2,802 results
Search Results
2. Overview of virus and cancer relationships. Position paper
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O Fernández-Capetillo, D Gracia, Joaquín Arribas, M Martín Jiménez, Rafael Bañares, M B Barragán, J.M. Eiros Bouza, J Tovar, Emilio Bouza, Luis Paz-Ares, A Torné, E Valencia, L Alemany, P Muñoz, Esteban Palomo, E Felip, J Bautista Mollar, and Rogelio López-Vélez
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Microbiology (medical) ,HPV ,Oncolytic virus ,viruses ,Review ,Cancer mortality ,Hepatitis C. HBV ,Virus ,Tumours ,EBV ,Neoplasms ,Tumor Virus ,Humans ,Medicine ,Papillomaviridae ,HHV-8 ,Tropism ,Cancer ,Pharmacology ,Vaccines ,business.industry ,Human Papillomavirus ,HIV ,virus diseases ,Oncogenes ,General Medicine ,Hepatitis B ,medicine.disease ,Virology ,Cancer-prevention ,Human T Lymphotropic Virus I ,Virus Diseases ,HTLV-1 ,Human Herpes Virus 8 ,HCV ,Etiology ,Position paper ,Oncogenic Viruses ,Cancer-economy ,business ,Epstein-Barr Virus ,Human Immunodeficiency Virus ,Biomedical sciences - Abstract
The role of certain viruses in the etiology of some tumors is today indisputable, but there is a lack, however, of annoverview of the relationship between viruses and cancer with amultidisciplinary approach. For this reason, the Health Sciences Foundation has convened a group of professionals from different areas of knowledge to discuss the relationship between viruses and cancer, and the present document is the result of these deliberations. Although viruses cause only 10-15% of cancers, advances in oncology research are largely due to the work done during the last century on tumor viruses. The clearest cancer-inducing viruses are: HPV, HBV, HCV, EBV and, depending on the geographical area, HHV-8, HTLV-1 and HIV. HPVs, for example, are considered to be the causative agents of cervical carcinomas and, more recently, of a proportion of other cancers. Among the Herpes viruses, the association with the development of neoplasms is well established for EBV and HHV-8. Viruses can also be therapeutic agents in certain neoplasms and, thus, some oncolytic viruses with selective tropism for tumor cells have been approved for clinical use in humans. It is estimated that the prophylaxis or treatment of viral infections could prevent at least 1.5 million cancer deaths per year.
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- 2021
3. Paper-based detection of Epstein-Barr virus using asymmetric polymerase chain reaction and gold silicon particles.
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Chen, Haoze, Lin, Shoujia, Wang, Yongxia, Fu, Shuqi, Ma, Yueting, Xia, Qianfeng, and Lin, Yingzi
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POLYMERASE chain reaction , *EPSTEIN-Barr virus , *NUCLEIC acids , *AVIDIN , *STREPTAVIDIN , *QUALITY control , *SILICA - Abstract
A new paper-based lateral flow nucleic acid (LFNA) test platform was established in this study using asymmetric polymerase chain ceaction (A-PCR) for signal amplification. This new method allowed a visual detection of Epstein-Barr virus (EBV) nucleic acids with high specificity and low cost. In addition, as part of our strategy we employed a sandwich system of capture probe (CP)/gold nanoparticles (AuNPS) and silicon dioxide (SiO2) (AuNPS@SiO2) nanospheres/target DNA/avidin complexes as the sensing platform. Biotin-labeled target DNA was obtained by A-PCR and later introduced in the LF device. The CP/target DNA/AuNPS@SiO2 complexes were captured on the test zone by the specific reaction between biotin and avidin, and the remaining CP/AuNPS@SiO2 particles were captured on the quality control zone by the hybridization between CP and a quality control probe. Au@SiO2 accumulation in the test and quality control zones of the device enabled a visual detection of the specific target sequences. The method detection limit was 50 nM of the target DNA, which was lower than that of the LFNA biosensor (LFNAB) without PCR amplification and Au@SiO2 particles. In conclusion, the novel paper-based platform described here is a low cost, efficient and fast visual detection method that offers high sensitivity and other benefits compared to alternative methods in use. [Display omitted] • This visual detection system is suitable in low-resource settings. • This new method allowed a visual detection of EBV nucleic acids with high specificity and low cost. • Au@SiO2 can load more capture probes due to its large specific surface area and good biological activity. • Asymmetric PCR using biotinylated primers produced a large number of biotinylated target sequences. • Compared with antibody detection, the nucleic acid detection in this paper has higher specificity. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Original paper Evaluation of the role of Epstein-Barr virus in cases of nodal or extranodal T- and NK-cell lymphoma using eber in situ hybridization
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Serap Karaarslan, Mine Hekimgil, Basak Doganavsargil, Yeşim Ertan, and Saliha Soydan
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Pathology ,medicine.medical_specialty ,business.industry ,T cell ,General Medicine ,In situ hybridization ,medicine.disease ,medicine.disease_cause ,Epstein–Barr virus ,Virology ,Virus ,Pathology and Forensic Medicine ,Lymphoma ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Virus latency ,Medicine ,business ,NODAL ,Epstein–Barr virus infection - Abstract
Various racial and geographic differences have been observed in studies questioning the role of Epstein-Barr virus (EBV) infection in the etiology of T- and NK-cell lymphomas. The aim of this study was to evaluate the relationship of EBV with nodal or extranodal (skin excluded) T- and NK-cell lymphoma subtypes encountered in our geographic area. Sixty-two cases of peripheral T-cell lymphoma were included in the study. EBV-encoded early RNA (EBER) was detected by in situ hybridization. The distributions of T- and NK-cell lymphoma subtypes were as follows: 32 peripheral T-cell lymphomas, unspecified (PTCL, NOS), 13 anaplastic large-cell lymphomas (ALCL), 8 angioimmunoblastic T-cell lymphomas (AITCL), 4 extranodal NK/T-cell lymphomas, nasal type (NKTCL), 3 enteropathy-type T-cell lymphomas (ETTCL), 1 hepatosplenic T-cell lymphoma (HSTCL), and 1 subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Using a cut-off value of >25% of EBER-positive neoplastic lymphoid cells, EBV was positive in 22.6% of all cases. According to subtype, the neoplastic cells of 31.3% of PTCL, NOS and 100% of extranodal NKTCL, nasal type were EBER positive, whereas some cases of ALCL, AITCL, and ETTCL presented EBER-positive non‑neoplastic cells, and all cells of HSTCL and SPTCL were EBV negative. Extranodal NKTCL, nasal type, presented the strongest association with EBV, followed by PTCL, NOS.
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- 2015
5. Sequence variations of Epstein--Barr virus LMP1 gene in gastric cancer and chronic gastritis isolates from Iranian patients.
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Sarshari, Behrang, Mohebbi, Seyed Reza, Ravanshad, Mehrdad, Shahrokh, Shabnam, and Aghdaei, Hamid Asadzadeh
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STOMACH tumors ,SEQUENCE analysis ,BIOPSY ,DNA ,PAPER chromatography ,MICROBIAL genetics ,GASTRITIS ,GENETIC variation ,EPSTEIN-Barr virus ,DESCRIPTIVE statistics ,POLYMERASE chain reaction - Abstract
Aim: The current study aimed to investigate sequence variations in the C-terminus of latent membrane protein 1 (LMP1) in Epstein- Barr virus (EBV) isolates from Iranian patients with chronic gastritis or gastric cancer (GC). Background: LMP1, an essential viral oncoprotein, is the critical element in the immortalization of B cells. It contains a small twenty-four amino acid cytoplasmic N-terminal region, six transmembrane segments, and a two hundred amino acid cytoplasmic Cterminal domain. Most LMP1-mediated signal transduction events are moderated by some functional parts of the cytoplasmic Cterminal domain. Methods: Thirty-two EBV-positive biopsy tissues were obtained from patients with gastric cancer and patients with chronic gastritis. The C-terminal nucleotide sequences of LMP1 were amplified using nested-PCR and analyzed by DNA sequencing. Results Four to eight copies of the 11 repeat elements (codon 254--302) were observed in the carboxyl-terminal site of patients, but no relationship was found between the number of repeat sequences and disease status. The 30-bp deletion corresponding to codon 345--354 of the B95-8 strain was observed in 34% of isolates, and the remaining samples were non-deleted. In the gastric cancer group, a higher number of 33-bp repeats (≥5 repeats) was observed in 30-bp-deletion (100%) than in non-deleted (42%) isolates, and the difference was statistically significant. Analysis revealed that a gastritis isolate may be the result of recombination between Alaskan and China1 strains. Conclusion: Overall, the current results showed no association between C-terminal sequence variations of LMP1 and malignant or non-malignant isolate origin. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Overview of virus and cancer relationships. Position paper.
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Bouza, Emilio, Martín Jiménez, Miguel, Alemany, Laia, Arribas, Joaquín, Bañares, Rafael, Barragán, Maria Begoña, Eiros Bouza, José María, Felip, Enriqueta, Fernández-Capetillo, Oscar, Gracia, Diego, López-Vélez, Rogelio, Bautista Mollar, Juan, Muñoz, Patricia, Paz-Ares, Luis, Torné, Aureli, Tovar, Javier, Valencia, Eulalia, and Palomo, Esteban
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TUMORS ,VIRUSES ,CANCER ,PAPILLOMAVIRUSES ,HEPATITIS B ,HEPATITIS C ,EPSTEIN-Barr virus - Abstract
Copyright of Revista Española de Quimioterapia is the property of Sociedad Espanola de Quimioterapia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2021
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7. The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit selective autophagy
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Päivi Ylä-Anttila, Soham Gupta, and Maria G. Masucci
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0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,viruses ,SQSTM1/p62 ,Biology ,Transfection ,medicine.disease_cause ,Deubiquitinating enzyme ,Selective autophagy ,Protein Aggregates ,03 medical and health sciences ,EBV ,Macroautophagy ,Sequestosome-1 Protein ,Autophagy ,medicine ,Humans ,Viral Regulatory and Accessory Proteins ,Molecular Biology ,large tegument protein ,Huntingtin Protein ,Deubiquitinating Enzymes ,Host Microbial Interactions ,030102 biochemistry & molecular biology ,Ubiquitination ,Cell Biology ,Epstein–Barr virus ,Cell biology ,deubiquitinase ,030104 developmental biology ,Mutation ,biology.protein ,Microtubule-Associated Proteins ,Research Article ,Research Paper ,HeLa Cells - Abstract
Macroautophagy/autophagy plays an important role in the control of viral infections and viruses have evolved multiple strategies to interfere with autophagy to avoid destruction and promote their own replication and spread. Here we report that the deubiquitinase encoded in the N-terminal domain of the Epstein-Barr virus (EBV) large tegument protein, BPLF1, regulates selective autophagy. Mass spectrometry analysis identified several vesicular traffic and autophagy related proteins as BPLF1 interactors and potential substrates, suggesting that the viral protein targets this cellular defense during productive infection. Direct binding of BPLF1 to the autophagy receptor SQSTM1/p62 (sequestosome 1) was confirmed by co-immunoprecipitation of transfected BPLF1 and by in vitro affinity isolation of bacterially expressed proteins. Expression of the catalytically active BPLF1 was associated with decreased SQSTM1/p62 ubiquitination and failure to recruit LC3 to SQSTM1/p62-positive aggregates. Selective autophagy was inhibited as illustrated by the accumulation of large protein aggregates in BPLF1-positive cells co-transfected with an aggregate-prone HTT (huntingtin)-Q109 construct, and by a slower autophagy-dependent clearance of protein aggregates upon transfection of BPLF1 in cells expressing a tetracycline-regulated HTT-Q103. The inhibition of aggregate clearance was restored by overexpression of a SQSTM1/p62[E409A,K420R] mutant that does not require ubiquitination of Lys420 for cargo loading. These findings highlight a previously unrecognized role of the viral deubiquitinase in the regulation of selective autophagy, which may promote infection and the production of infectious virus. Abbreviations: BPLF1, BamH1 fragment left open reading frame-1; EBV, Epstein-Barr virus; GFP, green fluorescent protein; HTT, huntingtin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; PB1, Phox and Bem1 domain; PE, phosphatidylethanolamine; SQSTM1/p62, sequestosome 1; UBA, ubiquitin-associated domain
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- 2021
8. A novel vaccine candidate based on chimeric virus-like particle displaying multiple conserved epitope peptides induced neutralizing antibodies against EBV infection
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Qi Sheng Feng, Mingmei Ding, Qinjian Zhao, Mu Sheng Zeng, Bingchun Zhao, Claude Krummenacher, Yi Xin Zeng, Ling Gao, Yinfeng Kang, Miao Xu, Yang Yu, Shuo Song, Tong Xiang, and Xiao Zhang
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0301 basic medicine ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,medicine.drug_class ,Conserved epitope peptide ,Recombinant Fusion Proteins ,Medicine (miscellaneous) ,Envelope glycoprotein ,Monoclonal antibody ,medicine.disease_cause ,Antibodies, Viral ,Epitope ,Viral Matrix Proteins ,03 medical and health sciences ,gp350 ,Epitopes ,Mice ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Epstein-Barr virus ,Animals ,030212 general & internal medicine ,Neutralizing antibody ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Mice, Inbred BALB C ,Vaccines ,biology ,Immunogenicity ,Vaccination ,Virology ,Fusion protein ,Epstein–Barr virus ,Antibodies, Neutralizing ,030104 developmental biology ,HBc149 ,Immunoglobulin G ,Chimeric virus-like particle ,biology.protein ,Immunization ,Antibody ,Peptides ,Research Paper - Abstract
Rationale: Epstein-Barr virus (EBV) is the causative pathogen for infectious mononucleosis and many kinds of malignancies including several lymphomas such as Hodgkin's lymphoma, Burkitt's lymphoma and NK/T cell lymphoma as well as carcinomas such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBV-GC). However, to date no available prophylactic vaccine was launched to the market for clinical use. Methods: To develop a novel vaccine candidate to prevent EBV infection and diseases, we designed chimeric virus-like particles (VLPs) based on the hepatitis B core antigen (HBc149). Various VLPs were engineered to present combinations of three peptides derived from the receptor binding domain of EBV gp350. All the chimeric virus-like particles were injected into Balb/C mice for immunogenicity evaluation. Neutralizing titer of mice sera were detected using an in vitro cell model. Results: All chimeric HBc149 proteins self-assembled into VLPs with gp350 epitopes displayed on the surface of spherical particles. Interestingly, the different orders of the three epitopes in the chimeric proteins induced different immune responses in mice. Two constructs (149-3A and 149-3B) induced high serum titer against the receptor-binding domain of gp350. Most importantly, these two VLPs elicited neutralizing antibodies in immunized mice, which efficiently blocked EBV infection in cell culture. Competition analysis showed that sera from these mice contained antibodies to a major neutralizing epitope recognized by the strong neutralizing mAb 72A1. Conclusion: Our data demonstrate that HBc149 chimeric VLPs provide a valuable platform to present EBV gp350 antigens and offer a robust basis for the development of peptide-based candidate vaccines against EBV.
