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N6-methyladenosine methylation regulates the tumor microenvironment of epstein-barr virus-associated gastric cancer

World Journal of Gastrointestinal Oncology 2024年第6期16卷 2555-2570页

作者： Yu Zhang Fang Zhou Ming-Yu Zhang Li-Na Feng Jia-Lun Guan Ruo-Nan Dong Yu-Jie Huang Su-Hong Xia Jia-Zhi Liao Kai Zhao Department of Gastroenterology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030Hubei ProvinceChina Institute of Liver and Gastrointestinal Diseases Hubei Key Laboratory of Hepato-Pancreato-Biliary DiseasesTongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030Hubei ProvinceChina Department of Pharmacy Wuhan Fourth HospitalWuhan 430030Hubei ProvinceChina

BACKGROUND N6-methyladenosine(m6A)methylation modification exists in epstein-barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric cancer(EBVaGC)is a distinctive molecular subtype of GC.We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.METHODS First,The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC(EBVnGC).Second,we identified Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment of m6A-related differentially expressed genes.We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment(TME).Finally,cell counting kit-8 cell proliferation test,transwell test,and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1(IGFBP1)in EBVaGC cell lines.RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC.Compared with EBVnGC,the expression levels of m6A methylation regulators Wilms tumor 1-associated protein,RNA binding motif protein 15B,CBL proto-oncogene like 1,leucine rich pentatricopeptide repeat containing,heterogeneous nuclear ribonucleoprotein A2B1,IGFBP1,and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC(P<0.05).The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher(P=0.046).GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC.Compared with EBVnGC,the infiltration of activated CD4+T cells,activated CD8+T cells,monocytes,activated dendritic cells,and plasm

关键词： N6-methyladenosine methylation Tumor microenvironment epstein-barr virus Gastric cancer Insulin-like growth factor binding protein 1

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Research Advances in Infectious Mononucleosis Caused by epstein-barr virus

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Open Journal of Pediatrics 2024年第1期14卷 108-121页

作者： Yuying Wang Peng Chen Department of Pediatrics The Second Hospital of Jilin University Changchun China

Infectious mononucleosis (IM), primarily caused by the epstein-barr virus (EBV), manifests as the classic triad of fever, pharyngitis, and cervical lymphadenopathy. Severe cases may involve organ damage, most commonly affecting the liver. Diagnosis relies on a combination of clinical presentation and laboratory parameters, with commonly used indicators including EBV-specific antibodies, EBV-DNA load, and the ratio of atypical lymphocytes. Treatment primarily involves symptomatic supportive care, with a cautious approach to the routine use of antiviral medications. In recent years, significant research in traditional Chinese medicine has been conducted in China, showing promising advancements. This article provides a comprehensive review of EBV-induced infectious mononucleosis, offering insights for clinical diagnosis and treatment.

关键词： epstein-barr virus Infectious Mononucleosis Children

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The Viral Load of epstein-barr virus in Blood of Children after Hematopoietic Stem Cell Transplantation

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Biomedical and Environmental Sciences 2022年第9期35卷 804-810页

作者： WANG Wen Jun FENG Shun Qiao HE Feng DU Hai Jun FENG Miao WANG Rui Fang MEI Guo Yong LIU Mi LIU Rong YAO Hai Lan HAN Jun State Key Laboratory of Infectious Disease Prevention and Control National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China Department of Hematology Children’s Hospital of Capital Institute of PediatricsBeijing 100020China Department of Biochemistry&Immunology Capital Institute of PediatricsBeijing 100020China

Objective To detect the epstein-barr virus(EBV)viral load of children after hematopoietic stem cell transplantation(HSCT)using chip digital PCR(cdPCR).Methods The sensitivity of cdPCR was determined using EBV plasmids and the EBV B95-8 strain.The specificity of EBV cdPCR was evaluated using the EBV B95-8 strain and other herpesviruses(herpes simplex virus 1,herpes simplex virus 2,varicella zoster virus,human cytomegalovirus,human herpesvirus 6,and human herpesvirus 7).From May 2019 to September 2020,64 serum samples of children following HSCT were collected.EBV infection and the viral load of serum samples were detected by cdPCR.The epidemiological characteristics of EBV infections were analyzed in HSCT patients.Results The limit of detection of EBV cdPCR was 110 copies/mL,and the limit of detection of EBV quantitative PCR was 327 copies/mL for the pUC57-BALF5 plasmid.The result of EBV cdPCR was up to 121 copies/mL in the EBV B95-8 strain,and both were more sensitive than that of quantitative PCR.Using cdPCR,the incidence of EBV infection was 18.75%in 64 children after HSCT.The minimum EBV viral load was 140 copies/mL,and the maximum viral load was 3,209 copies/mL using cdPCR.The average hospital stay of children with EBV infection(184±91 days)was longer than that of children without EBV infection(125±79 days),P=0.026.Conclusion EBV cdPCR had good sensitivity and specificity.The incidence of EBV infection was 18.75%in 64 children after HSCT from May 2019 to September 2020.EBV cdPCR could therefore be a novel method to detect EBV viral load in children after HSCT.

