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We describe the case of a 57-year-old male with jaundice, abdominal distension and fatigue. He was diagnosed as chronic active Epstein-Barr virus infection (CAEBV) due to intermittent elevated liver enzymes, hepatosplenomegaly and pancytopenia, with persistent positive of EBV biomarkers in blood and also positive in liver tissue. The patient was reinfected by SARS-CoV-2 within 2 months companied with CAEBV. The patient's second infection with SARS-CoV-2 led to the aggravated liver dysfunction with pneumonia and re-admission. After receiving symptomatic treatment, the patient showed significantly improvement of symptoms with partially restoration of liver function. After discharge, the patient's health status continued to deteriorate and eventually died. The instances of SARS-CoV-2 co-infection with the original chronic virus are not uncommon, but the exact mechanism of EBV and SARS-CoV-2 coinfection and the relationship between them are still unclear. Since co-infection of SARS-CoV-2 with original chronic virus might affect each other and lead disease aggravated and complicated, it is necessary to differentiate in the diagnosis of disease and it is important to be aware of the re-infection signs of SARS-CoV-2 in people with chronic virus infection diseases, as well as the risk of co-infection of SARS-CoV-2 with other viruses. [ABSTRACT FROM AUTHOR]

Background: Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM). Methods: We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (Tonset). Results: All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (rs = 0.345, 0.418, and 0.356, respectively) within the first two weeks after Tonset, but no correlation with the number of detectable EBV-reactive CD4+ T cells. Conclusions: All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity. [ABSTRACT FROM AUTHOR]

The article presents the discussion on case study of 10-year-old girl with vulvar herpes ulcers. Topics include young patient and her mother have received skeptical responses from the emergency department physician and the pediatrician who have seen her; and frequency of Lipschütz ulcers is uncertain as the condition is often misdiagnosed, and patients with it are usually seen in outpatient facilities.

This article presents a case study of a young woman who suffered sudden vision loss in her left eye. The article explores the various potential causes of her condition, including lymphoma, multiple sclerosis, stroke, and other eye-related conditions. Through laboratory tests and imaging studies, the doctors were able to diagnose the patient with sarcoidosis, a condition characterized by the development of non-caseating granulomas in different organs. The article highlights the importance of considering sarcoidosis as a possible cause of vision loss, even in the absence of other symptoms. [Extracted from the article]