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- 2020
9. Epstein-Barr virus miR-BART1-3p suppresses apoptosis and promotes migration of gastric carcinoma cells by targeting DAB2
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Kyoungmi Min, Suk Kyeong Lee, and Jun Yeob Kim
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Untranslated region ,cell migration ,Blotting, Western ,DAB2 ,Apoptosis ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,03 medical and health sciences ,BART miRNA ,Cell Movement ,microRNA ,medicine ,Epstein-Barr virus ,Humans ,RNA, Small Interfering ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,Wound Healing ,Cell growth ,Chemistry ,Cell migration ,Cell Biology ,Transfection ,Epstein–Barr virus ,Molecular biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,cell proliferation ,HEK293 Cells ,Carcinogenesis ,Apoptosis Regulatory Proteins ,Developmental Biology ,Research Paper - Abstract
Although Epstein-Barr virus (EBV) is known to encode over 40 different miRNAs of its own, the roles of most EBV miRNAs remain unknown. Disabled homolog 2 (DAB2) is a putative tumor suppressor, but its role in gastric carcinoma (GC), especially in EBV-associated GC, needs to be clarified. Our qRT-PCR and mRNA microarray results showed that DAB2 expression was down-regulated in EBV-positive GC cells compared to EBV-negative cells. Four BART miRNAs that might target DAB2 were predicted, and we found, using a luciferase reporter assay, that miR-BART1-3p directly targeted the 3'-UTR of DAB2. The miR-BART1-3p transfection decreased DAB2 expression at both mRNA and protein levels, while transfection of an inhibitor of miR-BART1-3p, miR-BART1-3p(i), increased DAB2 expression. In addition, miR-BART1-3p as well as siDAB2 increased migration and decreased apoptosis. Meanwhile, miR-BART1-3p(i) or pcDNA3.1-DAB2 transfection decreased migration and increased apoptosis in EBV-infected GC cells. Furthermore, decreased migration by miR-BART1-3p(i) was abrogated by co-transfected siDAB2, while decreased migration by miR-BART1-3p(i) was further suppressed by a co-transfected DAB2 over-expression vector. Our data suggest that miR-BART1-3p plays an important role in the tumorigenesis of EBV-associated GC by directly targeting DAB2.
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- 2020
10. EB virus-positive tumors are inhibited by rBCG expressing hGM-CSF and LMP2A
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Hong-Hua Zhang, Qing-Jie Xue, Ting Chen, Shuang Wang, Shigen Li, Hui Wang, Xiu-Zhen Li, Yingchun Yan, Ang Liu, Yuan-Yuan Yang, Longyu Zhao, and Yunqing Li
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Signal peptide ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Tuberculosis ,Eb virus ,Recombinant Fusion Proteins ,030231 tropical medicine ,Immunology ,medicine.disease_cause ,complex mixtures ,Virus ,law.invention ,Mice ,03 medical and health sciences ,0302 clinical medicine ,law ,Neoplasms ,hemic and lymphatic diseases ,medicine ,Animals ,Immunology and Allergy ,030212 general & internal medicine ,Pharmacology ,Bacillus (shape) ,biology ,Granulocyte-Macrophage Colony-Stimulating Factor ,biology.organism_classification ,medicine.disease ,Virology ,Epstein–Barr virus ,Recombinant DNA ,bacteria ,Research Paper - Abstract
For the development of safe and effective EBV (Epstein-Barr virus) vaccines, the Ag85A signal peptide from M. tuberculosis H37Rv was used to construct a recombinant secretory BCG (Bacillus Chalmette-Guérin) plasmid. The Ag85A gene, fused to the EBV LMP2A (latent membrane protein) and hGM-CSF (human granulocyte/macrophage colony-stimulating factor) genes, was inserted into the pMV261 vector (secretory BCG plasmid). The expression levels of the hGM-CSF and LMP2A proteins in rBCG (recombinant BCG) were measured by Western blot analysis. Humoral immunity, cellular immunity, and antitumor effects were determined by a series of experiments. The recombinant pMVGCA plasmid effectively expressed GCA (hGM-CSF and LMP2A fusion protein) in BCG after transformation, and the rBCG proteins were recognized by antibodies against hGM-CSF and LMP2A. Six weeks after immunization, the maximum dose of rBCG resulted in antibody titers of 1:19,800 (hGM-CSF antibody) and 1:21,800 (LMP2A antibody). When the effector:target ratio was 40:1, specific lysis was maximal and approximately two times stronger than that in mice immunized with the control. Tumorigenicity was lower in the rBCG treatment group, with a tumor inhibition rate of 0.81 ± 0.09 compared with the control groups. EB virus-positive tumors are inhibited by rBCG expressing an hGM-CSF and LMP2A fusion protein.
- Published
- 2019
11. Epstein-Barr virus circRNAome as host miRNA sponge regulates virus infection, cell cycle, and oncogenesis
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Wenjie Yang, Xuequn Zhao, Jun Liu, and Yan-Wei Qiao
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Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Carcinogenesis ,lcsh:Biotechnology ,Population ,Bioengineering ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Virus ,Circrna ,03 medical and health sciences ,0302 clinical medicine ,EBV ,oncogenesis ,lcsh:TP248.13-248.65 ,hemic and lymphatic diseases ,microRNA ,medicine ,cancer ,Humans ,education ,Gene ,030304 developmental biology ,miRNA ,0303 health sciences ,education.field_of_study ,herpes virus ,Cell Cycle ,General Medicine ,RNA, Circular ,Cell cycle ,Epstein–Barr virus ,Virology ,MicroRNAs ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,RNA, Viral ,Oncovirus ,Biotechnology ,Research Paper - Abstract
Epstein-Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world’s population. The proteins and miRNAs encoded by EBV are involved in multiple human malignancies. Recently R-resistance RNA-seq demonstrated that EBV-encoded circular RNAs. The current research aims to explore their functions in EBV-associated malignancies. Total 56 miRNAs were sponged by circRNAome. 24 and 9 in EBV host B and epithelial cells out of 56 miRNAs were detectable by miRNA-seq. 18 and 5 miRNAs were down-regulated in both types of host cells, respectively, after EBV infection. The network between five miRNAs and their targets included 1414 genes, 1419 nodes, and 2423 edges. These targets were enriched in multiple categories, and most of them were up-regulated in EBV-infected cells. These data represented the first report that EBV circRNAs could sponge the miRNAs to promote the up-regulated expression of their targets, involving in malignancies associated with EBV., Graphical Abstract
- Published
- 2019
12. Epstein-Barr Virus Lytic Transcripts Correlate with the Degree of Myocardial Inflammation in Heart Failure Patients.
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Baumeier, Christian, Harms, Dominik, Altmann, Britta, Aleshcheva, Ganna, Wiegleb, Gordon, Bock, Thomas, Escher, Felicitas, and Schultheiss, Heinz-Peter
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EPSTEIN-Barr virus ,HEART failure patients ,T cells ,INFLAMMATION ,NUCLEOTIDE sequencing ,IMMUNOSTAINING ,GENETIC transcription - Abstract
The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3
+ T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment. [ABSTRACT FROM AUTHOR]- Published
- 2024
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13. 基于“浊邪害清”理论探讨鼻咽癌的病因病机及治法.
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杜炎远, 朱潇雨, 高劲, 于惠博, 熊宏泰, 陈欣, 马苏苏, and 郑红刚
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EPSTEIN-Barr virus ,NASOPHARYNX cancer ,CHINESE medicine ,QING dynasty, China, 1644-1912 ,BLOOD flow ,NASAL polyps ,HEAT stroke - Abstract
Copyright of Journal of Beijing University of Traditional Chinese Medicine is the property of Journal of Beijing University of Traditional Chinese Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2023
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14. An autoantigen-ome from HS-Sultan B-Lymphoblasts offers a molecular map for investigating autoimmune sequelae of COVID-19.
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Wang, Julia Y., Zhang, Wei, Roehrl, Victor B., Roehrl, Michael W., and Roehrl, Michael H.
- Abstract
To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID autoantigens (autoAgs). Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs) of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. Furthermore, B-cell-specific IgM-associated endoplasmic reticulum (ER) complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design. This paper investigates the autoantigenic proteome ('autoantigen-ome') of human B cells and shows that a large fraction of these DS-binding autoantigens is affected during SARS-CoV-2 infection, giving rise to a diverse pool of autoAgs that may lead to infection-induced autoimmune diseases. The COVID autoantigen-ome provided in this paper may serve as a molecular map and resource for investigating autoimmune phenomena of SARS-CoV-2 infection and its long-term sequelae. Understanding immunogenic proteins of COVID may also enhance vaccine target design. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Activation of sterol regulatory element‐binding protein 1 (SREBP1)‐mediated lipogenesis by the Epstein–Barr virus‐encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma
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Lo, Angela Kwok‐Fung, Lung, Raymond Wai‐Ming, Dawson, Christopher W, Young, Lawrence S, Ko, Chuen‐Wai, Yeung, Walter Wai, Kang, Wei, To, Ka‐Fai, and Lo, Kwok‐Wai
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Male ,Herpesvirus 4, Human ,Pyridines ,Mice, Nude ,Antineoplastic Agents ,Epstein–Barr virus ,Viral Matrix Proteins ,Cell Line, Tumor ,otorhinolaryngologic diseases ,Animals ,Humans ,Naphthyridines ,Luteolin ,lipogenesis ,LMP1 ,Cell Proliferation ,Original Paper ,Mice, Inbred BALB C ,Nasopharyngeal Carcinoma ,TOR Serine-Threonine Kinases ,Nasopharyngeal Neoplasms ,Lipid Droplets ,Middle Aged ,Original Papers ,Xenograft Model Antitumor Assays ,Fatty Acid Synthase, Type I ,stomatognathic diseases ,Thiazoles ,Disease Progression ,Female ,SREBP1 ,Sterol Regulatory Element Binding Protein 1 ,Signal Transduction - Abstract
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein–Barr virus (EBV) infection. The EBV‐encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element‐binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV‐infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1‐mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1‐mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1‐mediated lipogenesis promotes tumor cell growth and is involved in EBV‐driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
- Published
- 2018
16. Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies
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Qi Sheng Feng, Sai Juan Chen, Mu Sheng Zeng, Tong Xiang, Bing Luo, Lin Feng, Qing Zhu, Yi Xin Zeng, Gui Ping He, You Yuan Yao, Zhao Lei Zeng, Yuchen Jiao, Wei Li Zhao, Zhe Zhang, Shanshan Zhang, Wei Hua Jia, Rou Jun Peng, Miao Xu, Rui-Hua Xu, and Wei Long Zhang
- Subjects
0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Virus Integration ,Medicine (miscellaneous) ,Biology ,medicine.disease_cause ,Genome ,TNFAIP3 ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Gene ,Genetics ,nasopharyngeal carcinoma (NPC) ,Genome, Human ,Sequence Analysis, DNA ,Epstein–Barr virus ,Epstein-Barr virus (EBV) ,030104 developmental biology ,DNA integration ,Genetic Loci ,030220 oncology & carcinogenesis ,DNA, Viral ,Human genome ,Carcinogenesis ,Viral genome replication ,Research Paper - Abstract
Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.
