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Introduction: Gastric cancer is the fifth most common cancer worldwide and the fourth most common cause of cancer-related death. Two molecular subtyping classifications were recently introduced: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) classifications. Methods: We classified a cohort of 283 gastric cancer patients undergoing surgery at Helsinki University Hospital between 2000 and 2009. We constructed a tumour tissue microarray immunostained for the following markers: microsatellite instability (MSI) markers MSH2, MSH6, MLH1, and PMS2; p53; E-cadherin; and EBERISH. Results: In the univariate survival analysis for disease-specific survival, the Epstein–Barr virus (EBV) -positive subtype exhibited the worst prognosis with a hazard ratio (HR) of 2.49 (95% confidence interval [CI] 1.19–5.25, p = 0.016) compared with the most benign subtype, chromosomal instability (CIN). Using TCGA's classification, the genetically stable (GS) and MSI subtypes exhibited a worse survival compared with CIN (HR 1.73 [95% CI 1.15–2.60], p = 0.009 and HR 1.74 [95% CI 1.06–2.84], p = 0.027, respectively). Using the ACRG classification, the p53 aberrant subtype exhibited the best prognosis, whereas wild-type p53, MSI, and the epithelial–mesenchymal transition (EMT) subtypes exhibited poorer prognoses (EMT: HR 1.90 [95% CI 1.30–2.77], p < 0.001) when compared with aberrant p53. Conclusions: Immunohistochemical analysis can identify prognostically different molecular subtypes of gastric cancer. The method is inexpensive and fast, yet reveals significant information for clinical decision-making. However, our study did not find that either molecular subtyping performed better than the other classification. Thus, further development of the most optimal grouping of different molecular subtypes is still needed. [ABSTRACT FROM AUTHOR]

Dysregulated long non-coding RNA (lncRNA) expression is linked to various cancers and may be influenced by oncogenic Epstein–Barr virus (EBV) infection, a known and detectable risk factor in oral squamous cell carcinoma (OSCC) patients. However, research on the oncogenic role of EBV-induced lncRNAs in OSCC is limited. To identify lncRNA-associated EBV infection and OSCC carcinogenesis, the differential expression of RNA-seq datasets from paired normal adjacent and OSCC tissues, and microarray data from EBV-negative and EBV-positive SCC25 cells, were identified and selected, respectively, for interaction, functional analysis, and CCK-8 cell proliferation, wound healing, and invasion Transwell assays. In OSCC tissues, 6731 differentially expressed lncRNAs were identified when compared to normal tissues from RNA-seq datasets, with 295 linked to EBV-induced OSCC carcinogenesis from microarray datasets. The EBV-induced lncRNA VWA8-AS1 showed significant upregulation in EBV-positive SCC25 cells and EBV-infected adjacent and OSCC tissue samples. VWA8-AS1 potentially promotes OSCC via the lncRNA–miRNA–mRNA axis or direct protein interactions, affecting various cellular processes. Studies in OSCC cell lines revealed that elevated VWA8-AS1 levels enhanced cell migration and invasion. This study demonstrates VWA8-AS1's contribution to tumor progression and possible interactions with its targets in OSCC, offering insights for future research on functional mechanisms and therapeutic targets in EBV-associated OSCC. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the estimate of causal relationship between Epstein-Barr virus (EBV) antibody levels and autoimmune diseases (AIDs), such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), through bidirectional two-sample Mendelian randomization (MR) analysis. Despite 50 years of research into the link between EBV infection and AIDs, inconsistent results persist due to the complex mechanisms of EBV within the body. We utilized large-scale genome-wide association studies (GWAS) data from the Integrative Epidemiology Unit (IEU) Open GWAS Project database to conduct rigorous MR analysis, incorporating various sensitivity analyses to assess potential impacts and ensure robustness. EBV antibodies (including VCA-IgG, ZEBRA-IgG, EBNA-1-IgG, and EA-D-IgG) were used as exposure variables, whereas RA and SLE served as outcome variables. In the reverse analysis, RA and SLE were treated as exposure variables and EBV antibodies as outcome variables. When EBV antibodies are designated as the exposure variables, the random-effects inverse-variance weighted (IVW) analysis indicated a significant negative genetic causal relationship between EBV EA-D antibody levels and RA (p = 0.007, odds ratio [OR] = 0.700, 95% confidence interval [CI] = [0.539–0.907]). No significant genetic causal relationship was found between SLE and EBV antibody levels. When RA and SLE are designated as the exposure variables, the random-effects IVW analysis revealed significant positive genetic causal relationships between SLE and EBV ZEBRA antibody levels (p = 0.009, OR = 1.028, 95% CI = [1.007–1.050]) and EBV EA-D antibody levels (p = 0.005, OR = 1.032, 95% CI = [1.009–1.054]). No significant genetic causal relationship was observed between RA and EBV antibody levels. This study offers compelling evidence of a causal relationship between EBV antibody levels and AIDs through MR analysis. Our findings lay a new foundation and perspective for future research directions, clinical prognosis, and treatment. [ABSTRACT FROM AUTHOR]

