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1.
Adv Exp Med Biol ; 1225: 127-135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030652

RESUMO

Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) constitute the human γ-herpesviruses and two of the seven human tumor viruses. In addition to their viral oncogenes that primarily belong to the latent infection programs of these viruses, they encode proteins that condition the microenvironment. Many of these are early lytic gene products and are only expressed in a subset of infected cells of the tumor mass. In this chapter I will describe their function and the evidence that targeting them in addition to the latent oncogenes could be beneficial for the treatment of EBV- and KSHV-associated malignancies.


Assuntos
Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/patogenicidade , Neoplasias/tratamento farmacológico , Neoplasias/virologia , Oncogenes , Microambiente Tumoral , Replicação Viral , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/genética , Herpesvirus Humano 8/efeitos dos fármacos , Herpesvirus Humano 8/genética , Humanos , Oncogenes/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
2.
Cancer Sci ; 111(1): 72-83, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691433

RESUMO

Capn4, also known as CapnS1, is a member of the calpain family, which plays a crucial role in maintaining the activity and function of calpain. We previously reported that Capn4 also plays an essential role in the migration of nasopharyngeal carcinoma (NPC) cells through regulation of (MMP-2) by nuclear factor-kappa B activation. Epstein-Barr virus latent membrane protein 1 (LMP1) is closely related to the malignant functions of NPC; however, the relationship between LMP1 and Capn4 in NPC remain unclear. Immunohistochemical studies showed that the level of LMP1 and Capn4 expression was high in both primary and metastatic NPC tissues, with a significantly positive correlation. We further found that LMP1 was able to upregulate the Capn4 promoter in a dose-dependent way through the C-terminal activation region (CTAR)1 and CTAR2 domains to activate AP-1. Moreover, we also found that LMP1 activated AP-1 through ERK/JNK phosphorylation. These findings indicate that Capn4 coordination with LMP1 promotes actin rearrangement and, ultimately, cellular migration. These results show that Capn4 coordination with LMP1 enhances NPC migration by increasing actin rearrangement involving ERK/JNK/AP-1 signaling. Therapeutically, additional and more specific LMP1 and Capn4 targeted inhibitors could be exploited to treat NPC.


Assuntos
Calpaína/genética , Sistema de Sinalização das MAP Quinases/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica/genética , Fator de Transcrição AP-1/genética , Proteínas da Matriz Viral/genética , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/patogenicidade , Humanos , NF-kappa B/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Metástase Neoplásica/patologia , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Regulação para Cima/genética
3.
Cancer Sci ; 111(1): 279-287, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743514

RESUMO

Epstein-Barr virus (EBV) is a well-established tumor virus that has been implicated in a wide range of immunodeficiency-associated lymphoproliferative disorders (LPDs). Although rituximab, a CD20 mAb, has proven effective against EBV-associated LPDs, prolonged use of this drug could lead to resistance due to the selective expansion of CD20- cells. We have previously shown that cyclin-dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins; however, the therapeutic effect of CDK inhibitors against EBV-associated LPDs is not clear. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with alsterpaullone, an inhibitor of the CDK2 complex, resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1 cell cycle arrest and apoptosis in EBV-positive B cells. These results suggest that alsterpaullone suppresses cell cycle progression, resulting in the antitumor effect observed in vivo.


Assuntos
Antineoplásicos/farmacologia , Benzazepinas/farmacologia , Herpesvirus Humano 4/patogenicidade , Indóis/farmacologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/virologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Fase G1/efeitos dos fármacos , Células HEK293 , Humanos , Transtornos Linfoproliferativos/genética , Camundongos , Camundongos Endogâmicos NOD
4.
Int J Cancer ; 146(1): 181-191, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31090066

RESUMO

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.