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- 2019
17. A combined marker based on plasma D-dimer and serum albumin levels in patients with nasopharyngeal carcinoma is associated with poor survival outcomes in a retrospective cohort study
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Yong Chen, Chengtao Wang, Yan Wang, Meiyan Zhu, Sha-Sha He, Xing-Li Yang, and Dan-Ming Chen
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0301 basic medicine ,medicine.medical_specialty ,Multivariate analysis ,Serum albumin ,medicine.disease_cause ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,D-dimer ,Nasopharyngeal carcinoma ,medicine ,Platelet ,albumin ,biology ,business.industry ,Albumin ,Retrospective cohort study ,medicine.disease ,Epstein–Barr virus ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,prognosis ,business ,Research Paper - Abstract
Background: Activation of the clotting-fibrinolytic system in cancer patients is common and results in an unfavorable clinical outcome. This study aimed to investigate the role of pretreatment plasma D-dimer levels and the combination of D-dimer and albumin (DA) on the prediction of survival prognosis in patients with nasopharyngeal carcinoma (NPC). Methods: The study comprised 511 patients with NPC. Pretreatment plasma D-dimer and serum albumin levels were measured. DA was classified as a new biomarker where D-dimer and albumin levels were combined and was grouped by the cutoff value of both. The correlations of plasma D-dimer levels with clinicopathological features and survival outcome were calculated using the Chi-square test. Kaplan-Meier estimates were performed to analyze the survival functions and were compared using log-rank tests. Cox proportional hazard regression analysis was used to assess the effects of D-dimer and DA on distant overall survival (OS) and distant metastasis-free survival (DMFS). Results: The median follow-up period was 45.2 months (range 2.1-79.8). Elevated plasma D-dimer levels were positively associated with age at diagnosis (P = 0.034), platelet levels (P = 0.043), and Epstein Barr Virus (EBV) DNA copy number (P = 0.035). Additionally, multivariate analysis demonstrated that elevated plasma D-dimer levels were strongly associated with a poorer OS (HR 2.074, 95% CI 1.190-3.612, P = 0.010), but not DMFS. After adjustment for other variables, DA stratification acted as an independent prognostic marker for OS (P = 0.038) and DMFS (P = 0.031) in patients with NPC, when combined with albumin levels. Conclusions: Increased plasma D-dimer levels accurately predict poor OS and may be an effective independent prognostic factor in patients with NPC. Moreover, in conjunction with serum albumin, DA may serve as a factor in predicting OS and DMFS.
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- 2019
18. EBV miR-BART10-3p Promotes Cell Proliferation and Migration by Targeting DKK1
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Kyoungmi Min and Suk Kyeong Lee
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musculoskeletal diseases ,Untranslated region ,Herpesvirus 4, Human ,cell migration ,Blotting, Western ,Biology ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,BART miRNA ,03 medical and health sciences ,Cell Movement ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,Epstein-Barr virus ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Wound Healing ,0303 health sciences ,DKK1 ,Cell growth ,Microarray analysis techniques ,Cell migration ,Cell Biology ,Transfection ,Epstein–Barr virus ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,cell proliferation ,Tumor progression ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Research Paper ,Developmental Biology - Abstract
In Epstein-Barr virus (EBV)-infected epithelial cancers, BamHI A rightward transcript (BART) miRNAs are highly expressed. However, only a few target genes of BART miRNAs have been investigated. Our mRNA microarray data showed that DKK1 was markedly down-regulated in EBV-associated gastric carcinoma (EBVaGC) cells. Using luciferase reporter assay we tested whether miR-BART10-3p regulates DKK1 by directly targeting the 3'-UTR of DKK1 mRNA. We observed that miR-BART10-3p transfection decreased DKK1 expression, while an LNA inhibitor of miR-BART10-3p (LNA-miR-BART10-3p(i)) increased DKK1 expression. Furthermore, miR-BART10-3p and siDKK1 promoted cell proliferation and migration. In contrast, transfecting GC cells with LNA-miR-BART10-3p(i) or DKK1 over expression vector suppressed cell proliferation and migration. Our results suggest that miR-BART10-3p may be involved in the tumor progression of EBVaGC by targeting DKK1.
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- 2019
19. Natural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma
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Shao Yi Huang, Si Qi Dong, Fang Wang, Mu Jianbing, Jiang Bo Zhang, Tong-Min Wang, Wei Hua Jia, Xi Zhao Li, Yong Qiao He, and Xiao Hui Zheng
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0301 basic medicine ,Male ,China ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Research paper ,BRLF1 ,Variation ,Biology ,medicine.disease_cause ,BZLF1 ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Immediate-Early Proteins ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,medicine ,Epstein-Barr virus ,Humans ,Risk factor ,Promoter Regions, Genetic ,Gene ,Nasopharyngeal Carcinoma ,Haplotype ,Genetic Variation ,Promoter ,Nasopharyngeal Neoplasms ,General Medicine ,medicine.disease ,Reactivation ,Epstein–Barr virus ,030104 developmental biology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Immunology ,Trans-Activators ,Female - Abstract
Background: Epstein-Barr virus (EBV) infection is a crucial risk factor for nasopharyngeal carcinoma (NPC), but the mechanism for its elevated activation level in NPC endemic areas remains unclear. This study aims to identify the EBV natural variations contributed to the different reactivation potential between NPC endemic and non-endemic areas. Methods: 1030 subjects were recruited in China, including 303 healthy individuals from two NPC non-endemic areas, 483 healthy people from three endemic areas and 244 NPC patients. Among which, saliva DNA samples from 244 participants were sequenced for the EBV immediate early (IE) genes of BRLF1 and BZLF1, their promoters were included; the rest 786 subjects were used for the validation of significant variations among three different populations. Haplotype and population structure analysis were conducted. Dual-luciferase assay was used to detect the promoter activity. Results: A total of 246 distinct variations were detected, 29 showed significant difference in the frequencies between healthy people from NPC endemic area and non-endemic area. Population structure analysis clustered EBV strains into 9 subgroups mostly in accordance with the geographical origin of samples. Interestingly, two EBV genotypes, Rp-V1 and Rp-V2, were identified according to the linkage relationship of the variations in BRLF1 promoter (Rp). Rp-V1 has higher frequency in NPC endemic areas than in non-endemic areas (52.38% vs 18.15%, P=2.07×10-14), and was associated with higher oral EBV DNA levels (adjusted OR=1.64, 95% CI=1.21-2.24, P=0.002), suggesting a more powerful activation ability of Rp-V1 than that of the wild type Rp-WT of the EBV strain; On the contrary, Rp-V2 has higher frequency in NPC non-endemic areas than in endemic areas (18.48% vs 0.38%, P=1.17×10-7), might represent a reduced activation potential of EBV. Further dual-luciferase assay showed Rp-V1 has higher promoter activity while compared with Rp-V2 (P
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- 2018
20. Epstein-Barr Virus-Associated Smooth Muscle Tumors of Larynx: A Clinicopathologic Study and Comprehensive Literature Review of 12 Cases
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Rumeal D Whaley and Lester D.R. Thompson
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0301 basic medicine ,Larynx ,Male ,Pathology ,medicine.medical_specialty ,Herpesvirus 4, Human ,Context (language use) ,In situ hybridization ,medicine.disease_cause ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Laryngeal Neoplasms ,Smooth Muscle Tumor ,Original Paper ,business.industry ,Laryngeal Neoplasm ,Middle Aged ,Epstein–Barr virus ,Kidney Transplantation ,Transplant Recipients ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Otorhinolaryngology ,Pleomorphism (cytology) ,030220 oncology & carcinogenesis ,RNA, Viral ,Female ,business - Abstract
Laryngeal mesenchymal neoplasms are rare, with smooth muscle tumors comprising a small subset. Specifically, Epstein-Barr virus (EBV)-associated smooth muscle tumors are exceptionally rare, lacking a comprehensive evaluation of their clinical and histologic features. Two patients (a 59 year old male and 51 year old female) had received renal transplants 156 and 240 months, respectively prior to onset of laryngeal symptoms. Supraglottic polypoid masses were identified and removed conservatively. Histologically, the tumors were hypercellular, showing alternating light and dark areas, the latter composed of primitive appearing round cells, while a more characteristic spindled tumor cell population was noted in the remaining areas. Cytoplasmic vacuoles were noted adjacent to the nucleus. There was no tumor necrosis or pleomorphism, but increased mitotic figures (11–12/2 mm(2)) were seen, without atypical forms. The tumor cells were strongly immunoreactive with smooth muscle actin and smooth muscle myosin heavy chain and with Epstein-Barr virus encoded RNA (EBER) by in situ hybridization. These patients were reviewed in the context of a thorough English literature review, which demonstrates a wide age range at presentation without a sex predilection, but with most patients from specific ethnic groups (Chinese, Thai, Pilipino). Three-quarters of patients are part of multifocal disease and the majority are post-renal transplantation patients. Conservative management seems to yield the best overall outcome for these indolent tumors. In conclusion, EBV-associated smooth muscle tumors should be considered in any immunocompromised patient with a head and neck smooth muscle tumor, especially when EBER is documented by in situ hybridization. Conservative management may be employed, even when multifocal tumors are documented.
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- 2021
21. Requirement for containing etoposide in the initial treatment of lymphoma associated hemophagocytic lymphohistiocytosis
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Yue Song, Jingshi Wang, Zhao Wang, Yini Wang, and Lin Wu
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Cancer Research ,medicine.medical_specialty ,Epstein-Barr Virus Infections ,Lymphoma ,medicine.medical_treatment ,medicine.disease_cause ,Gastroenterology ,Lymphohistiocytosis, Hemophagocytic ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Survival rate ,Etoposide ,Retrospective Studies ,Pharmacology ,Response rate (survey) ,Chemotherapy ,Hemophagocytic lymphohistiocytosis ,business.industry ,Standard treatment ,medicine.disease ,Epstein–Barr virus ,Oncology ,Molecular Medicine ,business ,medicine.drug ,Research Paper - Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status caused by a hereditary or acquired immunoregulatory abnormality. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It has the worst prognosis among sHLH. However, there’s still no standard treatment strategy. The argument mainly focuses on whether an HLH-directed or malignancy-directed approach should initially be adopted. Etoposide is one of the key drugs in HLH treatment, also effective in lymphomas. We sought to identify the importance of containing etoposide in initial treatment, comparing with the chemotherapy which directed at lymphoma but without etoposide. Methods: 66 patients diagnosed as LAHS in our center between Jan 1 2015 and Dec 31 2017 were divided into two groups according to weather the initial treatment containing etoposide, or other lymphoma-directed chemotherapy without etoposide. Results: The remission rate of the initial etoposide group (52 patients) is significantly better than that of no initial etoposide group (14 patients) (73.1% vs. 42.9%, p = 0.033). The relapse occurrence between two groups shows difference (26.3% vs. 50%) but not significant (p = 0.339). There were 28 deaths in patients with initial etoposide (mortality rate 53.8%) and 12 deaths in the without-initial-etoposide group (mortality rate 85.7%). A significant difference in mortality was noted between the two groups (p = 0.030). The 2-month survival (79.8% vs. 46.8%, p = 0.019) and overall survival (median survival time 25.8w vs. 7.6w, p = 0.048) of the initial etoposide contained group is also better. Multivariate cox analysis revealed that for patients without EBV infection (37 cases), initial treatment with etoposide could significantly improve prognosis (p = 0.010, Exp(B) = 0.183), but for patients with positive EBV, it’s not significant. Conclusions: We concluded that containing etoposide is essential in the initial treatment of LAHS, weather using the HLH directed or lymphoma directed strategy. It provides higher response rate, lower mortality rate and better survival, especially for EBV negative patients.
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- 2020
22. A Systematic Review of the Potential Implication of Infectious Agents in Myasthenia Gravis.
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Leopardi, Victoria, Chang, Yu-Mei, Pham, Andrew, Luo, Jie, and Garden, Oliver A.
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MYASTHENIA gravis ,NEURAL transmission ,MYONEURAL junction ,SYMPTOMS ,DIAGNOSIS ,EPSTEIN-Barr virus - Abstract
Background: Myasthenia gravis (MG) is an autoimmune disorder of unknown etiology in most patients, in which autoantibodies target components of neuromuscular junctions and impair nerve to muscle transmission. Objective: To provide a synthesis of the evidence examining infectious agents associated with the onset of MG. Hypothesis: We hypothesized that microbes play a pathogenic role in the initiation of MG. For clinical cases, the onset of clinical signs is used as a proxy for the true onset of autoimmunity. Methods: We searched PubMed and Web of Science. Papers captured through database searching (n = 827) were assessed, yielding a total of 42 publications meeting the inclusion and exclusion criteria. An additional 6 papers were retrieved from the reference lists of relevant articles. For each pathogen, an integrated metric of evidence (IME) value, from minus 8 to plus 8, was computed based on study design, quality of data, confidence of infectious disease diagnosis, likelihood of a causal link between the pathogen and MG, confidence of MG diagnosis, and the number of infected patients. Negative IME values corresponded to studies providing evidence against a role for microbes as triggers of MG. Results: One hundred and sixty-nine myasthenic patients infected with 21 different pathogens were documented. Epstein-Barr virus (median = 4.71), human papillomavirus (median = 4.35), and poliovirus (median = 4.29) demonstrated the highest IME values. The total median IME was 2.63 (mean = 2.53; range −3.79–5.25), suggesting a general lack of evidence for a causal link. Conclusions: There was a notable absence of mechanistic studies designed to answer this question directly. The question of the pathogenic contribution of microbes to MG remains open. [ABSTRACT FROM AUTHOR]
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- 2021
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23. EPSTEIN-BARR VIRUS: CAUSES, CONSEQUENSES, DIAGNOSIS AND TREATMENT OF EPSTEIN-BARR VIRUS IN HUMAN.