Objective: To do the etiological analysis of ocular herps virus infection, revealing the pathogen species and the distribution of different virus types within the eye. Methods: Samples were collected from 2017 to 2021 at the Department of Ophthalmology, Peking University Third Hospital and tested using real-time PCR for common ocular viruses: herpes simplex virus 1 (HSV-1), cytomegalovirus (CMV), varicella-zoster virus (VZV) and Epstein-Barr virus (EBV). The pathogenesis of the different viruses was classified and analyzed according to the site of infection. Results: Viral PCR detections were performed on 3627 samples collected over the 5-years and 649 (17.89%) samples contained one or more of the viruses tested. The overall detection rate of CMV was highest at 9.93%. Of all sample types, aqueous humor was the most common (1752 cases), of which 340 were positive (19.41% positive rate). Corneal samples were the next most common, with 1481 cases and 250 positive results (16.88% positive rate). CMV positivity was higher in aqueous humor and corneal samples than other viruses; vitreous body had the highest positive rate at 36.36% (20/55), among which 18 cases were VZV positive. Conclusions: Distribution of virus types differed among infection sites, with CMV the most common virus type detected in the cornea and aqueous humor, while VZV was the most common virus detected in the vitreous body. Key message: What is known: • In recent years, ocular viral infections have attracted increasing attention from ophthalmologists, as more diseases with unknown etiology are now confirmed to be related to viral infection. • The Herpesviridae family is the most common cause of ocular viral infection. What is new: • We retrospectively analyzed the results of 3627 specimens from 2017 to 2021. No statistical analysis with large sample size and complete sample types similar to this study currently exists in the published literature. • Distribution of virus types differed among infection sites, with CMV the most common virus type detected in the cornea and aqueous humor, while VZV was the most common virus detected in the vitreous body. [ABSTRACT FROM AUTHOR]

Background: To report a case of coinfection of Toxoplasma gondii (Tg) and Epstein Barr Virus (EBV) in a diabetic patient with rheumatoid arthritis and immunosuppressive biological therapy. Case presentation: A 70-year-old female with a history of rheumatoid arthritis on therapy with corticosteroids, methotrexate, and abatacept presented bilateral granulomatous panuveitis associated with retinal necrosis and macular involvement. A diagnostic vitrectomy detected Tg and EBV. Treatment with clindamycin, trimethoprim-sulfamethoxazole, and acyclovir was established, achieving improvement. Conclusions: Patients undergoing immunosuppressive therapy are at risk of developing opportunistic infections, often presenting with severe and atypical clinical manifestations. In such cases, multiplex polymerase chain reaction is an invaluable diagnostic tool that helps identify the specific pathogens involved. This enables healthcare professionals to make informed treatment decisions and provide targeted therapy for each identified pathogen. [ABSTRACT FROM AUTHOR]

Background: Junctional epithelium (JE) provides the front-line defense against pathogens invading periodontium. The breakdown of the JE barrier is the hallmark of periodontitis. Recent studies have implicated the Epstein-Barr virus (EBV) as one of the etiopathogenetic factors of periodontitis. EBV exhibits tropism for two target cells invivo: B cells, where it primarily remains latent, and epithelial cells, where viral replication occurs. Objective: Our knowledge of junctional epithelial cell (JEC) infection with EBV has been limited by the difficulty of generating cell cultures and the inability to infect JECs invitro readily. Design: To study EBV infection in JECs, we developed human JEC cultures derived from a periodontitis patient. Furthermore, we established a successful contact-free co-culture infection model between the EBV-donor B95–8 cell line and the EBV-permissive JEC culture. JECs and EBV infection of JECs were detected using immunofluorescent staining of cytokeratin 19 and EBNA1, respectively. In addition, EBV infection was confirmed by RT-qPCR for EBNA1, LMP1, and BZLF1 expression. Results and conclusions: Our results suggest that the infection of JECs with EBV can occur in an invitro experimental model. These outcomes have the potential to enhance our understanding of EBV's involvement in periodontitis and advance periodontal research. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) was the first tumor virus identified in humans, and it is mostly linked to lymphomas and cancers of epithelial cells. Nevertheless, there is no FDA-licensed drug feasible for this ubiquitous EBV viral contagion. EBNA1 (Epstein-Barr nuclear antigen 1) plays several roles in the replication and transcriptional of latent gene expression of the EBV, making it an attractive druggable target for the treatment of EBV-related malignancies. The present study targets EBV viral reactivation and upkeep by inhibiting EBNA1 utilizing a drug-repurposing strategy. To hunt novel EBNA1 inhibitors, a SuperDRUG2 database (> 4,600 pharmaceutical ingredients) was virtually screened utilizing docking computations. In accordance with the estimated docking scores, the most promising drug candidates then underwent MDS (molecular dynamics simulations). Besides, the MM-GBSA approach was applied to estimate the binding affinities between the identified drug candidates and EBNA1. On the basis of MM-GBSA//200 ns MDS, bezitramide (SD000308), glyburide (SD001170), glisentide (SD001159), and glimepiride (SD001156) unveiled greater binding affinities towards EBNA1 compared to KWG, a reference inhibitor, with ΔGbinding values of −44.3, −44.0, −41.7, −40.2, and −32.4 kcal/mol, respectively. Per-residue decomposition analysis demonstrated that LYS477, ASN519, and LYS586 significantly interacted with the identified drug candidates within the EBNA1 binding pocket. Post-dynamic analyses also demonstrated high constancy of the identified drug candidates in complex with EBNA1 throughout 200 ns MDS. Ultimately, electrostatic potential and frontier molecular orbitals analyses were performed to estimate the chemical reactivity of the identified EBNA1 inhibitors. Considering the current outcomes, this study would be an adequate linchpin for forthcoming research associated with the inhibition of EBNA1; however, experimental assays are required to inspect the efficiency of these candidates. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV) is a ubiquitous gamma‐herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV‐related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune‐suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor‐infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune‐checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD‐1 and CTLA‐4 blockades in treating EBV‐associated tumors, several novel inhibitory receptors (e.g., CD47, LAG‐3, TIM‐3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV‐associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV‐associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are classified into the gammaherpesvirus subfamily of Herpesviridae, which stands out from its alpha- and betaherpesvirus relatives due to the tumorigenicity of its members. Although structures of human alpha- and betaherpesviruses by cryogenic electron tomography (cryoET) have been reported, reconstructions of intact human gammaherpesvirus virions remain elusive. Here, we structurally characterize extracellular virions of EBV and KSHV by deep learning-enhanced cryoET, resolving both previously known monomorphic capsid structures and previously unknown pleomorphic features beyond the capsid. Through subtomogram averaging and subsequent tomogram-guided sub-particle reconstruction, we determined the orientation of KSHV nucleocapsids from mature virions with respect to the portal to provide spatial context for the tegument within the virion. Both EBV and KSHV have an eccentric capsid position and polarized distribution of tegument. Tegument species span from the capsid to the envelope and may serve as scaffolds for tegumentation and envelopment. The envelopes of EBV and KSHV are less densely populated with glycoproteins than those of herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), representative members of alpha- and betaherpesviruses, respectively. Also, we observed fusion protein gB trimers exist within triplet arrangements in addition to standalone complexes, which is relevant to understanding dynamic processes such as fusion pore formation. Taken together, this study reveals nuanced yet important differences in the tegument and envelope architectures among human herpesviruses and provides insights into their varied cell tropism and infection. IMPORTANCE Discovered in 1964, Epstein-Barr virus (EBV) is the first identified human oncogenic virus and the founding member of the gammaherpesvirus subfamily. In 1994, another cancer-causing virus was discovered in lesions of AIDS patients and later named Kaposi's sarcoma-associated herpesvirus (KSHV), the second human gammaherpesvirus. Despite the historical importance of EBV and KSHV, technical difficulties with isolating large quantities of these viruses and the pleiomorphic nature of their envelope and tegument layers have limited structural characterization of their virions. In this study, we employed the latest technologies in cryogenic electron microscopy (cryoEM) and tomography (cryoET) supplemented with an artificial intelligence-powered data processing software package to reconstruct 3D structures of the EBV and KSHV virions. We uncovered unique properties of the envelope glycoproteins and tegument layers of both EBV and KSHV. Comparison of these features with their non-tumorigenic counterparts provides insights into their relevance during infection. [ABSTRACT FROM AUTHOR]