Assuntos
Citidina Desaminase/genética , DNA de Neoplasias/genética , Herpesvirus Humano 4/patogenicidade , Neoplasias Gástricas/virologia , Carcinogênese , Genes Virais , Herpesvirus Humano 4/genética , Humanos , Mutação , Neoplasias Gástricas/patologia
5.
Virchows Arch ; 475(6): 757-762, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673776

RESUMO

Epstein-Barr virus (EBV) has been associated with about 9% of all gastric carcinomas, but its role in gastric carcinogenesis remains unclear since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa. This study intends to determine the prevalence of EBV in gastric dysplasia and superficial neoplasia to clarify whether EBV infection is an early or late event in gastric cancer development. This retrospective study included a total of 242 gastric lesions from 199 consecutive patients who were referred for endoscopic resection. The histological classification of lesions includes 137 low- and high-grade dysplasia and 105 superficial carcinomas. EBV infection was investigated by EBER-ISH. Results showed that EBV was not detected in any epithelial cells of any case with dysplasia or superficial carcinomas, although we observed the presence of a small number of EBV-infected lymphocytes in 2.1% of all lesions. These results showed that EBV is not present in gastric dysplasia neither in superficial carcinomas suggesting that EBV carcinogenesis is a late event in well/moderately differentiated gastric carcinogenesis.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/patogenicidade , Neoplasias Gástricas/virologia , Estômago/virologia , Idoso , Carcinoma/patologia , Carcinoma/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Feminino , Mucosa Gástrica/patologia , Mucosa Gástrica/virologia , Humanos , Hibridização In Situ/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estômago/patologia , Neoplasias Gástricas/patologia
6.
PLoS Pathog ; 15(9): e1008030, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31518366

RESUMO

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival.


Assuntos
Linfócitos B/virologia , Ácidos Graxos/biossíntese , Herpesvirus Humano 4/patogenicidade , Ácido Mevalônico/metabolismo , Alquil e Aril Transferases/metabolismo , Linfócitos B/patologia , Proliferação de Células , Sobrevivência Celular , Colesterol/biossíntese , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Redes e Vias Metabólicas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteínas Virais/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
7.
Virus Genes ; 55(6): 779-785, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31552622

RESUMO

Epstein-Barr virus (EBV) is a widely prevalent pathogen currently infecting over 90% of the human population and is associated with various lymphomas and carcinomas. Lytic replication of EBV is regulated by the expression of the immediate-early genes BZLF1 and BRLF1. In B lymphocytes, BZLF1 transcripts have been shown to be processed to a fully spliced form, as well as zDelta, a spliced variant containing only the first and third exons. While splice variants have been reported in nasopharyngeal carcinoma biopsies, alternative splicing of BZLF1 in EBV-positive epithelial cell lines has not yet been characterized. In this study, we identified the consistent expression of three distinct BZLF1 transcripts in the EBV-positive epithelial cell lines D98/HR1, AGS-BDneo, and AGS-BX1. These BZLF1 transcripts consisted of not only the normally spliced variant but also a completely unspliced and a spliced variant containing exons one and three only. In contrast, we detected only the normally spliced version of the BZLF1 transcript in B-cell lines (B95-8, IM-9, Raji and Daudi). Previous work has also demonstrated that inhibition of the mTOR pathway, via rapamycin, altered total levels of BZLF1 transcripts. We examined the production of specific transcript variants under rapamycin treatment and found that rapamycin alters the production of transcripts in a cell-type, as well as transcripts in variant-type, manners. The expression of these transcript variants may play a role in modulating the replication cycle of EBV within epithelial cells.


Assuntos
Células Epiteliais/virologia , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Transativadores/genética , Linfócitos B/virologia , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Infecções por Vírus Epstein-Barr/virologia , Regulação Viral da Expressão Gênica/genética , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/patogenicidade , Humanos , Regiões Promotoras Genéticas/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Ativação Viral/genética , Latência Viral/genética
8.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370144

RESUMO

Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein-Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Indóis/farmacologia , Oximas/farmacologia , Ubiquitina Tiolesterase/genética , Proteínas da Matriz Viral/genética , Antineoplásicos/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Indóis/química , Micelas , Boca/metabolismo , Boca/patologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Nasofaringe/metabolismo , Nasofaringe/patologia , Oxazóis/química , Oximas/química , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Proteínas da Matriz Viral/metabolismo
9.
Anticancer Res ; 39(8): 4003-4010, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366481

RESUMO

Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is classified as one of four GC subtypes by comprehensive molecular characterization. Though the mechanism of tumorigenesis by EBV infection has not yet been fully clarified, EBV infection might contribute to the malignant transformation of GC cells by involving various cellular processes and signaling pathways. EBVaGC has shown the following distinct characteristics in contrast to other subtypes: extreme DNA hypermethylation, recurrent phosphatidylinositol 4,5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutations, overexpression of programmed cell death ligand 1/2 (PD-L1/2), and occasional immune cell signaling activation. Therefore, using these molecular features as guides, targeted agents need to be evaluated in clinical trials for EBVaGC. Accordingly, this review uses the best available evidence to focus on novel therapeutic approaches using the distinct pathologic characteristics of EBVaGC patients.