Simple Summary: Epstein–Barr virus (EBV)-associated gastric cancer is accepted as a distinct entity among gastric adenocarcinomas. It is particularly frequent in gastric remnant cancer (GCR), defined as cancer in the gastric stump several decades after distal gastric resection for benign disease. Gastric cancer in the West is a comparatively rare disease, and most of the published data stem from the East. Using population-based data from the West spanning the years from 2001 to 2016, we were able to show that a significantly higher proportion of GRCs compared to non-GRC proximally located cancers were EBV-positive, even in the West. The mode of presentation and findings at upper endoscopy were more subtle and differed significantly from proximally located non-GRC cancers, possibly making the GRCs more difficult to diagnose. Epstein–Barr virus (EBV) is associated with 5–10% of gastric cancers and is recognized as a distinct molecular subtype. EBV positivity is particularly high in gastric remnant cancer (GRC), which may inform the mode of clinical presentation and findings at endoscopy. Most data are from the East, and the question remains how this applies to a Western cohort. We conducted a population-based study in Central Norway, 2001–2016. Patients with GRC (n = 78) and patients with non-GRC proximally located cancer and available tissue for EBV status (n = 116, control group) were identified from the Norwegian Cancer Registry. Relevant data were collected from the individual patient journals. EBV status was assessed using in situ hybridization. The median latency time from the distal gastrectomy to GRC was 37.6 (range 15.7–68.0) years. GRC more often presented with GI bleeding, 31.0% vs. 16.1%, p = 0.017, and at endoscopy more seldom with an ulcer, 19.7% vs. 38.2%, p = 0.012, or a tumour, 40.8% vs. 66.4%, p < 0.001. For GRC, 18.7% were EBV-positive compared to 6.0% among the controls, p = 0.006. EBV status was not associated with patient age, sex, or Lauren histological type. No difference in long-term survival rates between GRC and controls was found or between EBV-positive vs. -negative GRCs. In conclusion, a higher proportion of GRC cases, compared to controls, are EBV positive, indicating different causative factors. The mode of clinical presentation and findings at endoscopy were more subtle in the patients with GRC. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7–15 days) and five days (interquartile range, 3.75–9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases (P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs. Author summary: EBV is a human gamma herpesvirus that causes infectious mononucleosis and cooperates with translocation of the Myc oncogene to induce Burkitt lymphoma (BL). EBV-infected BLs are derived from germinal center B cells and contain highly latent forms of EBV infection that do not express the two major EBV oncogenes, EBNA2 and LMP1. It has been difficult to model how latent EBV infection cooperates with Myc translocation to form BLs, as EBV cannot transform B cells in vitro in the absence of EBNA2 or LMP1. Here we show that human cord blood B cells co-infected with both an EBNA2-deleted EBV mutant and a Myc-expressing retrovirus form BL-like tumors in immunosuppressed mice, while cells infected with EBNA2-deleted EBV alone or the Myc-expressing retrovirus alone do not. These BL-like tumors express many cellular genes over-expressed in human BLs (including genes associated with a germinal center B cell phenotype) and do not express either EBNA2 or LMP1. Furthermore, we show that Myc blocks expression of the highly immunogenic LMP1 protein in BLs by inhibiting the transcriptional activator, STAT3. This new model should be useful for dissecting the mechanisms by which latent EBV infection and Myc translocation cooperatively induce human BLs. [ABSTRACT FROM AUTHOR]

Burkitt lymphoma (BL) is a subtype of non-Hodgkin lymphoma. It is strongly associated with HIV infection and has a highly aggressive clinical course. The involvement of the maxillofacial region in BL has rarely been reported. A 36-year-old woman with HIV-positive status had painless bilateral swelling of the oral mucosa and middle and lower thirds of the face. Microscopic analysis of the oral lesion revealed an atypical lymphoid infiltrate with a starry sky pattern. The lymphoid cells expressed cluster of differentiation 20, cluster of differentiation 10, B-cell lymphoma 6, and c-Myc; the Ki-67 proliferative index was high. The tumor cells were positive for Epstein-Barr virus. These results led to the diagnosis of HIV-related BL. BL and other immunodeficiency-related lymphoproliferative malignancies may affect the oral and maxillofacial regions and should be included in the differential diagnosis of rapidly expanding swelling in young patients. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma is one of the most common malignant tumors in the head and neck region. The carcinogenesis is a complex process stimulated by many factors. Although the etiological factors and pathogenic mechanisms are not elucidated, the genetic susceptibility, environmental factors, and association with latent infection with Epstein–Barr Virus play an important role. The aim of this study was to present the main clinical and epidemiological data, as well as the morphological aspects and the immunohistochemical profile, of patients with nasopharyngeal carcinoma diagnosed in western Romania. The study was retrospective and included 36 nasopharyngeal carcinomas. The histopathological diagnosis was completed using immunohistochemical reactions for the following antibodies: p63, p53 and p16 protein, cytokeratins (CK) AE1/AE3, CK5, CK7, CK20 and 34βE12, epithelial membrane antigen (EMA), Epstein–Barr virus (EBV), leukocyte common antigen (LCA), CD20, CD4, CD8, CD68, CD117, and CD1a. The squamous malignant component of nasopharyngeal carcinoma presented with positivity for cytokeratins AE1/AE3, CK5, 34βE12, and p63. Undifferentiated nasopharyngeal carcinoma was positive for EMA in 67% of cases, and 28% of cases showed an immunoreaction for CD117 in the malignant epithelial component. Also, the p53 protein was positive in all the cases. One case of undifferentiated nasopharyngeal carcinoma was p16-positive, and two cases were positive for EBV. A peri- and intratumor cellular infiltrate rich in lymphocytes, with a predominance of CD20-positive B lymphocytes, interspersed with T lymphocytes, was observed. The T cells were CD4- and CD8-positive, predominantly intratumoral, and the CD4:CD8 ratio was 1:1 for 75% of the undifferentiated subtype and 89% for differentiated non-keratinized squamous cell carcinoma. All subtypes of nasopharyngeal carcinoma presented with an inflammatory infiltrate with numerous plasma cells, eosinophils, and dendritic cells, presenting as antigen CD1a- and CD68-positive, as well as in CD117-positive mast cells. [ABSTRACT FROM AUTHOR]