The article focuses on the prevalence of herpesviruses among the Yanomami indigenous population and their association with Heck's disease. Topics include the detection of various herpesviruses (such as HSV-1, EBV, and HHV-6) in saliva, the clinical presentation of Heck's disease, and the demographic factors influencing viral excretion and disease manifestation.

Since Epstein–Barr Virus (EBV) was isolated 60 years ago, it has been studied clinically, epidemiologically, immunologically, and molecularly in the ensuing years. These combined studies allow a broad mechanistic understanding of how this ubiquitous human pathogen which infects more than 90% of adults can rarely cause multiple types of lymphomas. We survey these findings to provide a coherent description of its oncogenesis. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV), a member of the gamma herpesvirus, is the first identified human oncovirus and is associated with various malignancies. Understanding the intricate interactions between EBV antigens and cellular pathways is crucial to unraveling the molecular mechanisms in EBV-mediated diseases. However, fully elucidating EBV–host interactions and the associated pathogenesis remains a significant challenge. In this study, we employed large language models (LLMs) to screen 36,105 EBV-relevant scientific publications and summarize the current literature landscape on various EBV-associated diseases like Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and so on. LLM-generated data indicate that the most-studied EBV-associated pathways are enriched in immune response, apoptosis, cell growth, and replication. The analyses of protein–protein interactions (PPIs) reveal three principal EBV-related protein clusters: TP53-centered apoptotic factors, EBV-associated transcription factors, and immune response elements. Utilizing our dataset and public databases, we demonstrated that BLLF3-targeted TLR2-associated factors are effective diagnostic markers for DLBCL. Next, we confirmed the co-expression of LMP1-targeted calcium pathway factors in BL. Finally, we demonstrated the correlation and co-expression of LMP1-induced PARP1, HIF1A, HK2, and key glycolysis-related factors, further suggesting that LMP1 actively regulates the glycolysis pathway. Therefore, our study presents a comprehensive functional encyclopedia of the interactions between EBV antigens and host signaling pathways across various EBV-associated diseases, providing valuable insights for the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

The article focuses on pediatric sore throats in the emergency department, highlighting the need to differentiate viral and bacterial causes, identify life-threatening conditions like epiglottitis, and implement effective diagnostic and treatment strategies.

