal lymphoma type arises from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT). The aetiology of MZ lymphomas suggests that they are associated with chronic antigenic stimulation by microbial pathogens, among which Helicobacter pylori-associated gastric MALT lymphoma is the best studied. Recently, MALT lymphomas have been described in the context of chronic conjunctivitis, which can be associated with Chlamydia spp. infection. Studies from Italy showed the presence of Chlamydia psittaci in 87% of ocular adnexal lymphomas (OAL), and C. psittaci has been described in a large part of samples from Austria and Korea as well. However, this finding was not always confirmed by other studies, suggesting that the association with C. psittaci may depend on geographic heterogeneity. Interestingly, none of the studies up to now has been carried out in the African population, where a strong association between infectious agents and the occurrence of human neoplasms has been reported. This study was designed to investigate the possible association of Chlamydia psittaci in cases retrieved from Kenya, compared to cases from Italy. Our results showed that there was a marked variation between the two geographical areas in terms of association with C. psittaci, as 17% (5/30) of the samples from Italy were positive for C. psittaci, whereas no association with this pathogen was observed in any of the African samples (0/9), suggesting that other cofactors may determine the OAL occurrence in those areas. OAL cases are often characterized by down-regulation of p16/INK4a expression and promoter hypermethylation of the p16/INK4a gene. Our results showed a partial methylation of p16/INK4a promoter in C. psittaci-negative cases, whereas no hypermethylation of this gene was found in C. psittaci-positive cases, suggesting that mechanisms other than promoter hypermethylation lead to p16/INK4a silencing in C. psittaci-positive cases. We may conclude that the role of epidemiologic, environmental and genetic factors, must be considered in the aetiology of this disease.


Asunto(s)
Chlamydophila psittaci/genética , Chlamydophila psittaci/aislamiento & purificación , Infecciones Bacterianas del Ojo/microbiología , Neoplasias del Ojo/microbiología , Linfoma de Células B de la Zona Marginal/microbiología , Psitacosis/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Bacteriano/análisis , Regulación hacia Abajo , Ensayo de Cambio de Movilidad Electroforética , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Italia , Kenia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas
13.
J Cell Physiol ; 216(3): 576-82, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18546201

RESUMEN

Adult skeletal muscle contains a specialized population of myogenic quiescent stem cells, termed satellite cells, which contribute to repair myofibers after injury. During muscle regeneration, satellite cells exit their normal quiescent state, proliferate, activating MyoD and Myf-5 expression, and finally differentiate and fuse to reconstitute the injured muscle architecture. We have previously reported that cdk9 is required for myogenesis in vitro by activating MyoD-dependent transcription. In myoblasts induced to differentiate, MyoD recruits cdk9 on the chromatin of muscle-specific regulatory regions. This event correlates with chromatin-modifying enzyme recruitment and phosphorylation of cdk9-specific target residues at the carboxyl-terminal domain of RNA polymerase II. Here we report that a second cdk9 isoform, termed cdk9-55, plays a fundamental role in muscle regeneration and differentiation in vivo. This alternative form is specifically induced in injured myofibers and its activity is strictly required for the completion of muscle regeneration process.


Asunto(s)
Quinasa 9 Dependiente de la Ciclina/metabolismo , Desarrollo de Músculos/fisiología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Isoformas de Proteínas/metabolismo , Regeneración/fisiología , Células Madre/fisiología , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Quinasa 9 Dependiente de la Ciclina/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/citología , Músculo Esquelético/citología , Músculo Esquelético/fisiología , Proteína MioD/genética , Proteína MioD/metabolismo , Isoformas de Proteínas/genética , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/metabolismo , Células Madre/citología
14.
J Cell Physiol ; 215(1): 276-82, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18205180

RESUMEN

Cdk9/Cyclin T1 complex is very important in controlling specific differentiative pathways of several cell types. Limited data are available regarding the expression of Cdk9/Cyclin T1 in hematopoietic and lymphoid tissues. Cdk9/Cyclin T1 expression seems to be related to particular stages of lymphoid differentiation/activation. In this study, we observed that the expression level of Cdk9/Cyclin T1 in vivo increases in memory B cells compared to naïve B cells, and in activated B cells, compared to non-activated ones. The expression level of the Cdk9/Cyclin T1 complex does not increase in cells induced to differentiate in vitro. In addition, we showed that Cdk9 interacts with E12 and E47, specifically activated during Germinal Center (GC) reaction. Taken together this data suggests an active role for the Cdk9/Cyclin T1 complex during lymphoid differentiation through germinal center reaction.