Assuntos
Carcinogênese/genética , Infecções por Vírus Epstein-Barr/terapia , Neoplasias Gástricas/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Metilação de DNA/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/virologia
10.
World Neurosurg ; 130: 165-169, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299306

RESUMO

BACKGROUND: Ossified chronic subdural hematoma (CSH) associated with neoplasm has rarely been reported in the literature. We describe a patient with ossified CSH and underlying large B-cell lymphoma and discuss the relationship between lymphoma and CSH, emphasizing clinical characteristics, tumorigenic mechanism, and histopathologic analysis. CASE DESCRIPTION: A 46-year-old man with a history of alcohol abuse and a right frontotemporoparietal and left frontal ossified CSH that was diagnosed 2 years previously presented with headache and memory loss over 6 days. The patient was being followed with serial imaging, which showed the static state of the mass and no other lesions 7 months before admission. He underwent right frontotemporoparietal craniectomy to remove the ossified CSH and tumor. When the bone was lifted and the thin dura was opened, a hard, thick, ossified capsule was observed. No apparent tumor invasion was noted in the skull or epidural space. Despite refusing further chemotherapy and radiation therapy, the patient has been disease-free and working for 5 years. CONCLUSIONS: Based on reported cases and relevant literature, large B-cell lymphoma may be associated with ossified CSH.


Assuntos
Dura-Máter/cirurgia , Hematoma Subdural Crônico/cirurgia , Linfoma de Células B/virologia , Linfoma/cirurgia , Calcinose/complicações , Calcinose/cirurgia , Dura-Máter/patologia , Dura-Máter/virologia , Hematoma Subdural Crônico/complicações , Hematoma Subdural Crônico/diagnóstico , Herpesvirus Humano 4/patogenicidade , Humanos , Linfoma/complicações , Linfoma/virologia , Linfoma de Células B/diagnóstico , Linfoma de Células B/cirurgia , Masculino , Pessoa de Meia-Idade
11.
Cancer Biomark ; 25(3): 259-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282408

RESUMO

BACKGROUND: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. METHODS: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. RESULTS: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). CONCLUSIONS: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.


Assuntos
Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/genética , Linfoma/genética , Neuropilina-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Imuno-Histoquímica , Linfoma/classificação , Linfoma/patologia , Linfoma/virologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
12.
Int J Cancer ; 145(9): 2468-2477, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265124

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are prevalent in sub-Saharan Africa, together with HIV; the consequent burden of disease is grave. The cofactors driving transmission of the two viruses and pathogenesis of associated malignancies are not well understood. We measured KSHV and EBV DNA in whole blood and saliva as well as serum antibodies levels in 175 Cameroonians with Kaposi's sarcoma and 1,002 age- and sex-matched controls with and without HIV. KSHV seroprevalence was very high (81%) in controls, while EBV seroprevalence was 100% overall. KSHV DNA was detectable in the blood of 36-46% of cases and 6-12% of controls; EBV DNA was detected in most participants (72-89%). In saliva, more cases (50-58%) than controls (25-28%) shed KSHV, regardless of HIV infection. EBV shedding was common (75-100%); more HIV+ than HIV- controls shed EBV. Cases had higher KSHV and EBV VL in blood and saliva then controls, only among HIV+ participants. KSHV and EBV VL were also higher in HIV+ than in HIV- controls. Cases (but not controls) were more likely to have detectable KSHV in blood if they also had EBV, whereas shedding of each virus in saliva was independent. While EBV VL in saliva and blood were modestly correlated, no correlation existed for KSHV. Numerous factors, several related to parasitic coinfections, were associated with detection of either virus or with VL. These findings may help better understand the interplay between the two gammaherpesviruses and generally among copathogens contributing to cancer burden in sub-Saharan Africa.