关键词： Chip digital PCR epstein-barr virus Hematopoietic stem cell transplantation Quantitative PCR

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Development of epstein-barr virus-associated gastric cancer:Infection,inflammation,and oncogenesis

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World Journal of Gastroenterology 2022年第44期28卷 6249-6257页

作者： Hisashi Iizasa Andy Visi Kartika Sintayehu Fekadu Shunpei Okada Daichi Onomura Afifah Fatimah Azzahra Ahmad Wadi Mosammat Mahmuda Khatun Thin Myat Moe Jun Nishikawa Hironori Yoshiyama Department of Microbiology Shimane University Faculty of MedicineIzumo 693-8501ShimaneJapan Faculty of Medicine Muslim University of IndonesiaMakassar 90231Indonesia Department of Medical Microbiology and Parasitology Hawassa UniversityCollege of Medicine and Health ScienceHawassa 1560Ethiopia Faculty of Laboratory Science Yamaguchi University Graduate School of MedicineUbe 755-8505Japan

epstein-barr virus(EBV)-associated gastric cancer(EBVaGC)cells originate from a single-cell clone infected with EBV.However,more than 95%of patients with gastric cancer have a history of Helicobacter pylori(H.pylori)infection,and H.pylori is a major causative agent of gastric cancer.Therefore,it has long been argued that H.pylori infection may affect the development of EBVaGC,a subtype of gastric cancer.Atrophic gastrointestinal inflammation,a symptom of H.pylori infection,is observed in the gastric mucosa of EBVaGC.Therefore,it remains unclear whether H.pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H.pylori and EBV infections act independently on gastric cancer formation.It has been reported that EBV infection assists in the oncogenesis of gastric cancer caused by H.pylori infection.In contrast,several studies have reported that H.pylori infection accelerates tumorigenesis initiated by EBV infection.By reviewing both clinical epidemiological and experimental data,we reorganized the role of H.pylori and EBV infections in gastric cancer formation.

关键词： Helicobacter pylori epstein-barr virus epstein-barr virus-associated gastric cancer Coreceptor Inflammation Oncogenesis

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epstein–barr-virus-associated hepatitis with aplastic anemia: A case report

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World Journal of Clinical Cases 2022年第23期10卷 8242-8248页

作者： Wan-Jun Zhang Li-Qiang Wu Jun Wang Sheng-Yun Lin Bo Wang Department of Hematology The First Affiliated HospitalZhejiang Chinese Medical UniversityHangzhou 310006Zhejiang ProvinceChina

BACKGROUND Hepatitis-associated aplastic anemia(HAAA) is a rare condition. Patients with HAAA usually present with acute hepatitis, jaundice and significantly increased transaminase. After 1–2 mo, hepatitis gradually improves, but progressive hemocytopenia, bone marrow hematopoietic failure, and severe or extremely severe aplastic anemia are manifest. Most cases of HAAA are fulminant and usually lethal if left untreated. The literature on epstein–barr virus(EBV)-associated HAAA is sparse.CASE SUMMARY We report a 30-year-old man who was admitted to our hospital because of pale yellow urine and skin with a simultaneous decrease in peripheral blood ternary cells. We made a diagnosis of EBV-associated HAAA. The treatment strategy for this patient included eltrombopag, an immunosuppressive regimen of rabbit antihuman thymocyte immunoglobulin, cyclosporine, and supportive care. The patient was discharged in normal physical condition after five months. A hemogram performed on follow-up revealed that he had achieved a complete response.CONCLUSION Eltrombopag plus anti-thymocyte globubin and cyclosporine may be a therapeutic option for EBV-associated HAAA.Larger studies are warranted to confirm.

关键词： epstein-barr virus Hepatitis-associated aplastic anemia Immunosuppressive therapy Eltrombopag Case report

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Positive correlation between latent epstein-barr virus infection and severity of illness in inflammatory bowel disease patients

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World Journal of Gastrointestinal Surgery 2023年第3期15卷 420-429页

作者： Hong-Tao Wei Xiao-Wei Xue Qing Ling Peng-Yan Wang Wei-Xun Zhou Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Department of Pathology Molecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical ScienceBeijing 100730China