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Marko, Koprivica
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EPSTEIN-Barr virus diseases ,AUTOIMMUNE diseases ,THROMBOCYTOPENIA ,HAND washing ,HYGIENE - Abstract
Copyright of Sanamed is the property of Sanamed and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2024
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24. Implementing an On-Slide Molecular Classification of Gastric Cancer: A Tissue Microarray Study.
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Costache, Simona, de Havilland, Rebecca, Diaz McLynn, Sofia, Sajin, Maria, Baltan, Adelina, Wedden, Sarah, and D'Arrigo, Corrado
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STOMACH tumors ,TISSUE arrays ,ONCOGENES ,CYTOSKELETAL proteins ,MOLECULAR biology ,EPITHELIAL-mesenchymal transition ,HISTOLOGICAL techniques ,GENOMICS ,EPSTEIN-Barr virus ,TUMOR markers ,MEMBRANE proteins ,ALGORITHMS - Abstract
Simple Summary: Personalised cancer treatment improves outcome for patients but requires that each individual tumour is classified using molecular tools. Extensive genomic studies for each individual patients are out of reach for the majority of the population, therefore, pathologists need to apply readily available tests to achieve molecular classification for all cancer patients. This paper describes how gastric cancer can be classified using on slide tests already used by histopathologists. Using this classification, oncologists can select more effective treatment for each patient. Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein–Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial–mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Ex-vivo delivery of monoclonal antibody (Rituximab) to treat human donor lungs prior to transplantation
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Deepali Kumar, Shaf Keshavjee, Atul Humar, Terrance J.Y. Ku, Marcelo Cypel, M. Galasso, R. Ribeiro, and Victor H Ferreira
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0301 basic medicine ,Epstein-Barr Virus Infections ,Research paper ,medicine.drug_class ,medicine.medical_treatment ,lcsh:Medicine ,Monoclonal antibody ,General Biochemistry, Genetics and Molecular Biology ,Lymphocyte Depletion ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Preoperative Care ,Medicine ,Lung transplantation ,Humans ,Epstein-Barr virus ,Monoclonal therapy ,Lung ,Ex-vivo lung perfusion ,CD20 ,lcsh:R5-920 ,B-Lymphocytes ,biology ,business.industry ,lcsh:R ,Antibodies, Monoclonal ,General Medicine ,Tissue Donors ,Transplantation ,Perfusion ,030104 developmental biology ,PTLD ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Immunohistochemistry ,Cytokines ,Rituximab ,Antibody ,Inflammation Mediators ,lcsh:Medicine (General) ,business ,Ex vivo ,Biomarkers ,medicine.drug ,Lung Transplantation - Abstract
Background Ex-vivo lung perfusion (EVLP) is an innovative platform for assessing donor lungs in the pre-transplant window. In this study, we demonstrate an extension of its utility by administering the anti-CD20 monoclonal antibody, Rituximab, during EVLP. We hypothesized that this would lead to targeted depletion of allograft B-cells which may provide significant clinical benefit, including the potential to reduce latent Epstein-Barr virus (EBV) and decrease the incidence of post-transplant lymphoproliferative malignancies. Methods Twenty human donor lungs rejected for transplantation were placed on EVLP with (n = 10) or without (n = 10) 500 mg of Rituximab. Safety parameters such as lung physiology and inflammatory cytokines were evaluated. We measured the delivery efficacy through flow cytometry, immunohistochemistry and ELISA. An in-vitro culture assay, in the presence of complement, was further conducted to monitor whether B-cell depletion would occur in Rituximab-perfused samples. Findings Rituximab was successfully delivered to human lungs during EVLP as evidenced by flow cytometric binding assays where lung tissue and lymph node biopsies demonstrated occupied CD20 epitopes after perfusion with the antibody. Lymph nodes from Rituximab perfusions demonstrated a 10.9 fold-reduction in CD20+ staining compared to controls (p = 0.0003). In lung tissue, Rituximab resulted in an 8.75 fold-reduction in CD20+ staining relative to controls (p = 0.0002). This decrease in CD20+ binding illustrates the successful delivery and occupation of epitopes after perfusion with the Rituximab. No apparent safety concerns were seen as exhibited by markers associated with acute cell injury (e.g., proinflammatory cytokines), cell death (e.g., TUNEL staining), or pulmonary physiology. In a post-perfusion tissue culture model, the addition of complement (human serum) resulted in evidence of B-cell depletion consistent with what would be expected with posttransplant activation of bound Rituximab. Interpretation Our experiments illustrate the potential of EVLP as a platform to deliver monoclonal antibody therapies to treat donor lungs pretransplant with the goal of eliminating a latent virus responsible for considerable morbidity after lung transplantation. Funding Supported by the University Health Network Transplant Center.
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- 2020
26. Accumulation of LOX-1
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Xing, Li, Jin-Long, Li, Nan, Jiang, Jie, Chen, Zi-Ming, Liang, Zhen-Lin, Zhao, and Yan-Fang, Xing
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Adult ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Viral Matrix Proteins ,Hepatitis B, Chronic ,Immune Tolerance ,Humans ,Epstein-Barr virus ,chronic hepatitis B ,Aged ,Cell Proliferation ,Nasopharyngeal Carcinoma ,Myeloid-Derived Suppressor Cells ,Nasopharyngeal Neoplasms ,Free Radical Scavengers ,Middle Aged ,Endoplasmic Reticulum Stress ,Prognosis ,Scavenger Receptors, Class E ,polymorphonuclear myeloid-derived suppressor cell ,Acetylcysteine ,lectin-type oxidized LDL receptor-1 ,Epstein-Barr Virus Nuclear Antigens ,NADPH Oxidase 2 ,Female ,Neoplasm Recurrence, Local ,Reactive Oxygen Species ,Research Paper - Abstract
Chronic hepatitis B (CHB) has been reported to be associated with impaired prognosis for patients with nasopharyngeal carcinoma (NPC). However, the latent mechanism is unclear. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) induce immune suppression in CHB and promote the development of hepatocellular carcinoma. Lectin-type oxidized LDL receptor-1 (LOX-1) was recently identified as a specific marker for PMN-MSDC. We found NPC survivors with CHB had high levels of LOX-1+ PMN-MDSCs. LOX-1+ PMN-MDSCs significantly reduced T cell proliferation and activation. Endoplasmic reticulum stress was induced in LOX-1+ PMN-MDSCs. In addition, LOX-1+ PMN-MDSCs increased their expression of NOX2, a key reactive oxygen species (ROS)-related genes, and levels of ROS illustrated by the DCFDA test. The ROS inhibitor N-acetylcysteine abrogated the suppression of LOX-1+ PMN-MDSCs on T cell activation. The EBV DNA-positivity rate was higher in NPC survivors with CHB than in NPC patients without CHB. Those presenting with positive EBV DNA displayed higher LOX-1+ PMN-MDSC levels. LOX-1+ PMN-MDSCs suppressed the CD8+ T cell response against EBV. This study revealed LOX-1+ PMN-MDSC accumulation and activation in NPC survivors with CHB. LOX-1+ PMN-MDSCs might suppress the host immune response to EBV through ER stress/ROS pathway. These results explained the association of CHB with unfavorable NPC prognosis.
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- 2020
27. Efficacy of Chemiluminescence Immunoassays on VCA-IgA and EBNA1-IgA Antibodies of Epstein-Barr Virus in Diagnosing Nasopharyngeal Carcinoma
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Hong Zhu, Liying Gan, Fugui Li, Weimin Cheng, Biaohua Wu, Fenghua Yang, Pu Liao, Mingfang Ji, Yajun Huang, Xia Yu, Youde Cao, Fuzhen Xia, Wenjing Yu, Yonggang Lou, Yijun Gong, Jiang Li, Huiyun Fang, and Lei Zhang
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0301 basic medicine ,medicine.medical_specialty ,Central china ,medicine.disease_cause ,Gastroenterology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,law ,Internal medicine ,medicine ,otorhinolaryngologic diseases ,Chemiluminescence ,EBNA1-IgA ,biology ,business.industry ,Healthy population ,nasopharyngeal carcinoma ,Healthy subjects ,VCA-IgA ,medicine.disease ,Epstein–Barr virus ,stomatognathic diseases ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,biology.protein ,ELISA ,Antibody ,CLIA ,business ,Research Paper - Abstract
Background: IgA antibodies against Epstein-Barr virus (EBV) capsid antigen (VCA) and nuclear antigen 1 (EBNA1) have been proposed to facilitate the diagnosis and early detection of nasopharyngeal carcinoma (NPC) in high-incidence regions. However, while new methodologies and new platforms for the detection of VCA-IgA and EBNA1-IgA have become available, proper interassay simultaneous comparisons have not been carried out. The study was to compare the performance of the chemiluminescent immunoassays (CLIA) and enzyme-linked immunosorbent assay (ELISA) for VCA-IgA and EBNA1-IgA antibodies, and to evaluate the levels of EBV antibodies in healthy population from different areas of China. Methods: CLIA and ELISA for VCA-IgA and EBNA1-IgA were performed in NPC and healthy populations from high-incidence areas of NPC in South China (N=555), medium-incidence areas of NPC in Central China (N=318) and low-incidence areas of NPC in North China (N=379), and the results were compared and analyzed. Results: (1) The highest sensitivity in total, early and advanced NPC were 91.5% (CLIA for VCA-IgA), 86.4% (CLIA and ELISA-2 for EBNA1-IgA) and 93.6% (CLIA for VCA-IgA). However, the specificity of EBV-IgA measured by CLIA was relatively lower than ELISA. The top three seromarkers with the largest AUC was CLIA for VCA-IgA (AUC: 0.929, 95% CI: 0.905-0.953), ELISA-2 for EBNA1-IgA (AUC: 0.922, 95% CI: 0.896-0.947) and CLIA for EBNA1-IgA (AUC:0.919, 95% CI: 0.893-0.945), respectively. The positive and negative coincidence rates of the two EBNA1-IgA kits were 69.5% and 91.9%, respectively. However, the coincidence rates of VCA-IgA were relatively low. CLIA kits had good repeatability between different laboratories. (2) The positive rates of EBV-IgA antibodies were relatively high in high-incidence areas of NPC (P < 0.017), while there was no significant difference in the antibody positive rates between medium-incidence areas and low-incidence areas of NPC (P > 0.05). Conclusions: The performance of EBV-IgA antibodies measured by CLIA has good repeatability, higher sensitivity and similar specificity. The higher EBV-IgA positive rate in healthy subjects by CLIA raises concern about its suitability for NPC-risk screening and requires further analysis.
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- 2020
28. Co-presence of Epstein-Barr virus and high-risk human papillomaviruses in Syrian colorectal cancer samples
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Queenie Fernandes, Ishita Gupta, Mohammed I. Malki, Semir Vranic, Ala-Eddin Al Moustafa, Hamda Al-Thawadi, Amber Yasmeen, and Tahar Aboulkassim
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Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,high-risk HPV ,Colorectal cancer ,viruses ,030231 tropical medicine ,Immunology ,colorectal cancer ,Alphapapillomavirus ,medicine.disease_cause ,Virus ,Syrian population ,03 medical and health sciences ,0302 clinical medicine ,EBV ,hemic and lymphatic diseases ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Co presence ,Pharmacology ,Syria ,business.industry ,Papillomavirus Infections ,virus diseases ,medicine.disease ,Epstein–Barr virus ,Virology ,cancer phenotype ,High risk hpv ,Colorectal Neoplasms ,business ,Research Paper - Abstract
We recently performed two studies exploring the presence of Epstein-Barr virus (EBV) and high-risk human papillomaviruses (HPVs) types 16, 18, 31, 33 and 35 in human colorectal cancers from the Syrian population. Herein, we report that EBV and high-risk HPVs are co-present in colorectal cancers from Syria. We reveal that 17 (~17%) of 102 cancer samples are positive for both EBV and high-risk HPVs and their co-presence is associated with high/intermediate grade invasive carcinomas. These data suggest that EBV and high-risk HPVs are co-present in human colorectal cancers where they might cooperate on the initiation and/or progression of these cancers. Thus, we believe that future studies are necessary to confirm the co-presence of these oncoviruses and their cooperative role in human colorectal carcinogenesis. This work was supported by grants from Qatar University: QUHI-CMED-19/20-1 and GCC # 2017-002 QU/KU.