Assuntos
Infecções por HIV/sangue , Infecções por HIV/virologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/patogenicidade , Saliva/virologia , Sarcoma de Kaposi/sangue , Sarcoma de Kaposi/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Camarões , Estudos de Casos e Controles , Coinfecção/sangue , Coinfecção/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto Jovem
13.
J Clin Pathol ; 72(10): 651-658, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31315893

RESUMO

Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity. EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit. Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.


Assuntos
Antivirais/uso terapêutico , Suplementos Nutricionais , Infecções por Vírus Epstein-Barr/virologia , Genoma Viral/genética , Herpesvirus Humano 4/fisiologia , Vitaminas , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/psicologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Estresse Psicológico , Ativação Viral/efeitos dos fármacos , Latência Viral , Replicação Viral/efeitos dos fármacos
14.
Future Oncol ; 15(24): 2873-2885, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31342783

RESUMO

Despite the numerous publications regarding the role of Epstein-Barr virus (EBV) in breast cancer development, the topic has still remained controversial. The aim of the meta-analysis was to estimate the overall prevalence of EBV in the breast cancer population, and to investigate the association between EBV and breast cancer risk. The overall prevalence of EBV was calculated 26.37% (95% CI: 22-31%) from the 44 included studies. Meta-analysis of 30 case-control studies showed that the pooled association between EBV and risk of breast cancer is odds ratio 4.74 (95% CI: 2.92-7.69; Z = 6.30; p < 0.0001). Our analyses indicate a strong statistical relationship between EBV infection and risk of breast cancer, suggesting a potential role of EBV infection in the development of breast cancer.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/virologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/patogenicidade , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Razão de Chances , Prevalência
15.
PLoS Pathog ; 15(7): e1007458, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283782

RESUMO

Natural variation separates Epstein-Barr virus (EBV) into type 1 and type 2 strains. Type 2 EBV is less transforming in vitro due to sequence differences in the EBV transcription factor EBNA2. This correlates with reduced activation of the EBV oncogene LMP1 and some cell genes. Transcriptional activation by type 1 EBNA2 can be suppressed through the binding of two PXLXP motifs in its transactivation domain (TAD) to the dimeric coiled-coil MYND domain (CC-MYND) of the BS69 repressor protein (ZMYND11). We identified a third conserved PXLXP motif in type 2 EBNA2. We found that type 2 EBNA2 peptides containing this motif bound BS69CC-MYND efficiently and that the type 2 EBNA2TAD bound an additional BS69CC-MYND molecule. Full-length type 2 EBNA2 also bound BS69 more efficiently in pull-down assays. Molecular weight analysis and low-resolution structures obtained using small-angle X-ray scattering showed that three BS69CC-MYND dimers bound two molecules of type 2 EBNA2TAD, in line with the dimeric state of full-length EBNA2 in vivo. Importantly, mutation of the third BS69 binding motif in type 2 EBNA2 improved B-cell growth maintenance and the transcriptional activation of the LMP1 and CXCR7 genes. Our data indicate that increased association with BS69 restricts the function of type 2 EBNA2 as a transcriptional activator and driver of B cell growth and may contribute to reduced B-cell transformation by type 2 EBV.


Assuntos
Proteínas de Transporte/metabolismo , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Linfócitos B/metabolismo , Linfócitos B/virologia , Sítios de Ligação/genética , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular , Transformação Celular Viral/genética , Transformação Celular Viral/fisiologia , Antígenos Nucleares do Vírus Epstein-Barr/química , Genes Virais , Herpesvirus Humano 4/classificação , Herpesvirus Humano 4/patogenicidade , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Modelos Moleculares , Mutação , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Transativadores/química , Transativadores/genética , Transativadores/metabolismo , Proteínas Virais/química
16.
Pathol Int ; 69(7): 407-413, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215109

RESUMO

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed-Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS-like cells and numerous macrophages. The HRS-like cells were infected with Epstein-Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B-cell markers other than PAX5 were negative, and the HRS-like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified and EBV-positive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV-positive large B-cell neoplasms with reactive inflammatory cells and sometimes contains HRS-like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV-positive large B-cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.