Lung transplantation is an effective means of treating various end-stage lung diseases. However, compared with other solid organ transplants, the survival rate after lung transplantation is relatively low. The main reason is the numerous complications after lung transplantation, among which infection is one of the most common complications. Respiratory viral infections are an important type of infection after lung transplantation, which severely affect the survival time and quality of life of lung transplant recipients. Early identification, early prevention, and active diagnosis and treatment are of great significance in reducing the incidence and fatality of respiratory viral infections after lung transplantation. This article reviews the epidemiology, risk factors, prevention and treatment principles, and specific prevention and treatment progress of common viruses in respiratory viral infections after lung transplantation at home and abroad, in order to provide a reference for the prevention and treatment of respiratory viral infections after lung transplantation in clinical practice. [ABSTRACT FROM AUTHOR]

Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology. [ABSTRACT FROM AUTHOR]

Background: Information related to herpes simplex virus 1 and 2 (HSV-1 and 2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) seroprevalence in France is either lacking, incomplete, or outdated, despite their public health burden. Method: We used routinely collected serological data between 2018 and 2022 to estimate HSV-1, HSV-2, VZV, EBV, and CMV seroprevalence in France. To account for demographic differences between our analytic samples and the French population and get estimates for sparsely sampled districts and age classes, we used a multilevel regression and poststratification approach combined with Bayesian model averaging via stacking weights. Results: The observed seroprevalence (number of positive tests/number of tests) were 64.6% (93,294/144,424), 16.9% (24,316/144,159), 93.0% (141,419/152,084), 83.4% (63,199/75, 781), and 49.0% (23,276/47,525), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV. Between 2018 and 2022, France had a model-based average (equal-tailed interval at 95%) expected seroprevalence equal to 61.1% (60.7,61.5), 14.5% (14.2,14.81), 89.5% (89.3,89.8), 85.6% (85.2,86.0), and 50.5% (49.3,51.7), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV infections. We found an almost certain lower expected seroprevalence in Metropolitan France than in overseas territories for all viruses but VZV, for which it was almost certainly greater. The expected seroprevalences were likely greater among females for all viruses. Limitations: Our results relied on the assumption that individuals were sampled at random conditionally to variables used to build the poststratification table. Implications: The analysis highlights spatial and demographic patterns in seroprevalence that should be considered for designing tailored public health policies. [ABSTRACT FROM AUTHOR]

A DNA tumor virus called Epstein-Barr virus (EBV) is the cause of 1-2% of human cancers. EBV-associated carcinogenesis is caused by a persistent latent infection. The shortage of antiviral medications or vaccinations to control the virus led to a significant percentage of critically sickness individuals needing to be hospitalized. In the absence of an effective vaccine and approved drug, there is an immediate need for treatments that can combat EBV infection. Epstein Barr nuclear antigen 1 (EBNA1) is continually expressed in all malignancies linked to EBV; it is a desirable target for curative interference. Herein, natural product compounds from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database were mined to identify potent EBNA1 inhibitors. The performance of the molecular docking technique was initially assessed in expecting the ligand-target binding pose according to the available experimental data. On the basis of the estimated docking protocol, the NuBBE database was virtually screened toward the EBNA1 protein, and the natural compounds with binding scores less than KWG (calc. − 7. 8 kcal/mol) were subjected to molecular dynamics (MD) simulations followed by binding energy (Δ G binding ) calculation using MM/GBSA approach. Based on binding energy computations, NuBBE1460 revealed superior Δ G binding with a value of − 3 6. 2 kcal/mol, compared to KWG (calc. − 3 2. 4 kcal/mol). Post-MD analyses displayed a high steadiness of NuBBE1460 within the EBNA1 protein binding pocket. Furthermore, the physicochemical, pharmacokinetic and toxicity features of the identified compound were predicted, demonstrating high degrees of its oral bioavailability. The energetical and geometrical properties of NuBBE1460 were calculated using the DFT method. Conclusively, this study offers NuBBE1460 obtained from natural sources as a lead EBNA1 inhibitor for future investigation and development as a therapeutic for EBV. NuBBE database was virtually screened as potent EBNA1 inhibitors using in-silico calculations. Compared to KWG, a reference inhibitor, NuBBE1460 exhibited better binding affinity against EBNA1. NuBBE1460 demonstrated promising stability in complex with EBNA1 and unveiled good oral bioavailability. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur. [ABSTRACT FROM AUTHOR]

Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins—KNG1, MICB, and PKD2—with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications. [ABSTRACT FROM AUTHOR]

In Burkitt's lymphoma (BL), Epstein–Barr virus-encoded microRNAs (EBV miRNAs) are emerging as crucial regulatory agents that impact cellular and viral gene regulation. This review investigates the multifaceted functions of EBV miRNAs in the pathogenesis of Burkitt lymphoma. EBV miRNAs regulate several cellular processes that are essential for BL development, such as apoptosis, immune evasion, and cellular proliferation. These small, non-coding RNAs target both viral and host mRNAs, finely adjusting the cellular environment to favor oncogenesis. Prominent miRNAs, such as BART (BamHI-A rightward transcript) and BHRF1 (BamHI fragment H rightward open reading frame 1), are emphasized for their roles in tumor growth and immune regulation. For example, BART miRNAs prevent apoptosis by suppressing pro-apoptotic proteins, whereas BHRF1 miRNAs promote viral latency and immunological evasion. Understanding the intricate connections among EBV miRNAs and their targets illuminates BL pathogenesis and suggests novel treatment approaches. Targeting EBV miRNAs or their specific pathways offers a feasible option for developing innovative therapies that aim to disrupt the carcinogenic processes initiated by these viral components. future studies should focus on precisely mapping miRNA‒target networks and developing miRNA-based diagnostic and therapeutic tools. This comprehensive article highlights the importance of EBV miRNAs in Burkitt lymphoma, indicating their potential as biomarkers and targets for innovative treatment strategies. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE. [Display omitted] • Neoself-antigens are presented on MHC-II at low levels of the invariant chain • Lupus-like disease developed upon deletion of the invariant chain from adult mice • Clonal expansion of neoself-reactive T cells was found in SLE patients • Epstein-Barr virus reactivation is one of the factors for neoself-antigen presentation The discrimination of self- and neoself-antigens by T cells plays a crucial role in the activation of autoreactive T cells, leading to the development of autoimmunity. The reactivation of the Epstein-Barr virus is a possible factor that causes MHC class II molecules to present neoself-antigens by decreasing the expression of the invariant chain. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein-Barr virus (EBV) latently infects over 90% of adults worldwide and is linked to several cancers such as Burkitt lymphoma. Amongst the few factors expressed by the EBV during latent infection are microRNAs (miRNAs) that can regulate both viral and cellular gene expression. In this study, we examined cellular targets of EBV miRNAs. Through bioinformatics and molecular analysis, we provide evidence of 52 new functional interactions for EBV miRNAs with protein-coding transcripts involved in B cell differentiation, cell cycle, and intracellular trafficking. Collectively, these data provide a resource for EBV miRNA targets and yield important insight into functional roles for these viral factors in B cell cancers. MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1, IRF4, and MYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, and NPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, and RANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers. [ABSTRACT FROM AUTHOR]