This article discusses the use of intra-arterial methylprednisolone (IAM) as a treatment for pediatric gastrointestinal post-transplant lymphoproliferative disorder (PTLD). PTLD is a group of lymphoid disorders that occur in transplant recipients, particularly pediatric patients, and is characterized by uncontrolled B cell proliferation. The main treatment for PTLD is reduction of immunosuppression, but this can come with risks. IAM has been shown to be effective in controlling acute gastrointestinal bleeding in steroid-refractory transplant recipients, and this article describes the first use of IAM in a pediatric patient with PTLD. The patient experienced prompt cessation of bleeding and resolution of previous FDG uptake regions on a PET scan, although new regions of FDG uptake were observed. IAM was administered five times without complications. The article suggests that IAM can be a rapid and effective option for managing acute gastrointestinal bleeding in PTLD patients, particularly those on concurrent chemotherapy. Further research is needed to evaluate the utility of IAM in a larger pediatric population. [Extracted from the article]

Simple Summary: Nasopharyngeal carcinoma (NPC) is an epithelial cancer associated with Epstein–Barr virus (EBV) infection. EBV infection contributes to not only the tumorigenesis of NPC but also the formation of a complicated tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells are lymphoid members of the innate immune system exhibiting both anti-tumor and anti-virus abilities. The cytokine and cellular interaction features of NK cells are distinct from those of CD8+ cytotoxic T cells. This unique characteristic has not been fully described in EBV+ NPC. This review provides an overview of the complicated crosstalk between NK cells and the TIME of EBV+ NPC and potential therapeutic strategies. A new perspective is proposed to direct future exploration. Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein–Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is the fourth leading cause of cancer-related deaths in the world. The identification of gastric cancer subtypes related to recognizable microbial agents may play a pivotal role in the targeted prevention and treatment of this cancer. The current study is conducted to define the frequency of Epstein-Barr virus (EBV) infection in gastric cancers of four major provinces, with different incidence rates of gastric cancers, in Iran. Methods: Paraffin blocks of 682 cases of various types of gastric cancer from Tehran, South and North areas of Iran were collected. Twelve tissue microarray (TMA) blocks were constructed from these blocks. Localization of EBV in tumors was assessed by in situ hybridization (ISH) for EBV-encoded RNA (EBER). Chi-squared test was used to evaluate the statistical significance between EBV-associated gastric cancer (EBVaGC) and clinicopathologic tumor characteristics. Results: Fourteen out of 682 cases (2.1%) of gastric adenocarcinoma were EBER-positive. EBER was positive in 8 out of 22 (36.4%) of medullary carcinomas and 6 out of 660 (0.9%) of non-medullary type, which was a statistically significant difference (P < 0.001). The EBVaGCs were more frequent in younger age (P = 0.009) and also showed a trend toward the lower stage of the tumor (P = 0.075). Conclusion: EBV-associated gastric adenocarcinoma has a low prevalence in Iran. This finding can be due to epidemiologic differences in risk factors and exposures, and the low number of gastric medullary carcinomas in the population. It may also be related to gastric tumor heterogeneity not detected with the TMA technique. [ABSTRACT FROM AUTHOR]