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- 2020
29. Study of Epstein–Barr virus serological profile in Egyptian patients with Hashimoto’s thyroiditis: A case-control study
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Marwa Ahmed Meheissen, Saher N. Alnakhal, Samir Naeim Assaad, Tarek Salem, and Eman Tayae Elsayed
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medicine.medical_specialty ,endocrine system ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,medicine.disease_cause ,Gastroenterology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Thyroiditis ,Serology ,EBNA-1 IgG, Epstein–Barr nuclear antigen (EBNA-1) IgG ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Anti TPO Ab, Anti-thyroid peroxidase antibody ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Euthyroid ,EBV EA IgG, EBV early antigen (EA) IgG ,030212 general & internal medicine ,HT, Hashimoto’s thyroiditis ,EA ,EBNA-1 ,lcsh:RC648-665 ,biology ,Anti TGAb, Anti- thyroglobulin antibody ,business.industry ,Thyroid ,Case-control study ,Epstein Barr virus ,Hashimoto’s thyroiditis ,FT4, Free tetraiodothyronine ,medicine.disease ,Epstein–Barr virus ,VCA ,Autoimmune thyroid disease ,medicine.anatomical_structure ,Thyroid isthmus ,biology.protein ,TSH, Thyroid-stimulating hormone ,EBV, Epstein–Barr virus ,VCA, Viral capsid antigen ,Antibody ,business ,FT3, Free Triiodothyronine ,Research Paper - Abstract
Highlights • There is a possible association between Epstein–Barr virus infection and Hashimoto's thyroiditis. • The significant relation between anti TPO titer and serum EBNA-1 IgG levels in healthy control subjects may suggest a possible association between EBV and thyroid autoimmunity. • The serological EBV status did not differ in patients with euthyroid versus hypothyroid HT., Background Hashimoto’s thyroiditis (HT) is now considered one of the most prevalent autoimmune diseases. The aim of the present study was to determine the prevalence of different types of EBV antibodies in patients with HT in comparison to healthy controls, and to detect any correlation between EBV serological markers and different laboratory findings in HT patients. Subjects & methods This case-control study was conducted on 120 subjects divided into two groups: Sixty patients with HT (patients group), and sixty age and sex matched healthy volunteers (control group). All the participants were subjected to: Thyroid ultrasound, laboratory assessment including: Serum thyroid -stimulating hormone (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase antibody (anti-TPO Ab) and anti-thyroglobulin antibody (anti-TG Ab). Four types of EBV antibodies (VCA IgM, VCA IgG, EA IgG, and EBNA-1IgG) were measured in serum using ELISA. Results The mean serum levels of EBV VCA IgG and EA IgG were significantly higher in HT patients group in comparison to control group. In euthyroid HT patients, a significant positive correlation was observed between the age and EBV EA IgG. While in hypothyroid HT patients, a significant positive correlation between thyroid isthmus and EBNA-1IgG was observed. A significant negative correlation was found between the serum FT3 and EBNA-1IgG and a significant positive correlation was observed between serum TSH and EBV VCA IgG. Conclusions The high serum levels of EBV VCA IgG and EBV EA IgG in patients with HT suggest a possible association between EBV and HT.
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- 2020
30. Counteracting survival functions of EBNA3C in Epstein-Barr virus (EBV)-driven lymphoproliferative diseases by combination of SAHA and bortezomib
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Kwai Fung Hui, Po Ling Yeung, Alan K. S. Chiang, and Kam Pui Tam
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0301 basic medicine ,Phosphatase ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Epstein-Barr virus ,Inducer ,Gene ,lymphoproliferative disease ,EBNA3 ,Bortezomib ,Chemistry ,bortezomib ,SAHA ,medicine.disease ,Epstein–Barr virus ,Lymphoma ,030104 developmental biology ,Oncology ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,medicine.drug ,Research Paper - Abstract
Combination of suberoylanilide hydroxamic acid (SAHA) and bortezomib (SAHA/bortezomib) was shown to synergistically induce killing of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) of type III or Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins. We hypothesize that SAHA/bortezomib can counteract the survival functions conferred by the EBNA3 proteins. We tested the effect of SAHA/bortezomib on the survival of BL cell lines containing EBNA3A, -3B or -3C knockout EBV with or without the respective revertant EBNA3 genes. Isobologram analysis showed that SAHA/bortezomib induced significantly greater synergistic killing of EBNA3C-revertant cells when compared with EBNA3C-knockout cells. Such differential response was not observed in either EBNA3A or -3B revertant versus their knockout pairs. Interestingly, EBNA3C-knockout cells showed significant G2/M arrest whilst EBNA3C-revertant cells and LCLs escaped G2/M arrest induced by SAHA/bortezomib and became more susceptible to the induction of apoptosis. In parallel, SAHA/bortezomib induced stronger expression of p21WAF1 but weaker expression of p-cdc25c, an M-phase inducer phosphatase, in EBNA3C-expressing cells when compared with EBNA3C-knockout cells. SAHA/bortezomib also induced greater growth suppression of EBNA3C-expressing xenografts (EBNA3C-revertant and LCL) than that of EBNA3C-knockout xenografts in SCID mice. In conclusion, our data showed that SAHA/bortezomib could synergistically induce killing of BL and LCL through counteracting the survival functions of EBNA3C, providing a strong basis for clinical testing of this drug combination in patients with EBV-associated lymphoproliferative diseases.
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- 2018
31. MicroRNAs sequencing unveils distinct molecular subgroups of plasmablastic lymphoma
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Leonardo Del Porro, Lucia Mundo, Prasad Satya Vara, Shaheen Sayed, Sara Gazaneo, Maria Raffaella Ambrosio, Mohsen Navari, Stefano Ascani, Stefano Lazzi, Matteo Picciolini, Pier Paolo Piccaluga, Lorenzo Leoncini, Alessandro Ginori, Amhed Yonis, Giuseppe Lo Bello, Ambrosio, Maria Raffaella, Mundo, Lucia, Gazaneo, Sara, Picciolini, Matteo, Vara, Prasad Satya, Sayed, Shaheen, Ginori, Alessandro, Bello, Giuseppe Lo, Porro, Leonardo Del, Navari, Mohsen, Ascani, Stefano, Yonis, Amhed, Leoncini, Lorenzo, Piccaluga, Pier Paolo, and Lazzi, Stefano
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Aggressive lymphoma ,plasmablastic lymphoma ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Immunophenotyping ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Epstein-Barr virus ,Burkitt lymphoma ,Extramedullary plasmacytoma ,MiRNA expression profiling ,Pathology section ,Plasmablastic lymphoma ,extramedullary plasmacytoma ,Cytogenetics ,Epstein-Barr viru ,Plasma cell neoplasm ,medicine.disease ,Epstein–Barr virus ,Research Paper: Pathology ,Lymphoma ,030104 developmental biology ,Plasmacytoma ,miRNA expression profiling - Abstract
// Maria Raffaella Ambrosio 1,* , Lucia Mundo 1,* , Sara Gazaneo 1 , Matteo Picciolini 2 , Prasad Satya Vara 3 , Shaheen Sayed 4 , Alessandro Ginori 1,5 , Giuseppe Lo Bello 1 , Leonardo Del Porro 1 , Mohsen Navari 6,7,8 , Stefano Ascani 9 , Amhed Yonis 10 , Lorenzo Leoncini 1 , Pier Paolo Piccaluga 7,8,* and Stefano Lazzi 1,* 1 Department of Medical Biotechnology, Section of Pathology, University of Siena, Siena, Italy 2 Diatech Pharmacogenetics, Jesi, Italy 3 Aga Khan Hospital, Kisumu, Kenya 4 Aga Khan University Hospital, Nairobi, Kenya 5 Pathology Unit, Ospedale Civico di Carrara, Carrara, Italy 6 Research Center of Advanced Technologies in Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran 7 Department of Experimental, Diagnostic, and Experimental Medicine, Bologna University School of Medicine, Bologna, Italy 8 Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy 9 Section of Pathology, Azienda Ospedaliera S. Maria di Terni, University of Perugia, Perugia, Italy 10 Alexandria University, Alexandria, Egypt * These authors have contributed equally to this work Correspondence to: Lorenzo Leoncini, email: // Pier Paolo Piccaluga, email: // Keywords : plasmablastic lymphoma; miRNA expression profiling; Burkitt lymphoma; extramedullary plasmacytoma; Epstein-Barr virus; Pathology section Received : June 20, 2017 Accepted : September 08, 2017 Published : October 31, 2017 Abstract Plasmablastic lymphoma (PBL) is an aggressive lymphoma, often arising in the context of immunodeficiency and associated with Epstein-Barr virus (EBV) infection. The most frequently detected genetic alteration is the deregulation of MYC gene through the translocation - t(8;14)(q24;q32). The diagnosis of PBL is often challenging because it has an overlap in morphology, immunophenotype, cytogenetics and virus association with other lymphomas and plasma cell neoplasms; further, its molecular basis remains elusive. In the present study we aimed to better define the possible contribution of EBV infection as well as miRNA deregulation in PBL pathogenesis. We studied 23 cases of PBL, 19 Burkitt lymphomas (BL), and 17 extra-medullary plasmacytoma (EMPC). We used qPCR and immunohistochemistry to assess EBV latency patterns, while micro-RNA (miRNA) profiling was performed by next generation sequencing (Illumina) and validated by qPCR. Our analysis revealed a non-canonical EBV latency program with the partial expression of some proteins characterizing latency II and the activation of an abortive lytic cycle. Moreover, we identified miRNA signatures discriminating PBL from BL and EMPC. Interestingly, based on the miRNA profile, PBL appeared constituted by two discrete subgroups more similar to either BL or EMPC, respectively. This pattern was confirmed in an independent set of cases studied by qPCR and corresponded to different clinico-pathological features in the two groups, including HIV infection, MYC rearrangement and disease localization. In conclusion, we uncovered for the first time 1) an atypical EBV latency program in PBL; 2) a miRNA signature distinguishing PBL from the closest malignant counterparts; 3) the molecular basis of PBL heterogeneity.
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- 2017
32. Efficacy of recombinant adenovirus expressing a fusion gene from GM-CSF and Epstein-Barr virus LMP2A in a mouse tumor model
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Chunqing Yang, Xiu-Zhen Li, Yunqing Li, Qingjie Xue, Chunmei Wang, Xinxin Yang, Yingchun Yan, Bingyuan Ji, and Ting Chen
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0301 basic medicine ,Herpesvirus 4, Human ,Recombinant Fusion Proteins ,Genetic Vectors ,Immunology ,Transfection ,medicine.disease_cause ,Cancer Vaccines ,Adenoviridae ,law.invention ,Viral vector ,Viral Matrix Proteins ,Fusion gene ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,law ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Immunology and Allergy ,Pharmacology ,Immunity, Cellular ,biology ,HEK 293 cells ,Granulocyte-Macrophage Colony-Stimulating Factor ,Viral Vaccines ,Virology ,Molecular biology ,Epstein–Barr virus ,Immunity, Humoral ,Disease Models, Animal ,HEK293 Cells ,030104 developmental biology ,030220 oncology & carcinogenesis ,Recombinant DNA ,biology.protein ,Immunotherapy ,Antibody ,Research Paper - Abstract
In this study, purified GM-CSF and LMP2A mRNAs were amplified by PCR. Then, the GM-CSF and LMP2A sequences were connected by the polypeptide linker (Gly4Ser)3 using gene splicing by overlap extension. The constructed fusion gene GC2A was inserted into the adenovirus vector. Then the recombinant vector was introduced into HEK 293T cells by calcium phosphate transfection to package the adenovirus. The levels of antibodies against the GM-CSF and LMP2Afusion proteins were measured by ELISA, and the CTL activity of the mouse splenic lymphocytes was determined by lactate dehydrogenase (LDH) release assay. Immunotherapy of mouse tumor (EBV-positive epithelial tumor cell line (GT39)) tissues was performed, and their morphologies were assessed. Finally, the data of each group were analyzed using SPSS 11.5 statistical software. The recombinant adenovirus could replicate in HEK 293Tcells and induce humoral and cellular immune responses in the mice. The maximum dose resulted in an antibody titer of 18500 (184.5 ± 8.7 pg/ml). At an effector: target ratio of 40:1, maximum specific lysis was observed which was approximately three times that detected in the control immunized mice. The tumor inhibition rate was approximately 76% compared with the control groups, indicating the presence of significant differences among the groups. Tumor-infiltrating lymphocytes were detected by hematoxylin-eosin (HE) staining. The recombinant adenovirus induced humoral and cellular immune responses and inhibited tumor growth in mice. It provided a theoretical basis and candidate vaccine for further preclinical trials.
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- 2017
33. The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype
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Jeremy T Keane, David R. Booth, Stephen D. Schibeci, Ali Afrasiabi, Sanjay Swaminathan, and Grant P Parnell
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Medicine (General) ,Herpesvirus 4, Human ,Multiple Sclerosis ,viruses ,Multiple sclerosis research ,Genome-wide association study ,Biology ,eQTL ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,R5-920 ,EBV ,hemic and lymphatic diseases ,Genotype ,medicine ,GWAS ,Humans ,Lectins, C-Type ,Allele ,Alleles ,Cells, Cultured ,EBNA2 ,B-Lymphocytes ,TNF Receptor-Associated Factor 3 ,Multiple sclerosis ,Membrane Proteins ,MS ,General Medicine ,medicine.disease ,Epstein–Barr virus ,Epstein-Barr Virus Nuclear Antigens ,Receptors, Tumor Necrosis Factor, Type I ,Immunology ,Expression quantitative trait loci ,Medicine ,Apoptosis Regulatory Proteins ,Chromatin immunoprecipitation ,Research Paper ,Protein Binding ,Transcription Factors - Abstract
Background: Epstein-Barr virus (EBV) infection may be necessary for the development of Multiple sclerosis (MS). Earlier we had identified six MS risk loci that are co-located with binding sites for the EBV transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) in EBV-infected B cells (lymphoblastoid cell lines – LCLs). Methods: We used an allele-specific chromatin immunoprecipitation PCR assay to assess EBNA2 allelic preference. We treated LCLs with a peptide inhibitor of EBNA2 (EBNA2-TAT), reasoning that inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2. Findings: We found that EBNA2 binding was dependent on the risk allele for five of these six MS risk loci (p < 0·05). Treatment with EBNA2-TAT significantly altered the expression of TRAF3 (p < 0·05), CD40 (p < 0·001), CLECL1 (p
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- 2021
34. Epstein-Barr virus BRLF1 induces genomic instability and progressive malignancy in nasopharyngeal carcinoma cells
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Kuo-Chang Chu, Chung-Chun Wu, Yu-Jhen Cheng, Jen-Yang Chen, Sheng-Ping Chou, Sheng-Yen Huang, Yun-Jin Jiang, Ching-Hwa Tsai, and Su-Fang Lin
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0301 basic medicine ,Genome instability ,BRLF1 ,Malignancy ,medicine.disease_cause ,Virus ,Epstein–Barr virus ,03 medical and health sciences ,0302 clinical medicine ,otorhinolaryngologic diseases ,medicine ,chromosome mis-segregation ,Zebrafish ,biology ,nasopharyngeal carcinoma ,genomic instability ,biology.organism_classification ,medicine.disease ,Virology ,stomatognathic diseases ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,Lytic cycle ,030220 oncology & carcinogenesis ,Cancer research ,Immediate early gene ,Research Paper - Abstract
Nasopharyngeal carcinoma (NPC) is a serious health problem in China and Southeast Asia. Relapse is the major cause of mortality, but mechanisms of relapse are mysterious. Epstein-Barr virus (EBV) reactivation and host genomic instability (GI) have correlated with NPC development. Previously, we reported that lytic early genes DNase and BALF3 induce genetic alterations and progressive malignancy in NPC cells, implying lytic proteins may be required for NPC relapse. In this study, we show that immediate early gene BRLF1 induces chromosome mis-segregation and genomic instability in the NPC cells. Similar phenomenon was also demonstrated in 293 and zebrafish embryonic cells. BRLF1 nuclear localization signal (NLS) mutant still induced genomic instability and inhibitor experiments revealed that BRLF1 interferes with chromosome segregation and induces genomic instability by activating Erk signaling. Furthermore, the chromosome aberrations and tumorigenic features of NPC cells were significantly increased with the rounds of BRLF1 expression, and these cells developed into larger tumor nodules in mice. Therefore, BRLF1 may be the important factor contributing to NPC relapse and targeting BRLF1 may benefit patients.