BACKGROUND Emerging studies indicate the critical involvement of microorganisms,such as epstein-barr virus(EBV),in the pathogenesis of inflammatory bowel disease(IBD).Immunosuppressive therapies for IBD can reactivate latent EBV,complicating the clinical course of IBD.Moreover,the clinical significance of EBV expression in B lymphocytes derived from IBD patients’intestinal tissues has not been explored in detail.AIM To explore the clinical significance of latent EBV infection in IBD patients.METHODS Latent EBV infection was determined by double staining for EBV encoded RNA and CD20 in colon specimens of 43 IBD patients who underwent bowel resection.Based on the staining results,the patients were divided into two groups,according to their latent EBV infection states-negative(n=33)and positive(n=10).Illness severity of IBD were assigned according to Crohn’s disease activity index(ulcerative colitis)and Mayo staging system(Crohn’s disease).The clinicpathological data were analyzed between the two different latent EBV groups and also between the mild-to-moderate and severe disease groups.RESULTS Systolic pressure(P=0.005),variety of disease(P=0.005),the severity of illness(P=0.002),and pre-op corticosteroids(P=0.025)were significantly different between the EBV-negative and EBV-positive groups.Systolic pressure(P=0.001),variety of disease(P=0.000),pre-op corticosteroids(P=0.011)and EBV infection(P=0.003)were significantly different between the mild-to-moderate and severe disease groups.CONCLUSION IBD patients with latent EBV infection may manifest more severe illnesses.It is suggested that the role of EBV in IBD development should be further investigated,latent EBV infection in patients with serious IBD should be closely monitored,and therapeutic course should be optimized.

关键词： epstein-barr virus epstein-barr virus encoded RNA Inflammatory bowel disease Crohn’s disease Ulcerative colitis

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Machine learning algorithm as a prognostic tool for epstein-barr virus reactivation after haploidentical hematopoietic stem cell transplantation

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Blood Science 2023年第1期5卷 51-59页

作者： ShuangFan Hao-Yang Hong Xin-Yu Dong Lan-Ping Xu Xiao-Hui Zhang Yu Wang Chen-Hua Yan Huan Chen Yu-Hong Chen Wei Han Feng-Rong Wang Jing-Zhi Wanga Kai-Yan Liu Meng-Zhu Shen Xiao-Jun Huang Shen-Da Hong Xiao-Dong Mo Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijingChina The Chinese University of Hong Kong ShenzhenShenzhenChina National Institute of Health Data Science at Peking University Peking University Health Science CenterBeijingChina Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies Chinese Academy of Medical SciencesBeijingChina

epstein-barr virus(EBV)reactivation is one of the most important infections after hematopoietic stem cell transplantation(HSCT)using haplo-identical related donors(HID).We aimed to establish a comprehensive model with machine learning,which could predict EBV reactivation after HID HSCT with anti-thymocyte globulin(ATG)for graft-versus-host disease(GVHD)prophylaxis.We enrolled 470 consecutive acute leukemia patients,60%of them(n=282)randomly selected as a training cohort,the remaining 40%(n=188)as a validation cohort.The equation was as follows:Probability(EBV reactivation)=1/1+exp(−Y),where Y=0.0250×(age)–0.3614×(gender)+0.0668×(underlying disease)–0.6297×(disease status before HSCT)–0.0726×(disease risk index)–0.0118×(hematopoietic cell transplantation-specific comorbidity index[HCT-CI]score)+1.2037×(human leukocyte antigen disparity)+0.5347×(EBV serostatus)+0.1605×(conditioning regimen)–0.2270×(donor/recipient gender matched)+0.2304×(donor/recipient relation)–0.0170×(mononuclear cell counts in graft)+0.0395×(CD34+cell count in graft)–2.4510.The threshold of probability was 0.4623,which separated patients into low-and high-risk groups.The 1-year cumulative incidence of EBV reactivation in the low-and high-risk groups was 11.0%versus 24.5%(P<.001),10.7%versus 19.3%(P=.046),and 11.4%versus 31.6%(P=.001),respectively,in total,training and validation cohorts.The model could also predict relapse and survival after HID HSCT.We established a comprehensive model that could predict EBV reactivation in HID HSCT recipients using ATG for GVHD prophylaxis.

关键词： Anti-thymocyte globulin epstein-barr virus Haplo-identical hematopoietic stem cell transplant Machine learning Predictive model

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epstein-barr virus-induced infection-associated hemophagocytic lymphohistiocytosis with acute liver injury:A case report

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World Journal of Clinical Cases 2023年第17期11卷 4090-4097页

作者： Fang-Yuan Sun Bing-Qing Ouyang Xiao-Xiao Li Tao Zhang Wen-Tao Feng Yao-Guo Han Trauma Emergency Center The Seventh People’s Hospital of Shanghai University of Traditional Chinese MedicineShanghai 200137China