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT. [ABSTRACT FROM AUTHOR]

Chronic active Epstein-Barr virus infection (CAEBV) is a progressive and life-threatening disease characterized by persistent or recurrent EBV activation. It has been reported that, γδ T cells, a type of cytotoxic lymphocyte, play a critical role in restricting EBV. However, the functional status of γδ T cells in pediatric CAEBV patients has not yet been described. In this study, flow cytometry analysis was conducted to explore the cytokine production capacity of γδ T cells in CAEBV patients. A diminished frequency of γδ T cells and decreased expression of cytolytic molecule granzyme B were found in CAEBV patients, suggesting a dysfunction in the immune regulatory function of γδ T cells in this disease. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectivesMethodsResultsConclusionsMycotoxins, fungal metabolites prevalent in many foods, are recognized for their role in carcinogenesis, especially when interacting with oncogenic viruses.This scoping review synthesizes current evidence on the human cancer risk associated with mycotoxin exposure and oncogenic virus infections.Searches were conducted on PubMed, Embase, and Web of Science. Studies were selected based on the PECOS framework. Data extraction involved narrative and qualitative presentation of findings, with meta-analysis where feasible. Risk of bias and outcome quality were assessed using the OHAT tool and GRADE approach.From 25 included studies, 18 focused on aflatoxins and hepatitis viruses in hepatocellular carcinoma (HCC). Four studies examined aflatoxin B1 (AFB1) and human papilloma virus (HPV) in cervical cancer, while three investigated AFB1 with Epstein-Barr virus (EBV) in lymphomagenesis. The review highlights a significant synergistic effect between AFB1 and hepatitis B and C viruses in HCC development. Significant interactions between AFB1 and HPV, as well as AFB1 and EBV, were observed, but further research is needed.The synergistic impact of mycotoxins and oncogenic viruses is a critical public health concern. Future research, especially prospective cohort studies and investigations into molecular mechanisms, is essential to address this complex issue. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo explore the potential risk factors for the occurrence of human cytomegalovirus (HCMV) retinitis (CMVR) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients.This is a retrospective, nested case-control study conducted in hematological patients with CMVR who underwent allo-HSCT. Patients diagnosed with CMVR after allo-HSCT were included as the case group, and those without CMVR were matched by a ratio of 1:2 and were recruited as controls. We selected 19 pre- and post-transplant indicators for univariate analysis between the cases and controls, and then Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for exploration of risk factors of the CMVR occurrence.A total of 1308 allo-HSCT patients from January 1, 2020 to July 31, 2023 were analyzed, and 27 patients were diagnosed CMVR with a median onset time of 222 days after transplantation. In univariate analysis, donors of stem cells source, HLA-match types (including matched sibling donor, haploidentical donor, and unrelated donor), post-transplant Epstein-Barr virus (EBV) viremia, platelet implantation time, and serostatus of CMV-IgG were more easily to develop CMVR than controls (p < 0.001, p = 0.003, p < 0.001, p = 0.032, p = 0.038, respectively). Multivariate logistic regression analysis showed that stem cells source (OR 7.823, 95% CI 1.759-34.800), HLA-match types (OR 7.452, 95% CI 1.099-50.542), and post-transplant EBV infection (OR 7.510, 95% CI 1.903-29.640) were positively associated with the onset of CMVR.Stem cells derived from bone marrow and peripheral blood, HLA-match types, and post-transplant EBV viremia are important risk predictors of CMVR in allo-HSCT patients. These results suggest that clinicians should pay more attention to these indicators when formulating preventive measures pre- and post-transplant. [ABSTRACT FROM AUTHOR]

A study published in Acta Neuropathologica explores the use of targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded (FFPE) neuropathology specimens. The researchers conducted a proof-of-concept study using a viral nucleic acid enrichment protocol on 23 FFPE samples with confirmed viral infections. They found that the viral enrichment panel led to a significant enrichment of viral sequences, resulting in a high genome coverage and improved detection of viral integration sites. The study demonstrates that metagenomic sequencing of virus-enriched libraries from FFPE specimens is a valuable method for viral whole-genome sequencing, even in low-quality and low-biomass samples. [Extracted from the article]