The detection of anti-hepatitis E virus (HEV) antibodies contributes to the diagnosis of hepatitis E. The diagnostic suitability of two automated chemiluminescence immunoassays (CLIAs, LIAISON® MUREX Anti-HEV IgG/Anti-HEV IgM test, DiaSorin) was assessed by comparison with the results of a combination of enzyme immunoassays and immunoblots (recomWell HEV IgG/IgM ELISA, recomLine HEV IgG/IgM, MIKROGEN). Samples with a deviating result were analyzed with the WANTAI ELISAs. Compared to the recomWell ELISAs, the Anti-HEV IgG CLIA had a percentage overall agreement (POA) of 100% (149/149; 95% CI: 97.5–100%) and the Anti-HEV IgM CLIA had a POA of 83.3% (85/102; 95% CI: 74.9–89.3%); considering the recomLine HEV IgM results, the POA was 71.7% (38/53; 95% CI: 58.4–82%). The WANTAI test confirmed 52.9% (9/17) of negative CLIA IgMs; HEV RNA was not detectable. Since acute infection with the Epstein–Barr virus (EBV) or human cytomegalovirus (CMV) may influence the results of other serological assays, HEV antibodies were examined in 17 EBV and 2 CMV patients: One had an isolated and probably unspecific HEV IgM in the CLIA, as HEV RNA was not detectable. Both CLIAs are well suited for HEV diagnostics, but isolated IgM should be confirmed. An acute EBV/CMV infection can influence HEV serodiagnostics. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) is prevalent in southern China. EBV DNA is the most useful biomarker in NPC. However, the value of EBV DNA in posttreatment NPC patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. Methods: Sixty-four eligible NPC patients were enrolled between December 2022 and February 2023. Patients who met the following criteria were included: had non-metastatic NPC, completed radical treatment, were first firstly infected with SARS-CoV-2 and their EBV DNA changed from undetectable to detectable. Results: At the end of follow-up, 81.25% (52/64) of patients were confirmed not to relapse with undetectable EBV DNA (no-relapse). In addition, 18.75% (12/64) of patients experienced relapse with consistent detection of EBV DNA (yes-relapse). For all 64 patients, the average time from diagnosis of coronavirus disease 2019 (COVID-19) to detection of detectable EBV DNA was 35.41 days (2 to 139 days). For 52 no-relapse patients, the average time from EBV DNA changing from detectable to undetectable was 63.12 days (6 to 147 days). The levels of EBV DNA were greater in yes-relapse patients than that in no-relapse patients, and the average of EBV DNA levels were 1216 copies/ml and 53.18 copies/ml, respectively. Using 62.3 copies/mL as the threshold, the area under the curve for EBV DNA was 0.88 for distinguishing yes-relapse patients from no-relapse patients. The sensitivity and specificity were 81.97% (95% CI 0.71–0.95) and 86.67% (95% CI 0.70–0.95), respectively. Conclusion: For NPC patients infected with SARS-CoV-2, EBV DNA alone is insufficient for monitoring relapse after radical therapy. Long-term follow-up and underlying mechanistic investigations of EBV DNA changes are urgently needed. [ABSTRACT FROM AUTHOR]

Background and Objective: Prior Epstein–Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk. [ABSTRACT FROM AUTHOR]