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- 2017
35. Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?
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Raffaella Ghislandi, Barbara Galbardi, Stefania Marcuzzo, Carlo Antozzi, Pia Bernasconi, Lorenzo Maggi, Teresio Motta, Massimo Barberis, Sara Franzi, Tommaso De Pas, Paola Cavalcante, Luisella Spinelli, Lorenzo Novellino, Fabio Conforti, Antonella Buzzi, Renato Mantegazza, and Fulvio Baggi
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0301 basic medicine ,Thymoma ,medicine.disease_cause ,Virus ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Epstein-Barr virus ,B cell ,myasthenia gravis ,business.industry ,autoimmunity ,thymoma ,medicine.disease ,Epstein–Barr virus ,Myasthenia gravis ,BZLF1 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Lytic cycle ,toll-like receptors ,Immunology ,business ,030217 neurology & neurosurgery ,Research Paper - Abstract
The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.
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- 2017
36. Pretreatment Epstein-Barr virus DNA in whole blood is a prognostic marker in peripheral T-cell lymphoma
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Soo Jeong Kim, Woo Ick Yang, Ji Eun Jang, Yoo Hong Min, Jin Seok Kim, Yu Ri Kim, Haerim Chung, Yundeok Kim, and June-Won Cheong
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medicine.medical_specialty ,Pathology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,Statistical significance ,Internal medicine ,medicine ,Epstein-Barr virus ,Progression-free survival ,Stage (cooking) ,peripheral T-cell lymphoma ,Hematology ,business.industry ,Not Otherwise Specified ,whole blood ,medicine.disease ,Peripheral T-cell lymphoma ,prognostic score ,Lymphoma ,Oncology ,030220 oncology & carcinogenesis ,business ,030215 immunology ,Research Paper - Abstract
// Yu Ri Kim 1 , Soo-Jeong Kim 2 , June-Won Cheong 2 , Haerim Chung 2 , Ji Eun Jang 2 , Yundeok Kim 2 , Woo-Ick Yang 3 , Yoo Hong Min 2 and Jin Seok Kim 2 1 Division of Hematology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea 2 Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea 3 Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea Correspondence to: Jin Seok Kim, email: hemakim@yuhs.ac Keywords: peripheral T-cell lymphoma, Epstein-Barr virus, whole blood, prognostic score Received: July 25, 2017 Accepted: August 23, 2017 Published: September 23, 2017 ABSTRACT Because there are few studies regarding the clinical impact of circulating EBV-DNA in peripheral T-cell lymphomas (PTCLs), we tried to evaluate the role of EBV-DNA in whole blood as a prognostic factor for PTCL. We retrospectively reviewed 110 PTCL patients with median age of 63 (20-94) years. Forty-seven patients (42.7%) showed positive results for EBV-DNA, and these patients also had stage III/IV disease, elevated lactic dehydrogenase, and low albumin level ( P = 0.007, P = 0.004, P = 0.002, respectively). The 5-year overall survival (OS) and progression free survival (PFS) were 21.0% and 18.0%. Univariable analysis showed that positive EBV-DNA was related with inferior OS and PFS ( P = 0.015 and P < 0.001, respectively). Multivariable analysis showed that poor performance status, extranodal involvement more than one site and positive EBV-DNA results were related with OS and PFS ( P < 0.001, P < 0.001, P = 0.007 and P = 0.001, P = 0.002, P < 0.001, respectively). Using these three variables, we made a new prognostic model which classified patients on risk as follows: low, no adverse factors; intermediate, 1 factor; or high, 2-3 factors. The new prognostic model could stratify the three groups for OS and PFS better than either international prognostic index or prognostic index of PTCL-u, and showed statistical significance in PTCL, not otherwise specified. This study suggests that whole blood EBV-DNA is related with aggressive clinical characteristics and inferior survival. The new prognostic model, which incorporates EBV-DNA, could better stratify PTCL patients.
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- 2017
37. Characterization of the subcellular localization of Epstein-Barr virus encoded proteins in live cells
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Gengde Hong, Tao Peng, Tao Chen, Meili Li, Ping Wang, Zongmin Liao, Daixiong Chen, Xingmei Zou, Mingsheng Cai, Zuo Xu, Jinlu Huang, Si Jiang, and Yuanfang Wang
- Subjects
0301 basic medicine ,Biology ,Subcellular localization ,medicine.disease_cause ,Epstein–Barr virus ,Virology ,Virus ,03 medical and health sciences ,030104 developmental biology ,Plasmid ,Oncology ,Viral replication ,Capsid ,Cytoplasm ,subcellular localization ,medicine ,Epstein-Barr virus ,live cell microscopy ,Gene ,Research Paper - Abstract
// Mingsheng Cai 2 , Zongmin Liao 2 , Tao Chen 2 , Ping Wang 2 , Xingmei Zou 2 , Yuanfang Wang 2 , Zuo Xu 2 , Si Jiang 2 , Jinlu Huang 3 , Daixiong Chen 2 , Tao Peng 2 , Gengde Hong 4 and Meili Li 1, 2 1 Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong, China 2 Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, Guangdong, China 3 Guangdong Haid Group Co., Ltd., Guangzhou 511400, Guandong, China 4 The Third Clinical School of Guangzhou Medical University, Guangzhou 510150, Guangdong, China Correspondence to: Meili Li, email: meili_2011@hotmail.com Keywords: Epstein-Barr virus, subcellular localization, live cell microscopy Received: February 03, 2017 Accepted: June 29, 2017 Published: July 25, 2017 ABSTRACT Epstein-Barr virus (EBV) is the pathogenic factor of numerous human tumors, yet certain of its encoded proteins have not been studied. As a first step for functional identification, we presented the construction of a library of expression constructs for most of the EBV encoded proteins and an explicit subcellular localization map of 81 proteins encoded by EBV in mammalian cells. Viral open reading frames were fused with enhanced yellow fluorescent protein (EYFP) tag in eukaryotic expression plasmid then expressed in COS-7 live cells, and protein localizations were observed by fluorescence microscopy. As results, 34.57% (28 proteins) of all proteins showed pan-nuclear or subnuclear localization, 39.51% (32 proteins) exhibitted pan-cytoplasmic or subcytoplasmic localization, and 25.93% (21 proteins) were found in both the nucleus and cytoplasm. Interestingly, most envelope proteins presented pan-cytoplasmic or membranous localization, and most capsid proteins displayed enriched or complete localization in the nucleus, indicating that the subcellular localization of specific proteins are associated with their roles during viral replication. Taken together, the subcellular localization map of EBV proteins in live cells may lay the foundation for further illustrating the functions of EBV-encoded genes in human diseases especially in its relevant tumors.
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- 2017
38. Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection
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Ryota Yamanaka, Sayaka Funata, Shogo Yamamoto, Masashi Fukayama, Atsushi Okabe, Masaki Fukuyo, Atsushi Kaneda, Keisuke Matsusaka, and Hiroyuki Aburatani
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0301 basic medicine ,DNA methylation ,gastric cancer ,Biology ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,Histone ,Epigenetics of physical exercise ,Oncology ,biology.protein ,H3K4me3 ,Epstein-Barr virus ,Cancer epigenetics ,Epigenetics ,RNA-Directed DNA Methylation ,Epigenomics ,Research Paper - Abstract
Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were "DNA methylation-sensitive" genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A. The other half were "DNA methylation-resistant" genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site.
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- 2017
39. Combination of betulinic acid and chidamide synergistically inhibits Epstein-Barr virus replication through over-generation of reactive oxygen species
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Huawen Li, Weiguo Xie, Huanwen Tang, Hongjin Wu, Danli Kong, Xueru Chen, Paul Yao, Qiongfang Ruan, Wang Yifei, Xiaodong Huang, Zhigang Chu, Yuanling Ding, Haibing Yu, and Hongyu Zhang
- Subjects
0301 basic medicine ,DNA damage ,medicine.drug_class ,medicine.disease_cause ,Virus ,03 medical and health sciences ,chemistry.chemical_compound ,betulinic acid ,chidamide ,hemic and lymphatic diseases ,Chidamide ,medicine ,Epstein-Barr virus ,histone deacetylase inhibitor ,reactive oxygen species ,Histone deacetylase inhibitor ,Virology ,Epstein–Barr virus ,BZLF1 ,030104 developmental biology ,Oncology ,chemistry ,Lytic cycle ,Apoptosis ,Cancer research ,Research Paper - Abstract
Epstein-Barr virus (EBV) has widely infected more than 90% of human populations. Currently, there is no efficient way to remove the virus because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. In the effort to develop an efficient strategy for the removal of the EBV virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL (lymphoblastoid cell line) cells. Chidamide (CDM, CS055), a novel histone deacetylase inhibitor (HDACi), could significantly switch EBV from the latent stage to the lytic stage with increased gene expression of BZLF1 and BMRF1, but has a small effect on EBV replication due to the suppression effect of CDM-mediated ROS generation. Interestingly, a combination of BA and CDM synergistically inhibits EBV replication with ROS over-generation and subsequent DNA damage and apoptosis. Overexpression of SOD2 diminishes this effect, while SOD2 knockdown mimics this effect. An in vivo xenograft tumor development study with the tail vein injection of EBV-transformed LCL cells in nude mice proves that the combination of BA and CDM synergistically increases superoxide anion release in tumor tissues and suppresses EBV replication and tumor growth, and significantly prolongs mouse survival. We conclude that the combination of BA and CDM could be an efficient strategy for clinical EBV removal.
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- 2017
40. Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections
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Stefan Tudor, Meng Chen, Jeffrey J. Tarrand, Dana Elena Giza, Cristina Ivan, Maria Ciccone, Enrique Fuentes-Mattei, Michael J. Keating, Xinna Zhang, Osman Aykan Kargin, Florea Lupu, Nayra Soares do Amaral, George A. Calin, Catalin Vasilescu, Alessandra Ferrajoli, Masayoshi Shimizu, Pilar Mur, Sai Ching J. Yeung, John T. Manning, and Halk Sağlığı
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0301 basic medicine ,Micro RNAs ,Chronic lymphocytic leukemia ,viruses ,lcsh:Medicine ,Antibodies, Viral ,medicine.disease_cause ,Immunoglobulin G ,Serology ,Cohort Studies ,Leukocyte Count ,HHV4 ,Prevalence ,HHV8 ,In Situ Hybridization ,lcsh:R5-920 ,virus diseases ,General Medicine ,Viral Load ,3. Good health ,Real-time polymerase chain reaction ,Virus Diseases ,Herpesvirus 8, Human ,RNA, Viral ,lcsh:Medicine (General) ,Viral load ,Research Paper ,Herpesviruses ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Enzyme-Linked Immunosorbent Assay ,KSHV ,Biology ,Real-Time Polymerase Chain Reaction ,Viral miRNAs ,General Biochemistry, Genetics and Molecular Biology ,Virus ,03 medical and health sciences ,Antigen ,EBV ,medicine ,Humans ,Lymphocyte Count ,ComputingMethodologies_COMPUTERGRAPHICS ,Infection prevalence ,lcsh:R ,Reproducibility of Results ,Herpesvirus ,medicine.disease ,Epstein–Barr virus ,Virology ,MicroRNAs ,030104 developmental biology ,Immunology ,biology.protein - Abstract
Graphical abstract Image 1, Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P, Highlights • There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. • Measurement of the viral miRNAs in plasma by RT-qPCR allows a direct and accurate assessment of viral infection. • Measurement of the viral miRNAs in plasma by RT-qPCR shows prevalence of KSHV infection in immuno-depressed patients. • Measurement of plasma viral miRNAs for viral infection assessment has the potential to become a “gold” standard method in the clinical practice. Chronic viral infections represent risk factors for diseases and development of infection-related complications. There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. The current method used in the clinical practice (ELISA-test) identifies a great geographic variation in KSHV seroprevalence and may underestimate the true-prevalence of KSHV infection. Here we showed that detection of plasma viral miRNAs levels for the identification of viral infection (e.g., KSHV, Epstein-Bar virus or EBV) is more accurate than the current method for detection of virus-derived antigen, especially in patients with low number of immune cells.