Epstein–Barr virus (EBV) is a major cause of infectious mononucleosis (IM), characterized by fever, fatigue, sore throat, lymphadenopathy, atypical lymphocytosis, and elevated liver enzymes. However, ascites is a rare complication associated with IM. We present a rare case of IM with ascites and peritonitis in a patient who underwent a peritoneal biopsy. A 20‐year‐old woman presented with fatigue and abdominal distension. Laboratory examination revealed atypical lymphocytes in peripheral blood (54%) and elevated liver enzymes. EBV serological tests revealed a recent primary infection (EBV VCA IgM 1:160). Computed tomography revealed moderate ascites and peritonitis. Adenocarcinoma was suspected based on the ascites' cytology. Considering possible complications of IM and adenocarcinoma, a laparoscopic biopsy was performed. Histological findings of biopsy specimens from the peritoneum, omentum, and fimbria of the fallopian tube demonstrated severe inflammatory cell infiltration and focal aggregation of large EBV‐encoded RNA‐1 (EBER1)‐positive B cells, mimicking EBV‐positive polymorphous B‐cell lymphoproliferative disorder. Furthermore, intracytoplasmic inclusion bodies of Chlamydia trachomatis were observed by immunohistochemistry. Real‐time polymerase chain reaction detected C. trachomatis in cervical secretions. Two months after laparoscopy, ascites decreased, and the diagnosis was IM‐associated peritonitis with C. trachomatis infection. IM should be considered as a differential diagnosis in young patients with ascites. [ABSTRACT FROM AUTHOR]

This review focuses on three major aspects of oncoviruses' role in cancer development. To begin, we discuss their geographic distribution, revealing that seven oncoviruses cause 20% of all human cancers worldwide. Second, we investigate the primary carcinogenic mechanisms, looking at how these oncogenic viruses can induce cellular transformation, angiogenesis, and local and systemic inflammation. Finally, we investigate the possibility of SARS‐CoV‐2 infection reactivating latent oncoviruses, which could increase the risk of further disease. The development of oncovirus vaccines holds great promise for reducing cancer burden. Many unanswered questions about the host and environmental cofactors that contribute to cancer development and prevention remain, which ongoing research is attempting to address. [ABSTRACT FROM AUTHOR]

The mucosa of the oral cavity is exposed to a large number of different microorganisms such as archaea, bacteria, fungi, parasites, and viruses. Among those, viruses cause specific infections, which can easily be transmitted from one person to another. The infectious route may not only include patients and their relatives but also the dental professional team. Thus, a wide knowledge regarding specific viral infections is crucial for the daily routine. Signs and symptoms of oral viral infections can be completely absent or develop into a pronounced clinical picture, so that early detection and information determine the further course of the infection and its influence on other inflammatory diseases, such as periodontitis, as well as the safety of family members and the social environment. As the clinical manifestation of viral infections may be highly variable leading to heterogenous mucosal lesions it is, in most cases, mandatory to differentiate them by specific microbiological tests in addition to clinical examination procedures. This article will give an overview of the role of viruses infecting the oral mucosa, and in addition, describe their clinical manifestation and management. [ABSTRACT FROM AUTHOR]

Introduction: Immune reconstitution (IR) kinetics of paediatric patients underwent haploidentical haematopoietic stem cell transplantation (HSCT) with post‐transplant cyclophosphamide (PTCy) have not been extensively studied. We compared IR patterns of children receiving HSCT from haploidentical (n = 92) and HLA‐matched donors (n = 36), and analysed risk factors for viral infection in these patients. Methods: We prospectively measured lymphocyte subset numbers before HSCT and at 1, 3, 6 and 12 months after HSCT. Blood cytomegalovirus (CMV), Epstein–Barr virus, adenovirus, BK virus (BKV) and urine adenovirus and BKV viral loads were measured at designated time points. Results: The median numbers of total T and T helper cells at 1 month were significantly lower in the haploidentical group compared with the HLA‐matched group. Haploidentical HSCT recipients had significantly lower median numbers of several T cell subsets and B cells for 1 year after HSCT. The median NK cell count of the haploidentical group was lower at 1 month. BKV haemorrhagic cystitis, blood CMV and urine adenovirus reactivation were more frequently found in the haploidentical group. Post‐haploidentical HSCT patients receiving anti‐T lymphocyte globulin (ATG) had significantly lower median numbers of total T cells (at 1 month) and T helper cells (at 6 and 12 months) and higher rate of blood BKV reactivation compared with those without ATG. Conclusion: Paediatric patients who undergo haploidentical HSCT with PTCy are likely to have delayed IR and an increased risk of viral reactivation/infection compared with HLA‐matched HSCT. The addition of ATG to PTCy delayed T cell recovery and increased risk of BKV reactivation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the result of a complex interaction between environmental factors and genetic predisposition. Epstein-Barr virus (EBV) is a significant environmental risk factor associated with MS. Human- beta defensin2 (HβD-2) is a crucial innate immune response proteint that as an inflammatory marker protects humans from pathogens invading the body like viruses. Therefore, a case-control study was conducted on 90 subjected (48 patients with MS and 42 healthy controls) to examine the role of HβD-2 in EBV viral load infection and MS patients. An enzyme-linked immunosorbentassay kit was used to measure HβD-2 levels in serum. The viral load of EBV was determined using a real-time PCR. The findings revealed that median HβD-2 levels in patients were significantly lower than in controls. (96.62 vs.124.8 ng/mL; p < 0.01). According to the receiver operating characteristic curve analysis, HβD-2 is good predictor for MS disease (area under the curve=0.739; p < 0.001). EBV frequency was lower in MS patients compared to the controls, although difference was not statistically significant (25 vs. 38.1%; p = 0.181).On other hand, the median (EBV) load was substantially greater in patients than in healthy controls ( 8.55 vs. 1.4 DNA copy/100 cells). This study concluded that HβD-2 levels showed no significant differences in each age group, sex, Expanded Disability Status Scale (EDSS) of multiple sclerosis patients, rather showed an inverse significant correlation (correlation coefficient = - 0.432) with EBV load, which protect against human viral infections. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions. Materials and Methods: The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality. Results: Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (hazard ratio [HR], 5.320; 95% confidence interval [CI], 3.208 to 8.820; p < 0.001) and NPC (HR, 7.116; 95% CI, 1.617 to 31.314; p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR, 2.225; 95% CI, 1.858 to 2.663; p < 0.001). Conclusion: This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures. [ABSTRACT FROM AUTHOR]