Asunto(s)
Linfocitos B/citología , Linfocitos B/enzimología , Diferenciación Celular , Quinasa 9 Dependiente de la Ciclina/metabolismo , Ciclinas/metabolismo , Activación de Linfocitos/inmunología , Linfocitos B/metabolismo , Supervivencia Celular , Ciclina T , Quinasa 9 Dependiente de la Ciclina/genética , Ciclinas/genética , Regulación de la Expresión Génica , Centro Germinal/enzimología , Humanos , Células Jurkat , Ganglios Linfáticos/enzimología , Microscopía Confocal , Unión Proteica , Transporte de Proteínas , Factores de Transcripción TCF/metabolismo , Proteína 1 Similar al Factor de Transcripción 7
15.
Blood Lymphat Cancer ; 8: 33-45, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-31360092

RESUMEN

Since its discovery in 1958, Burkitt lymphoma (BL) has been extensively studied and has become a model for tumorigenesis, but its pathogenesis has not been completely explained and understood yet. The aim of this review was to summarize the current knowledge about BL and, in particular, to discuss the role of miRNAs in its pathogenesis and their possible use as diagnostic and prognostic indicators. The impact of viral-encoded miRNAs is also discussed, with the Epstein-Barr infection being almost invariably detected in the endemic variant of this tumor.

16.
Oncology ; 72(3-4): 243-7, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-18185018

RESUMEN

OBJECTIVES: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. METHODS: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. RESULTS: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). CONCLUSIONS: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.


Asunto(s)
Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Cadherinas/genética , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Linaje , Estudios Retrospectivos
17.
Leuk Lymphoma ; 48(10): 2014-21, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17917969

RESUMEN

Vascular Endothelial Growth Factor (VEGF)-D is a member of the VEGF family of angiogenic growth factors that activate the Vascular Endothelial Growth Factor Receptor (VEGFR)-2 and VEGFR-3, which are mainly expressed in blood and lymphatic vessels. Here we have analyzed by using monoclonal antibodies, the expression of VEGF-D and its cognate receptor VEGFR-3 in normal and pathologic bone marrow and lymph node biopsies. This analysis revealed that VEGF-D is expressed in B cells of the germinal centers, scattered B and T blasts, myeloid progenitors, acute leukemia, several types of non Hodgkin lymphoma, and classical Hodgkin's lymphoma. In normal tissues VEGFR-3 was only expressed in fenestrated capillaries of bone marrow and in lymphatic vessels of lymph nodes, while in VEGF-D expressing tumors newly formed vessels, but not malignant cells, showed high VEGFR-3 expression. These data suggest that VEGF-D could contribute to leukemia and lymphoma growth via the induction of angiogenesis in bone marrow and lymphoid tissues.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Linfocitos/metabolismo , Factor D de Crecimiento Endotelial Vascular/biosíntesis , Anticuerpos Monoclonales/química , Biopsia , Células de la Médula Ósea/metabolismo , Línea Celular Tumoral , Células HL-60 , Humanos , Células K562 , Ganglios Linfáticos/patología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo
18.
Front Microbiol ; 8: 229, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28298901

RESUMEN

Epstein-Barr virus (EBV) is a gammaherpesvirus linked to a number of lymphoid and epithelial malignancies, including Burkitt lymphoma (BL) in which its frequency ranges from 30% in sporadic cases to 100% in the endemic ones. The possible contribution of EBV to BL pathogenesis is largely unknown. It has been suggested that EBV may be associated with all of the cases, including those diagnosed as EBV negative by a mechanism of hit-and-run. Early during oncogenesis, viral genes are essential for initiating disease. Progressively, viral genome is lost to escape the immune system and host mutations accumulate in proto-oncogenic cell. The main problem with the hit-and-run hypothesis is the lack of evidence in primary tumors. The routine methods applied to detect the virus [i.e., immunohistochemistry and EBV-encoded RNAs (EBER) in situ hybridization (ISH)] have a low specificity and accuracy. The aim of this study was to identify the most suitable method to detect EBV infection in pathology samples by applying conventional and non-conventional methods (i.e., EBV-microRNAs detection and EBV viral load measurement). We investigated a total of 10 cases and we found that all the samples (n = 6) diagnosed as EBV negative by immunohistochemistry and EBER-ISH demonstrated the presence of EBV-microRNAs and EBV genome. This points at the possibility that EBV might have contributed to lymphomagenesis in all our patients, and propose microRNAs detection as the most specific and sensitive tool to recognize EBV vestiges. It is worth noting that our data would have considerable implications for EBV-related diseases control. By using anti-EBV vaccines, one could potentially prevent also some cancers less suspected of a viral origin because of viral genome loss.