Assuntos
Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Idoso , Linfócitos B/patologia , Linfócitos B/virologia , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/patologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/virologia , Humanos , Imunofenotipagem/métodos , Linfoma Difuso de Grandes Células B/diagnóstico , Masculino , Células de Reed-Sternberg/patologia , Células de Reed-Sternberg/virologia
17.
PLoS One ; 14(6): e0218660, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242229

RESUMO

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.


Assuntos
Hiperplasia do Linfonodo Gigante/virologia , Herpesvirus Humano 8/isolamento & purificação , Adulto , Idoso , Estudos de Casos e Controles , Hiperplasia do Linfonodo Gigante/etiologia , Hiperplasia do Linfonodo Gigante/patologia , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Reações Falso-Negativas , Feminino , Genoma Viral , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/patogenicidade , Humanos , Linfonodos/patologia , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Viroses/complicações , Viroses/virologia
18.
Pathol Res Pract ; 215(8): 152472, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174925

RESUMO

Gastric cancer (GC) is the third leading cause of cancer mortality worldwide, with an overall 5-y survival rate of 25%. The majority of GCs are caused by infectious agents, including the bacterium Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV). Furthermore, inappropriate repair of DNA damage can also result in genomic instability, which has shown to be a key factor in carcinogenesis of different regions including gastric region. Present study was designed to explore the association between base excision repair pathway genes, PARP1 and APEX1 and gastric pathology and H. pylori infection. Two hundred gastric cancer tissue samples (114 H. pylori positive and 86 H. pylori negative) and adjacent uninvolved area taken as controls was used for expression analysis of BER pathway genes at mRNA level and protein levels using quantitative PCR (qPCR) and immunohistochemistry (IHC) respectively. Oxidative stress and DNA damage was also determined by measuring the level of antioxidant enzymes and comet assay respectively. Significant upregulation in PARP1 (p < 0.001) and APEX1 (p < 0.02) was observed in GC tissue samples compared to controls and this upregulation was more pronounced in H. pylori positive cases (HPGC) (PARP1, p < 0.02: APEX1, p < 0.04) than H. pylori negative cases (HNGC). Upregulation of BER pathway genes in HPGC was found correlated with smoking status (p < 0.0001), T stage (p < 0.01) and lymph node metastasis (p < 0.03). Moreover, immunohistochemical staining of BER pathway genes was found correlated with a number of clinicopathological characteristics such as tumor type (p < 0.03), tumor size (p < 0.01) and lymph node metastasis (p < 0.01). Expression levels of APEX1 and PARP1 gene also correlated with increased oxidative burden (p < 0.0001) and DNA damage (p < 0.001) in GC patients. Survival analysis showed that upregulation of PARP1 gene was associated with poor overall survival outcome of gastric cancer patients (HR = 2.04 (95% CI = 1.10-3.76; p < 0.02). Univariate and multivariate cox regression analysis showed the upregulated PARP1 gene (HR = 5.03; 95%CI (2.22-11.35); p = 0.0001), positive smoking status (HR = 3.58; 95%CI (1.67-7.65); p = 0.001), positive status for H pylori infection (HR = 4.38; 95%CI (1.82-10.56); p = 0.001) and advance N-stage (HR = 5.29; 95%CI (2.28-12.24); p = 0.0001) were independent prognostic factors for gastric cancer and may serve as a valuable biomarker for the diagnosis and progression of GC and can be helpful in developing individualized treatment strategies for treating GC.


Assuntos
Metástase Linfática/patologia , Poli(ADP-Ribose) Polimerase-1/genética , Neoplasias Gástricas/patologia , Estômago/patologia , Adulto , Idoso , Biomarcadores/análise , Infecções por Vírus Epstein-Barr/virologia , Feminino , Infecções por Helicobacter/microbiologia , Herpesvirus Humano 4/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estômago/virologia , Neoplasias Gástricas/virologia
19.
Pediatr. aten. prim ; 21(82): e67-e70, abr.-jun. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-184588