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3–4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected) and low-risk groups (DS 1–2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1–2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL. [ABSTRACT FROM AUTHOR]

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV's lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi's Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV's lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV) is a double‐stranded DNA herpesvirus and establishes life‐long infection in 95% of the world's populations. Main body: EBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV‐mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV‐associated diseases. Conclusion: Growing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels. [ABSTRACT FROM AUTHOR]

Background: Thymoma is a tumor that originates in the thymus gland, a part of the human body located behind the breastbone. It is a malignant disease that is rare in children but more common in adults and usually does not spread outside the thymus. The exact cause of thymic disease is not known, but it is thought to be more common in people infected with the EBV virus at an early age. Various surgical methods are used in clinical settings to treat thymoma. Expert opinion is very important in the diagnosis of the disease. Recently, next-generation technologies have become increasingly important in disease detection. Today's early detection systems already use transformer models that are open to technological advances. Methods: What makes this study different is the use of transformer models instead of traditional deep learning models. The data used in this study were obtained from patients undergoing treatment at Fırat University, Department of Thoracic Surgery. The dataset consisted of two types of classes: thymoma disease images and non-thymoma disease images. The proposed approach consists of preprocessing, model training, feature extraction, feature set fusion between models, efficient feature selection, and classification. In the preprocessing step, unnecessary regions of the images were cropped, and the region of interest (ROI) technique was applied. Four types of transformer models (Deit3, Maxvit, Swin, and ViT) were used for model training. As a result of the training of the models, the feature sets obtained from the best three models were merged between the models (Deit3 and Swin, Deit3 and ViT, Deit3 and ViT, Swin and ViT, and Deit3 and Swin and ViT). The combined feature set of the model (Deit3 and ViT) that gave the best performance with fewer features was analyzed using the mRMR feature selection method. The SVM method was used in the classification process. Results: With the mRMR feature selection method, 100% overall accuracy was achieved with feature sets containing fewer features. The cross-validation technique was used to verify the overall accuracy of the proposed approach and 99.22% overall accuracy was achieved in the analysis with this technique. Conclusions: These findings emphasize the added value of the proposed approach in the detection of thymoma. [ABSTRACT FROM AUTHOR]

This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein–Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2−/− and C57BL/6J wild-type mice immunized with EBNA1386–405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. The PARK2−/− mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1386–405, only PARK2−/− exhibited symptoms resembling EAE. During the acute phase, PARK2−/− mice immunized with either MOG35–55 or EBNA1386–405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1386–405 -immunized PARK2−/− mice showed significantly increased frequencies of CD8a+ T cells and CD11c+ B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies. [ABSTRACT FROM AUTHOR]

Background and objective: The DNA load of EBV may play a part in CLL pathogenesis and prognosis. The objective of this cross-sectional study was to examine the prognostic value of EBV viral load in CLL patients in comparison with other common laboratory prognostic factors. Materials and methods: Whole blood and sera from forty untreated CLL patients were collected. Next, DNA was extracted from total white blood cells (WBC), and TaqMan real-time PCR was performed to determine the EBV-DNA load by amplifying a specific fragment in the BNRF1 gene. In addition, parameters such as complete blood counts (CBC) and lactate dehydrogenase (LDH) were determined using an automated clinical laboratory analyzer. Results: Twenty-one patients (52.5%) were positive for EBV by real-time PCR analysis (ranged 20 to 30000 copies/µL). The difference in LDH mean levels between EBV positive and negative patients was marginally significant (P = 0.05). Furthermore, platelet (PLT) count (P = 0.03) and CD5+/CD19+ count (P = 0.04), between EBV positive and negative subgroups, were substantially different. In addition, individuals with a severe form of illness, as defined by an increase in LDH, a decrease in PLT, and an 11q deletion, had considerably higher EBV-DNA copy numbers (the ranges of viral loads were 9966.66 ± 20033 in the severe form vs. 137.13 ± 245.41 in the mild form). Conclusion: The EBV-DNA load could be used as a prognostic factor in the initial examination of CLL patients to better characterize the disease outcome and prognosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate a possible link between acute Epstein-Barr virus infection and Lemierre syndrome, a rare yet life-threatening infection. Methods: A systematic review was conducted adhering to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Diagnosis criteria for Lemierre syndrome were established, and data extraction encompassed demographic data, clinical, and laboratory information. Results: Out of 985 initially identified papers, 132 articles were selected for the final analysis. They reported on 151 cases of Lemierre syndrome (76 female and 75 male patients with a median of 18 years) alongside interpretable results for Epstein-Barr virus serology. Among these, 38 cases (25%) tested positive for acute Epstein-Barr virus serology. There were no differences in terms of age, sex, or Fusobacterium presence between the serologically positive and negative groups. Conversely, instances of cervical thrombophlebitis and pulmonary complications were significantly higher (P = 0.0001) among those testing negative. The disease course was lethal in one case for each of the two groups. Conclusions: This analysis provides evidence of an association between acute Epstein-Barr virus infection and Lemierre syndrome. Raising awareness of this link within the medical community is desirable. [ABSTRACT FROM AUTHOR]