19.
Cancer Biol Ther ; 5(4): 371-4, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16627973

RESUMEN

RUNX3 is the oldest known gene in the RUNX family. Data have demonstrated its function to be thoroughly involved the neurogenesis of the dorsal root ganglia, T-cell differentiation and tumorigenesis of gastric epithelium. As a TGF-beta target, RUNX3 protein is believed to be involved in TGF-beta-mediated tumor suppressor pathway; however, little is known about its role in apoptosis. According to recent data reported by Yamamura et al., (J Biol Chem 2006; 281:5267-76), RUNX3 interacts with FoxO3a/FKHRL1 expressed in gastric cancer cells to activate Bim and induce apoptosis. The cooperation between RUNX3 and the PI3K/Akt signaling pathway component FoxO3a/FKHRL1 suggests the putative role of RUNX3 in the homoeostasis of gastric cells and in stomach cancer control. Here we discuss recent breakthroughs in our understanding of the mechanisms of RUNX3 in gastric malignancy and comment on possible future trends and perspectives.


Asunto(s)
Apoptosis , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/fisiología , Genes Supresores de Tumor , Neoplasias Gástricas/genética , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Epitelio/metabolismo , Mucosa Gástrica/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Modelos Biológicos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Gástricas/metabolismo
20.
J Hypertens ; 24(9): 1831-40, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16915033

RESUMEN

OBJECTIVE: We evaluated maternal and fetal plasma levels and placental mRNA expression of urocortin, a placental vasoactive neuropeptide, in singleton pregnancies (n = 70) complicated by hypertensive disorders classified as gestational hypertension (n = 36), pre-eclampsia (n = 19), and pre-eclampsia complicated by intrauterine growth restriction (PE/IUGR, n = 15), and in 70 healthy normotensive singleton pregnancies. METHODS: Plasma levels were assayed by radioimmunoassay, fetal biometry by ultrasound scans, utero-placental and fetal perfusion by Doppler velocimetry, and placental urocortin mRNA expression by quantitative real time reverse transcriptase-polymerase chain reaction. The main outcome measures were the correlation of urocortin concentrations with patterns of the utero-placental and fetal circulation, and the early prediction of a poor neonatal outcome such as the occurrence of perinatal death and intraventricular hemorrhage. RESULTS: Maternal and fetal urocortin levels were significantly (both P < 0.001) higher in gestational hypertension, pre-eclampsia and PE/IUGR women than in controls, and correlated with Doppler velocimetry patterns. Fetal concentrations were significantly (P < 0.0001) higher than and significantly (P < 0.0001) correlated to maternal levels. Placental mRNA expression did not change. Ten out of 140 newborns had a poor neonatal outcome, with an overall prevalence of 7.14% (pretest probability). Using the receiver operator characteristics curve analysis cut-off values, the probability of a poor neonatal outcome was 66.7% when urocortin was used, and was 0% if levels were unaltered. CONCLUSIONS: Maternal and fetal urocortin levels are increased in hypertensive disorders of pregnancy. Since urocortin has vasoactive properties, the evidence of increased urocortin levels in hypertensive disorders may represent an adaptive fetal response.


Asunto(s)
Hormona Liberadora de Corticotropina/sangre , Hipertensión Inducida en el Embarazo/sangre , Preeclampsia/sangre , Complicaciones Cardiovasculares del Embarazo , Adulto , Biometría , Hormona Liberadora de Corticotropina/biosíntesis , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Retardo del Crecimiento Fetal/genética , Humanos , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismo , Curva ROC , Radioinmunoensayo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento , Ultrasonografía Doppler , Urocortinas
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