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a severe hyperinflammatory reaction,which is rare and life-threatening.According to the pathogen,HLH is divided into genetic and acquired.The most common form of acquired HLH is infection-associated HLH,of which Herpes viruses,particularly epstein-barr virus(EBV),are the leading infectious triggers.However,it is difficult to distinguish between simple infection with EBV and EBV-induced infectionassociated HLH since both can destroy the whole-body system,particularly the liver,thereby increasing the difficulty of diagnosis and treatment.CASE SUMMARY This paper elaborates a case about EBV-induced infection-associated HLH and acute liver injury,aiming to propose clinical guides for the early detection and treatment of patients with EBV-induced infection-associated HLH.The patient was categorized as acquired hemophagocytic syndrome in adults.After the ganciclovir antiviral treatment combined with meropenem antibacterial therapy and methylprednisolone inhibition to inflammatory response,gamma globulin enhanced immunotherapy,the patient recovered.CONCLUSION From the diagnosis and treatment of this patient,attention should be paid to routine EBV detection and a further comprehensive understanding of the disease as well as early recognition and early initiation are keys to patients’survival.

关键词： epstein-barr virus Hemophagocytic lymphohistiocytosis Computed tomography Case report

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Reactivation of epstein-barr virus in SFTSV infected patients

Infectious Medicine

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Infectious Medicine 2023年第3期2卷 195-201页

作者： Li-Zhu Fang Yu-Hong Dong Zhi-Jian Yan Chuan-Min Zhou Xue-Jie Yu Xiang-Rong Qin Qingdao City Center for Disease Control and Prevention Qingdao 266033China Sixth People’s Hospital Qingdao 266033China State Key Laboratory of Virology School of Public HealthWuhan UniversityWuhan 430071China Department of Clinical Laboratory the Second Hospital of Shandong UniversityJinan 250033China

Background:Severe fever with thrombocytopenia syndrome(SFTS)is an emerging hemorrhagic fever caused by a tick-borne bunyavirus SFTSV with case fatality up to 30%.The reactivation of epstein-barr virus(EBV)has been proven to occur in individuals with various immune suppression conditions.Methods:Here,we diagnosed 22 SFTSV infected patients with PCR in a hospital in Shandong Province,China in 2020.To understand the consequences of SFTSV infection leading to EBV reactivation,we examined EBV reactivation in SFTSV-infected patients with PCR and RT-PCR.Results:We found that EBV was reactivated in 18.2%(4/22)of SFTS patients,suggesting that EBV reactivation is common in SFTS patients.Compared with SFTS patients without EBV reactivation,SFTS patients with EBV-reactivation had a significantly lower median level of serum albumin(32.45 g/L vs.26.95 g/L,p=0.03)and a significantly higher median number of urine red blood cells(0 cells/μL vs.9 cells/μL,p=0.04).Conclusion:SFTS infection can reactivate EBV in patients,which may make the clinical condition of patients worsen.

关键词： Severe fever with thrombocytopenia syndrome virus epstein-barr virus Reactivation Glomerular injury

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epstein-barr virus-associated smooth muscle tumors in immunocompromised patients:Six case reports

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World Journal of Clinical Oncology 2022年第6期13卷 540-552页

作者： Afshin A Khan Bassam N Estfan Anirudh Yalamanchali Djibril Niang Erica C Savage Clifton G Fulmer Hailey L Gosnell Jamak Modaresi Esfeh Department of Internal Medicine Cleveland Clinic FoundationClevelandOH 44195United States Department of Solid Tumor Oncology Taussig Cancer InstituteCleveland Clinic FoundationClevelandOH 44195United States Department of Pathology Cleveland ClinicClevelandOH 44195United States Department of Pathology Cleveland Clinic FoundationClevelandOH 44195United States Department of Gastroenterology Hepatology and NutritionCleveland ClinicClevelandOH 44195United States

BACKGROUND epstein-barr virus associated smooth muscle tumor(EBV-SMT)is a rare oncological entity.However,there is an increasing incidence of EBV-SMTs,as the frequency of organ transplantation and immunosuppression grows.EBV-SMT diagnosis relies on histopathology and immunochemical staining to distinguish it from post-transplant lymphoproliferative disorder(PTLD).There is no clear consensus on the treatment of EBV-SMTs.However,surgical resection,chemotherapy,radiation therapy,and immunosuppression reduction have been explored with varying degrees of success.CASE SUMMARY Our case series includes six cases of EBV-SMTs across different age groups,with different treatment modalities,adding to the limited existing literature on this rare tumor.The median latency time between immunosuppression and disease diagnosis is four years.EBV-SMTs present with variable degrees of aggressiveness and seem to have worse clinical outcomes in patients with tumor multiplicity and worse immunocompetency.CONCLUSION It is imperative to continue building on this knowledge and keeping EBV-SMTs on the differential in immunocompromised individuals.

关键词： epstein-barr virus Smooth muscle tumors Human immunodeficiency virus epstein-barr virusassociated smooth muscle tumors Immunocompromised Solid Organ Transplant Orthotopic heart transplant Orthotopic liver transplant Living related kidney transplant Post-transplant lymphoproliferative disorders Case report

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