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- 2017
41. Differentiated tumor immune microenvironment of Epstein-Barr virus-associated and negative gastric cancer: implication in prognosis and immunotherapy
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Zengshan Li, Mu Sheng Zeng, Jianhui Li, Kaichun Wu, Yongzhan Nie, Qiaoyi Liang, Jing Ma, Yiming Hao, Meirui Qian, and Jun Yu
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,tumor microenvironment ,Epstein-Barr virus ,immune checkpoint ,Tumor microenvironment ,Tissue microarray ,business.industry ,Tumor-infiltrating lymphocytes ,gastric cancer ,FOXP3 ,Immunotherapy ,Epstein–Barr virus ,Immune checkpoint ,030104 developmental biology ,tumor-infiltrating lymphocytes ,030220 oncology & carcinogenesis ,Immunology ,business ,Research Paper - Abstract
// Jing Ma 1, * , Jianhui Li 2, * , Yiming Hao 1, * , Yongzhan Nie 1 , Zengshan Li 1, 3 , Meirui Qian 1 , Qiaoyi Liang 4 , Jun Yu 4 , Musheng Zeng 5 and Kaichun Wu 1 1 Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China 2 Department of Infectious Diseases, Tangdu Hospital Affiliated to the Fourth Military Medical University, Xi'an, Shaanxi, China 3 The Pathology Department, Fourth Military Medical University, Xi'an, Shaanxi, China 4 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China and The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, China 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China * These authors have contributed equally to this work Correspondence to: Kaichun Wu, email: kaicwu@fmmu.edu.cn Keywords: gastric cancer, tumor microenvironment, Epstein-Barr virus, tumor-infiltrating lymphocytes, immune checkpoint Received: November 14, 2016 Accepted: March 01, 2017 Published: May 16, 2017 ABSTRACT Epstein-Barr virus-associated gastric cancer (EBVaGC) has been proposed to be a distinct subtype with a specific immune microenvironment. Here, we evaluated tumor-infiltrating T-cell subsets and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in 571 gastric cancers (GCs). Tissue microarrays were stained using EBER in situ hybridization for EBV and using immunohistochemistry for CD4, CD8, Foxp3, PD-1 and PD-L1. GCs were categorized into four types based on CD8 + infiltration and PD-L1 expression. The 5-year overall survival (OS) was evaluated according to EBV infection, T-cell subsets, PD-1 and PD-L1 expression and immune types. Thirty-two (5.3%) EBVaGCs were identified, which were more prevalent for CD8 + (p
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- 2017
42. Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication
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Jillian A. Bristol, Julie Plowshay, Shidong Ma, Elizabeth A. Barlow, Ming Han Tsai, Dhananjay M. Nawandar, Zhe Li, Shannon C. Kenney, Andrea Bilger, Henri Jacques Delecluse, and James C. Romero-Masters
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0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Genes, myc ,Hydroxybutyrates ,Apoptosis ,Virus Replication ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Virus latency ,Teriflunomide ,Cell Line, Transformed ,Leflunomide ,B-Lymphocytes ,NF-kappa B ,Virus Latency ,3. Good health ,BK virus ,Oncology ,Lytic cycle ,Crotonates ,Research Paper ,medicine.drug ,Gene Expression Regulation, Viral ,humanized mouse model ,Toluidines ,Lymphoproliferative disorders ,lymphoma ,03 medical and health sciences ,Cyclin E ,Nitriles ,medicine ,Animals ,Humans ,lymphoproliferative disease ,Cell Proliferation ,therapy ,business.industry ,Isoxazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,Epstein–Barr virus ,Virology ,Lymphoproliferative Disorders ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,Humanized mouse ,Immunology ,Virus Activation ,business ,FDA-approved - Abstract
// Andrea Bilger 1 , Julie Plowshay 2, 6 , Shidong Ma 1, 5 , Dhananjay Nawandar 3, 7 , Elizabeth A. Barlow 1 , James C. Romero-Masters 4 , Jillian A. Bristol 1 , Zhe Li 8 , Ming-Han Tsai 8 , Henri-Jacques Delecluse 8 and Shannon C. Kenney 1, 2 1 Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 2 Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 3 Department Cellular and Molecular Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, USA 4 Department of Cellular and Molecular Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 5 Sanofi Pharmaceuticals, Cambridge, Massachusetts, USA 6 Rocky Mountain Infectious Disease Specialists, Aurora, Colorado, USA 7 Department of Cancer Biology and Immunology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Cambridge, Massachusetts, USA 8 Joint DKFZ Inserm Unit U1074, German Cancer Center (DKFZ), Heidelberg, Germany Correspondence to: Shannon C. Kenney, email: skenney@wisc.edu Keywords: therapy, lymphoma, lymphoproliferative disease, humanized mouse model, FDA-approved Received: March 17, 2017 Accepted: April 27, 2017 Published: May 15, 2017 ABSTRACT EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.
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- 2017
43. Interaction of Epstein-Barr virus genes with human gastric carcinoma transcriptome
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Erik K. Flemington, Ruiyuan Zhang, Yu-Ping Wang, Melody Baddoo, Zhen Lin, Yao-Zhong Liu, and Michael J. Strong
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Gene Expression Regulation, Viral ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Genes, Viral ,RNA-Seq ,Biology ,medicine.disease_cause ,Virus ,Transcriptome ,03 medical and health sciences ,Stomach Neoplasms ,EBV ,hemic and lymphatic diseases ,Gene expression ,medicine ,Humans ,gastric carcinoma ,KEGG ,Gene ,Epstein–Barr virus ,Virology ,3. Good health ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,Human genome ,RNA-seq ,Research Paper - Abstract
// Ruiyuan Zhang 1 , Michael J. Strong 2 , Melody Baddoo 2 , Zhen Lin 2 , Yu-Ping Wang 3 , Erik K. Flemington 2 , Yao-Zhong Liu 1 1 Department of Global Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA 2 Department of Pathology and Laboratory Medicine, Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA, USA 3 Department of Biomedical Engineering, Tulane University School of Science and Engineering, New Orleans, LA, USA Correspondence to: Yao-Zhong Liu, email: yliu8@tulane.edu Erik K. Flemington, email: erik@tulane.edu Keywords: EBV, RNA-seq, gastric carcinoma Received: January 18, 2017 Accepted: March 13, 2017 Published: March 21, 2017 ABSTRACT Gastric carcinoma (GC) is a leading cause of mortality. 10% of GC cases are related with EBV (Epstein-Barr virus) infection. The detailed mechanistic roles EBV genes play and especially the interaction between the viral genes and human genes in GC remain unclear. In this study, raw fastq data from 285 GC samples were downloaded from TCGA (The Cancer Genome Atlas), including 25 EBV positive (EBV+) GC samples and 260 EBV negative (EBV−) GC samples. RNA-seq based expression data were generated for both human genes (among all the samples) and for the EBV genes (among the 25 EBV+ samples). Bioinformatics analyses were performed to identify differentially expressed (DEx) human genes and DEx KEGG pathways in EBV+ vs. EBV− samples and co-expressed human gene modules and hub genes among the DEx genes. Within the EBV+ samples, analyses were conducted to find correlation between EBV gene expression and the human gene expression modules, between EBV gene expression and the human hub genes, and between EBV gene expression and the DEx human pathways. EBV genes LMP-1, BALF1 and BALF2 were found to have significant correlation with human hub genes, CNTD2 and VANGL2. EBV genes BALF4 and BALF5 were found to correlate with human pathways, including Jak-STAT signaling and Phosphatidylinositol Signaling System. Our study has revealed the coordinated expression patterns between EBV and human GC transcriptome and identified several key EBV genes that may play an important role in EBV+ GC pathogenesis through their interactions with human genes and pathways.
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- 2017
44. Epstein-Barr virus encoded microRNA BART7 regulates radiation sensitivity of nasopharyngeal carcinoma
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Thian-Sze Wong, Min-Juan Zhang, Siqi Chen, Wei Gao, Jimmy Yu Wai Chan, Zeng-Hong Li, and Min Yin
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Male ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,medicine.medical_treatment ,Cell ,medicine.disease_cause ,Radiation Tolerance ,0302 clinical medicine ,Radiation sensitivity ,Child ,Zebrafish ,Oligonucleotide Array Sequence Analysis ,Nasopharyngeal Carcinoma ,radiation sensitivity ,Middle Aged ,Immunohistochemistry ,medicine.anatomical_structure ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,RNA, Viral ,Female ,Research Paper ,Adult ,Adolescent ,Blotting, Western ,Real-Time Polymerase Chain Reaction ,Virus ,Transforming Growth Factor beta1 ,Young Adult ,03 medical and health sciences ,EBV ,microRNA ,medicine ,Animals ,Humans ,Aged ,Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) ,MicroRNA BART7 ,business.industry ,Carcinoma ,Nasopharyngeal Neoplasms ,medicine.disease ,Epstein–Barr virus ,Radiation therapy ,MicroRNAs ,030104 developmental biology ,Nasopharyngeal carcinoma ,Immunology ,Cancer research ,business - Abstract
// Wei Gao 1, 2 , Zeng-Hong Li 3 , Siqi Chen 1, 2 , Jimmy Yu-Wai Chan 1, 2 , Min Yin 4 , Min-Juan Zhang 1, 2 , Thian-Sze Wong 1, 2 1 Department of Surgery, The University of Hong Kong, Hong Kong SAR 2 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Guangdong Province, China 3 Department of Otolaryngology, The First People's Hospital of Foshan, Guangdong Province, China 4 Department of Otorhinolaryngology Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China Correspondence to: Thian-Sze Wong, email: thiansze@gmail.com Keywords: nasopharyngeal carcinoma, EBV, radiation sensitivity, MicroRNA BART7 Received: April 18, 2016 Accepted: January 10, 2017 Published: February 20, 2017 ABSTRACT Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is very sensitive to radiotherapy. To date, the underlying mechanism remains poorly understood. Here, we demonstrated that expression of EBV-encoded microRNA BART7 (ebv-miR-BART7) increases responsiveness of NPC to radiation treatment by targeting GFPT1/TGFβ1 signaling. GFPT1 is the the key rate-limiting enzyme of the hexosamine signaling pathway and governs TGFβ1 production. TGFβ1, a pleotropic cytokine with the potency to trigger self-renewal and damage-repair machinery in somatic cells. TGFβ1 can protect zebrafish embryo from the lethal effects of radiation treatment. In silico analysis showed that ebv-miR-BART7 could target GFPT1 transcript. Correlation analysis on primary NPC tissues suggested that ebv-miR-BART7 and GFPT1 have negative expression correlation. Expression of GFPT1 and TGFβ1 were inducible by radiation in NPC cell with ebv-miR-BART7 expression. Further, suppressing endogenous GFPT1 expression inhibited TGFβ1 which subsequently increased the responsiveness of NPC to radiation treatment. Taken together, our results demonstrated that ebv-miR-BART7 controls TGFβ1 production by targeting GFPT1. Detection of ebv-miR-BART7 may provide useful indicator for monitoring NPC progression and predict therapeutic outcomes.
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- 2017
45. Clinical utility of circulating cell-free Epstein–Barr virus DNA in patients with gastric cancer
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Yuji Fujita, Katsutoshi Shoda, Shuhei Komatsu, Daisuke Ichikawa, Toshiyuki Kosuga, Atsushi Shiozaki, Hirotaka Konishi, Tomohiro Arita, Hidekazu Hiramoto, Junichi Hamada, Eigo Otsuji, Issei Imoto, Kiyoshi Masuda, and Kazuma Okamoto
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0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Carcinogenesis ,medicine.disease_cause ,Sensitivity and Specificity ,Virus ,law.invention ,Epstein–Barr virus ,03 medical and health sciences ,0302 clinical medicine ,law ,Predictive Value of Tests ,Stomach Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,Liquid biopsy ,Polymerase chain reaction ,Aged ,Neoplasm Staging ,liquid biopsy ,business.industry ,gastric cancer ,Cancer ,medicine.disease ,Prognosis ,Human genetics ,030104 developmental biology ,Treatment Outcome ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,DNA, Viral ,Cancer research ,Biomarker (medicine) ,Female ,Neoplasm Recurrence, Local ,business ,Research Paper - Abstract
// Katsutoshi Shoda 1 , Daisuke Ichikawa 1 , Yuji Fujita 1, 2 , Kiyoshi Masuda 2 , Hidekazu Hiramoto 1 , Junichi Hamada 1 , Tomohiro Arita 1 , Hirotaka Konishi 1 , Toshiyuki Kosuga 1 , Shuhei Komatsu 1 , Atsushi Shiozaki 1 , Kazuma Okamoto 1 , Issei Imoto 2 , Eigo Otsuji 1 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan 2 Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan Correspondence to: Daisuke Ichikawa, email: ichikawa@koto.kpu-m.ac.jp Issei Imoto, email: issehgen@tokushima-u.ac.jp Keywords: gastric cancer, Epstein–Barr virus, liquid biopsy Received: October 29, 2016 Accepted: February 6, 2017 Published: February 24, 2017 ABSTRACT Recent comprehensive molecular subtyping of gastric cancer (GC) identified Epstein–Barr virus (EBV)-positive tumors as a subtype with distinct salient molecular and clinical features. In this study, we aimed to determine the potential utility of circulating cell-free EBV DNA as a biomarker for the detection and/or monitoring of therapeutic response in patients with EBV-associated gastric carcinoma (EBVaGC). The EBV genes-to-ribonuclease P RNA component H1 ratios (EBV ratios) in the GC tumors and plasma samples were determined by quantitative real-time polymerase chain reaction in 153 patients with GC, including 14 patients with EBVaGC diagnosed by the conventional method. Circulating cell-free EBV DNA was detected in 14 patients with GC: the sensitivity and specificity of detection were 71.4% (10/14) and 97.1% (135/139), respectively. Plasma EBV ratios were significantly correlated with the size of EBVaGC tumors, and the plasma EBV DNA detected before surgery in EBVaGC cases disappeared after surgery. Patients with EBVaGC may have a better prognosis, but circulating cell-free EBV DNA had no or little impact on prognosis. In addition, repeated assessment of the plasma EBV ratio in EBVaGC showed a decrease and increase in plasma EBV DNA after treatment and during tumor progression/recurrence, respectively. These results suggest the potential utility of circulating cell-free DNA to reveal EBV DNA for the identification of the EBVaGC subtype and/or for real-time monitoring of tumor progression as well as treatment response in patients with EBVaGC.