RESUMO

La infección por el virus de Epstein-Barr (VEB) es habitual y generalmente ocurre en la infancia o en la adultez temprana. El VEB es la etiología de la mononucleosis infecciosa, generalmente asociada con fiebre, dolor de garganta, inflamación de los ganglios linfáticos en el cuello y en ocasiones esplenomegalia. El síndrome de Alicia en el País de las Maravillas (SAPM) o síndrome de Todd es una afección rara, que principalmente afecta la integración visual y somatoestética. El SAPM sigue siendo un síndrome poco conocido y probablemente mal diagnosticado, puede ocurrir a cualquier edad, pero sobre todo en los niños en los que se asocia principalmente con la migraña y la infección por VEB. Presentamos a una paciente de diez años que acudió al servicio de urgencias con distorsión visual de la forma corporal y comportamiento extraño, sospechado inicialmente como una patología psiquiátrica pero posteriormente diagnosticado con mononucleosis infecciosa e infección por VEB confirmada serológicamente. Este caso refleja la importancia de reconocer este síndrome por parte de los médicos de urgencias y evitar derivaciones inadecuadas al servicio psiquiátrico


Infection with Epstein-Barr virus (EBV) is common and usually occurs in childhood or early adulthood. EBV is the cause of infectious mononucleosis, usually associated with fever, sore throat, swollen lymph nodes in the neck, and sometimes an enlarged spleen. Alice in Wonderland Syndrome (AIWS), also called Todd's syndrome, is a rare condition, principally involving visual and somesthetic integration. AIWS remains a poorly known and probably misdiagnosed syndrome, can occur at any age but mostly in children is mostly associated with migraine and EBV infection. We present a 10-year-old patient who went to the emergency department with visual distortion of corporal form and bizarre behaviour, initially suspected as a psychiatric pathology but subsequently diagnosed with infectious mononucleosis and serologically confirmed Epstein-Barr virus (EBV) infection. This case reflects the importance of recognizing this syndrome by emergency physicians in order to avoid inadequate referrals to the psychiatric service


Assuntos
Humanos , Gravidez , Criança , Síndrome de Alice no País das Maravilhas/diagnóstico , Mononucleose Infecciosa/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Síndrome de Alice no País das Maravilhas/complicações , Mononucleose Infecciosa/complicações , Herpesvirus Humano 4/patogenicidade , Infecções por Vírus Epstein-Barr/complicações , Acetaminofen/uso terapêutico , Ibuprofeno/uso terapêutico
20.
Ann Hematol ; 98(8): 1877-1883, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144019

RESUMO

Secondary poor graft function (sPGF) is defined as secondary cytopenia after initial engraftment of allogeneic stem cell transplantation (allo-SCT). It has been shown to be associated with poor prognosis; however, there are very few reports on the incidence, risk factors, and outcomes of sPGF. Between January 2015 and December 2015, 564 patients, who received transplantation at Peking University People's Hospital, were retrospectively reviewed. Among the 490 patients who achieved initial engraftment of both neutrophils and platelets, 28 patients developed sPGF. The cumulative incidence of sPGF on day 100 was 5.7%. The median time of sPGF was 54.5 (34-91) days after transplantation. Low (< median) CD34+ cell dose (p = 0.019, HR 3.07 (95% CI, 1.207-7.813)), Epstein-Barr Virus (EBV) reactivation (p = 0.009, HR 3.648 (95%CI, 1.382-9.629)), and cytomegalovirus (CMV) reactivation (p = 0.003, HR 7.827 (95%CI, 2.002-30.602)) were identified as independent risk factors for sPGF. There was no significant difference in PGF incidence between the matched sibling donor (MSD) group and haploidentical donor (HID) group (p = 0.44). The overall survival of patients with sPGF at 1 year after transplantation was significantly poorer than that of patients with good graft function (GGF) (50.5% versus 87.2%, p < 0.001). In conclusion, sPGF developed in 5.7% patients after allo-SCT, especially in patients with CMV, EBV reactivation, or infusion with a low dose of CD34+ cells. The prognosis of sPGF is still poor owing to a lack of standard treatment.


Assuntos
Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Ativação Viral/imunologia , Adolescente , Adulto , Idoso , Antígenos CD34/imunologia , Criança , Pré-Escolar , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/patologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Feminino , Sobrevivência de Enxerto/fisiologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/virologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Humanos , Leucemia/mortalidade , Leucemia/patologia , Leucemia/virologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/virologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Haploidêntico
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