Purpose: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. Methods: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. Results: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein–Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. Conclusions: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease. [ABSTRACT FROM AUTHOR]

Aim: Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB‐MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM‐SBAs). Methods and Results: Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB‐MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM‐SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death‐ligand 1 (PD‐L1) and mismatch repair proteins was performed in both SB‐MCs and NM‐SBAs. SB‐MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein–Barr virus (EBV)‐encoded RNAs by in‐situ hybridization. MLH1 promoter methylation status was evaluated in MLH1‐deficient cases. Eleven SB‐MCs and 149 NM‐SBAs were identified. One (9%) SB‐MC was EBV‐positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB‐MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB‐MCs, both with isolated loss of ARID1A. Compared with NM‐SBAs, SB‐MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD‐L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB‐MC patients compared to NM‐SBA cases (P = 0.02). Conclusion: SB‐MCs represent a distinct histologic subtype, with peculiar features compared to NM‐SBAs, including association with coeliac disease, dMMR, PD‐L1 expression, and better prognosis. [ABSTRACT FROM AUTHOR]

Herpesviruses represent common and significant infectious complications after allogeneic haematopoietic cell transplantation (HCT). In the last decade, major advances in the prevention and treatment of these infections were accomplished. The aim of this paper is to review the recent advances in the prophylaxis and treatment of herpesvirus infections after allogeneic HCT, to assess the persisting challenges, and to offer future directions for the prevention and management of these infections. We searched PubMed for relevant literature regarding specific herpesviruses complicating allogeneic HCT through March 2024. The largest advances in this past decade were witnessed for cytomegalovirus (CMV) with the advent of letermovir for primary prophylaxis and the development of maribavir as an option for refractory and/or resistant CMV infections in transplant recipients. For varicella zoster virus, prevention of reactivation with the recombinant zoster vaccine offers an additional prophylactic intervention. Pritelivir is being explored for the treatment of drug-resistant or refractory Herpes simplex virus infections. Although rituximab is now an established option for preemptive therapy for Epstein-Barr virus, Human Herpesvirus-6 remains the most elusive virus of the herpesvirus family, with a lack of evidence supporting the benefit of any agent for prophylaxis or for optimal preemptive therapy. Although considerable advances have been achieved for the treatment and prevention of herpes virus infections, most notably with CMV, the coming years should hold additional opportunities to tame the beast in these herpesviruses postallogeneic HCT, with the advent of new antivirals, cell-mediated immunity testing, and cytotoxic T lymphocytes infusions. [ABSTRACT FROM AUTHOR]

Background and objectives: The impact of viral infections on disease susceptibility and progression has predominantly been studied in patients with relapse-onset MS (RMS). Here, we determined immune responses to ubiquitous viruses in patients with primary progressive MS (PPMS). Methods: Antibody responses to Epstein–Barr virus (EBV), specifically to the latent EBV nuclear antigen 1 and the lytic viral capsid antigen VCA, human herpesvirus 6 (HHV-6), human cytomegalovirus (HCMV), and measles virus were determined in a cohort of 68 PPMS patients with a mean follow-up of 8 years and compared with 66 healthy controls matched for sex and age. Results: Compared with controls, PPMS patients showed increased humoral immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to the lytic EBV capsid antigen (VCA) or to other viral antigens. Seroprevalence rates for HCMV were significantly higher in PPMS. Antiviral immune responses at baseline did not correlate with disability progression over time. Discussion: Elevated immune responses toward EBNA1 are selectively increased in people with primary progressive disease, indicating a link between EBNA1-targeting immune responses and the development of both RMS and PPMS. Our data also suggest that chronic HCMV infection is associated with progressive MS. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus meningoencephalitis is a rare central nervous system infection that lacks standardized treatment. Immunocompetent and immunosuppressed individuals with this condition frequently have poor prognostic outcomes, making the need to identify therapeutic interventions high. Here, we report 2 pediatric cases of severe Epstein-Barr virus meningoencephalitis, both unresponsive to immunoglobulin and corticosteroid therapy, who demonstrated rapid clinical recovery following rituximab administration. Prognostic outcomes revealed marked improvements in symptoms, neurologic function, and quality of life. Rituximab may offer therapeutic potential in severe and refractory Epstein-Barr virus meningoencephalitis through the medication's target of Epstein-Barr virus harboring B cells. This report emphasizes the need for timely evaluation and consideration of rituximab therapy in immunocompetent pediatric patients with Epstein-Barr virus meningoencephalitis. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein‐Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV‐ (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC‐associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene‐edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV‐coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV‐ and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies. [ABSTRACT FROM AUTHOR]