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- 2017
46. The association between circulating tumor cells and Epstein-Barr virus activation in patients with nasopharyngeal carcinoma
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Caiyun He, Xiao Zhang, Xin-Jun Huang, Xing Lv, Xiang Guo, Xuan Su, Jiang-Jun Ma, and Tao Tang
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Male ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,otorhinolaryngologic diseases ,medicine ,Humans ,In patient ,Clinical significance ,Antigens, Viral ,Pharmacology ,Nasopharyngeal Carcinoma ,Carcinoma ,Nasopharyngeal Neoplasms ,Middle Aged ,Neoplastic Cells, Circulating ,medicine.disease ,Epstein–Barr virus ,Clinical Practice ,stomatognathic diseases ,030104 developmental biology ,Oncology ,Nasopharyngeal carcinoma ,030220 oncology & carcinogenesis ,Molecular Medicine ,Capsid Proteins ,Research Paper - Abstract
Background: Circulating tumor cells (CTCs) and microemboli (CTM) are attracting increasing attention in medical biology and clinical practice. However, the clinical relevance of CTCs in nasopharyngeal carcinoma (NPC) has not yet been ascertained, and no study has focused on the influence of Epstein-Barr virus (EBV) status on CTCs in NPC patients. These issues were therefore examined. Methods: Peripheral blood samples were prospectively obtained from 33 NPC patients before treatment. CTCs and CTM were captured using the Isolation by Size of Epithelial Tumor (ISET) method. Immunohistochemistry on CK5/6 (cytokeratin5/6) and P63, as well as in situ hybridization of EBERs (EBV-encoded RNAs) were used to validate the harvested tumor cells. Results: Out of 33 NPC patients, CTCs were detected in 22 cases (66.7%), and CTM were observed in 2 cases (6.1%). CTCs were presented in all stages of NPC patients but had no association with the TNM stages (all P > 0.05). The presence of CTCs appeared to correlate with EBV activation status. Among the total NPC patients, the EBV VCA-IgA levels in CTC-positive cases were higher than that in CTC-negative cases (negative vs. positive: 3.88 vs. 4.86, P = 0.016). A similar result was observed in the patients without distant metastasis (negative vs. positive: 3.76 vs. 4.95, P = 0.009). When the number of CTCs was considered, CTC counts were found to correlate with EBV VCA-IgA (R = 0.382, P = 0.041) and EBV DNA load (R = 0.396, P = 0.033) for all NPC patients as well as NPC patients without distant metastases. Conclusions: These findings strongly suggested detectable CTCs/CTM in all stages of NPC patients and support a positive correlation between CTCs and EBV activation in NPC patients.
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- 2017
47. High level of viral microRNA-BART20-5p expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer
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Wansik Yu, Han Ik Bae, Byung Woog Kang, Hyojeung Kang, Seong Woo Jeon, Ho Young Chung, Yong-Hun Choi, Suk Kyeong Lee, Jong Gwang Kim, An Na Seo, Keun Hur, Seung Soo Lee, and Oh Kyoung Kwon
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Adult ,Male ,0301 basic medicine ,Gerontology ,Oncology ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,medicine.medical_specialty ,Normal tissue ,Adenocarcinoma ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Mirna expression ,Internal medicine ,microRNA ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,Neoplasm Staging ,Pathologic stage ,epstein-barr virus ,business.industry ,gastric cancer ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Epstein–Barr virus ,Tumor tissue ,Survival Rate ,MicroRNAs ,030104 developmental biology ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Female ,Cutoff point ,BART ,business ,Research Paper ,Follow-Up Studies - Abstract
// Byung Woog Kang 1, * , YongHun Choi 2, 3, * , Oh Kyoung Kwon 4 , Seung Soo Lee 4 , Ho Young Chung 4 , Wansik Yu 4 , Han Ik Bae 5 , An Na Seo 5 , Hyojeung Kang 6 , Suk Kyeong Lee 7 , Seong Woo Jeon 8 , Keun Hur 2, 3 , Jong Gwang Kim 1 1 Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Kyungpook National University Cancer Research Institute, Kyungpook National University, Daegu, South Korea 2 Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea 3 BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, South Korea 4 Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, South Korea 5 Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, South Korea 6 College of Pharmacy, Institute of Microorganisms and Research Institute of Pharmaceutical Sciences, Kyunpook National University, Daegu, South Korea 7 Department of Medical Lifescience, College of Medicine, Catholic University of Korea, Seoul, South Korea 8 Department of Gastroeneterology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, South Korea * These authors contributed equally to this work Correspondence to: Jong Gwang Kim, email: jkk21c@knu.ac.kr Keun Hur, email: KeunHur@knu.ac.kr Keywords: gastric cancer, epstein-barr virus, microRNA, prognosis, BART Received: August 02, 2016 Accepted: January 10, 2017 Published: January 19, 2017 ABSTRACT This study analyzed the relationship between several Epstein-Barr virus (EBV) microRNA (miRNA) expression profiles and the clinicopathologic features of patients with EBV-associated gastric cancer. The miRNA expression was examined in 59 tumor and 39 paired normal mucosal tissues from available formalin-fixed paraffin embedded tissue samples. The expression levels of miR-BamHI fragment A rightward transcript (BART)1-5p, miR-BART4-5p, and miR-BART20-5p were determined using a quantitative real-time polymerase chain reaction. The expression of all three analyzed EBV microRNAs was significantly higher in the tumor tissue than in the paired normal tissue ( P < 0.001 for each). When the median value of the EBV microRNA expression levels was used as the cutoff point, a high BART20-5p expression was associated with worse recurrence-free survival ( P = 0.034) in a multivariate analysis including age and pathologic stage. In conclusion, the expression level of BART20-5p may predict recurrence-free survival for patients with EBV-associated gastric cancer. Further studies are warranted to clarify the roles of EBV BART microRNAs in the carcinogenesis, and their potential as a biomarker and therapeutic target for EBV-associated gastric cancer.
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- 2017
48. Clinical impact of serum survivin positivity and tissue expression of EBV-encoded RNA in diffuse large B-cell lymphoma patients treated with rituximab-CHOP
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Jung Yong Hong, Seok Jin Kim, Chaehwa Park, Mineui Hong, Kyung Ju Ryu, Won Seog Kim, and Young Hyeh Ko
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Male ,0301 basic medicine ,Oncology ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Pathology ,Survivin ,Kaplan-Meier Estimate ,CHOP ,medicine.disease_cause ,Inhibitor of Apoptosis Proteins ,Cohort Studies ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Prospective Studies ,Prospective cohort study ,In Situ Hybridization ,epstein-barr virus ,Middle Aged ,Prognosis ,Treatment Outcome ,Vincristine ,030220 oncology & carcinogenesis ,RNA, Viral ,Female ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,Research Paper ,medicine.drug ,Adult ,medicine.medical_specialty ,diffuse large B-cell lymphoma ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,neoplasms ,Cyclophosphamide ,Aged ,Proportional Hazards Models ,business.industry ,medicine.disease ,Epstein–Barr virus ,Lymphoma ,030104 developmental biology ,Doxorubicin ,Concomitant ,Prednisone ,business ,Diffuse large B-cell lymphoma - Abstract
// Jung Yong Hong 1 , Kyung Ju Ryu 2 , Chaehwa Park 3 , Mineui Hong 4 , Young Hyeh Ko 5 , Won Seog Kim 6 , Seok Jin Kim 2, 6 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea 2 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea 3 Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea 5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Correspondence to: Seok Jin Kim, email: kstwoh@skku.edu Keywords: survivin, epstein-barr virus, diffuse large B-cell lymphoma Received: May 14, 2016 Accepted: January 03, 2017 Published: January 13, 2017 ABSTRACT Survivin is an inhibitor of apoptosis and is upregulated by Epstein–Barr virus (EBV) latent genes. Given the frequent association of EBV with lymphoid malignancies, survivin is expected to have prognostic value in diffuse large B-cell lymphoma (DLBCL). Thus, we measured the pretreatment serum level of survivin in DLBCL patients and analyzed its association with survival outcome and EBV status, as represented by EBV-encoded RNA (EBER) in DLBCL. Pretreatment serum survivin level was measured in patients registered in a prospective cohort study ( n = 210), and serum survivin-positivity was defined as any detectable level of survivin. EBV status was determined using EBER in situ hybridization, and EBER-positivity was defined as 20% of examined cells showing nuclear positivity. Mean serum survivin level was higher in patients with relapsed or refractory disease than with responsive disease (59.89 pg/mL versus 17.34 pg/mL, P = 0.041). Serum survivin-positive patients had worse overall and progression-free survival ( P = 0.023 and 0.022, respectively). Serum survivin positivity was associated with unfavorable characteristics including stage. In patients with non-germinal center B-cell type DLBCL, serum survivin-positive patients also had significantly worse survival than serum survivin-negative patients ( P < 0.001). EBER-positivity was found in 6.7% (14/210) of patients, and EBER-positive patients had worse survival ( P < 0.05). Patients having concomitant positivity for serum survivin and EBER expression (2.8%, 6/210) showed extremely poor prognosis. In the present era of rituximab in DLBCL, DLBCL with serum survivin positivity showed adverse clinical features and followed worse clinical course, especially in non-GCB subtype DLBCL. EBER-positivity was still associated with worse outcomes in DLBCL.
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- 2017
49. Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients
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Marie-José Melief, Marvin M van Luijn, Werner J. D. Ouwendijk, Anton W. Langerak, Samira S. Michels, Gijsbert P. van Nierop, Rogier Q. Hintzen, Georges M. G. M. Verjans, Malou Janssen, Virology, Immunology, and Neurology
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,CD8 T cells ,Pathogenesis ,CD8-Positive T-Lymphocytes ,Biology ,Autoantigens ,Pathology and Forensic Medicine ,Epstein–Barr virus ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Interleukin 21 ,0302 clinical medicine ,Antigen ,medicine ,Humans ,Cytotoxic T cell ,Antigen-presenting cell ,Aged ,Aged, 80 and over ,Original Paper ,Immunological synapse formation ,CD137 ,Middle Aged ,Flow Cytometry ,White Matter ,Granzyme B ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery ,CD8 ,030215 immunology - Abstract
T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1744-4) contains supplementary material, which is available to authorized users.
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- 2017
50. Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency
- Author
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Kimberly A. Malecka, Troy E. Messick, Andreas Wiedmer, Jayaraju Dheekollu, Paul M. Lieberman, Alan K. S. Chiang, Dario C. Altieri, and Henri Jacques Delecluse
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0301 basic medicine ,Biology ,survivin ,Recombinant virus ,medicine.disease_cause ,Virus ,03 medical and health sciences ,hemic and lymphatic diseases ,Survivin ,medicine ,otorhinolaryngologic diseases ,epstein-barr virus (EBV) ,latency ,EBNA1 ,nasopharyngeal carcinoma (NPC) ,DNA-binding domain ,medicine.disease ,Virology ,Epstein–Barr virus ,3. Good health ,stomatognathic diseases ,030104 developmental biology ,Oncology ,Lytic cycle ,Nasopharyngeal carcinoma ,Carcinogenesis ,Priority Research Paper - Abstract
// Jayaraju Dheekollu 1 , Kimberly Malecka 1 , Andreas Wiedmer 1 , Henri-Jacques Delecluse 2 , Alan K.S. Chiang 3 , Dario C. Altieri 1 , Troy E. Messick 1 and Paul M. Lieberman 1 1 The Wistar Institute, Philadelphia, PA USA 2 Deutsches Krebsforschungszentrum, Heidelberg, Germany 3 Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong Correspondence to: Paul M. Lieberman, email: // Keywords : epstein-barr virus (EBV), EBNA1, nasopharyngeal carcinoma (NPC), survivin, latency Received : October 29, 2016 Accepted : December 26, 2016 Published : January 06, 2017 Abstract Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.
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- 2017
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