Primary Epstein-Barr virus (EBV) infection manifests with diverse clinical symptoms, occasionally resulting in severe complications. This scoping review investigates the rare occurrence of acute acalculous cholecystitis (AAC) in the context of primary EBV infection, with a focus on understanding its prevalence, clinical features, and underlying mechanisms. The study also explores EBV infection association with Gilbert syndrome, a condition that potentially exacerbates the clinical picture. Additionally, a case report of an 18-year-old female presenting with AAC and ascites secondary to EBV infection enhances the review. A comprehensive literature review was conducted, analyzing reported cases of AAC secondary to EBV infection. This involved examining patient demographics, clinical presentations, laboratory findings, and outcomes. The search yielded 44 cases, predominantly affecting young females. Common clinical features included fever, cervical lymphadenopathy, tonsillitis/pharyngitis, and splenomegaly. Laboratory findings highlighted significant hepatic involvement. The review also noted a potential link between AAC in EBV infection and Gilbert syndrome, particularly in cases with abnormal bilirubin levels. AAC is a rare but significant complication of primary EBV infection, primarily observed in young females, and may be associated with Gilbert syndrome. This comprehensive review underscores the need for heightened clinical awareness and timely diagnosis to manage this complication effectively. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein–Barr virus (EBV) was first isolated in 1964 and has since become an important human tumor virus. With an estimated 90% of the human population infected with the virus, EBV has also been shown to cause several types of cancers. The virus has evolved numerous epigenetic mechanisms by which it can affect its host and contribute to the development and progression of cancer. In this review, we introduce four prominent epigenetic regulatory mechanisms that result in host-virus interactions for the purpose of EBV infection, persistence, and contribution to EBV-associated diseases. We then look at how epigenetic profiles of the host are altered in EBV-associated cancers to understand the precise ways EBV interacts with its host to cause disease. This work explores the viral epigenetics of EBV and provides insights into the knowns and unknowns of research into EBV and EBV-associated cancers. The Epstein–Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly efficient at infecting B-cells but can also infect epithelial cells, utilizing an array of epigenetic strategies to establish long-term latent infection. The association with histone modifications, alteration of DNA methylation patterns in host and viral genomes, and microRNA targeting of host cell factors are core epigenetic strategies that drive interactions between host and virus, which are necessary for viral persistence and progression of EBV-associated diseases. Therefore, understanding epigenetic regulation and its role in post-entry viral dynamics is an elusive area of EBV research. Here, we present current outlooks of EBV epigenetic regulation as it pertains to viral interactions with its host during latent infection and its propensity to induce tumorigenesis. We review the important epigenetic regulators of EBV latency and explore how the strategies involved during latent infection drive differential epigenetic profiles and host-virus interactions in EBV-associated cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is a cancer that is frequently associated with Epstein–Barr virus (EBV) infection, and this virus is thought to play a role in NPC development and malignant growth. Within tumor cells, the virus generally remains in a latent stage that supports cell survival and stimulates tumor growth. However, it has been postulated that it might be beneficial as part of cancer therapy to coax the virus out of its latent stage and into a lytic mode, which would result in tumor cell killing. A few agents are known to accomplish this switch, but their clinical success so far has been mixed. We are developing a novel compound, NEO212, that has shown anticancer activity in several preclinical tumor models. Here, in this report, we demonstrate that it is able to coax EBV into its lytic cycle, resulting in NPC cell death. We propose that NEO212 should be investigated further for its potential clinical usefulness as a therapeutic agent for NPC. The Epstein–Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which is thought to contribute to tumorigenesis. Current treatments are sub-optimal, and recurrence occurs in many cases. An alternative therapeutic concept is aimed at triggering the lytic cycle of EBV selectively in tumor cells as a means to add clinical benefit. While compounds able to stimulate the lytic cascade have been identified, their clinical application so far has been limited. We are developing a novel anticancer molecule, NEO212, that was generated by covalent conjugation of the alkylating agent temozolomide (TMZ) to the naturally occurring monoterpene perillyl alcohol (POH). In the current study, we investigated its potential to trigger the lytic cycle of EBV in NPC cells in vitro and in vivo. We used the established C666.1 cell line and primary patient cells derived from the brain metastasis of a patient with NPC, both of which harbored latent EBV. Upon treatment with NEO212, there was an increase in EBV proteins Zta and Ea-D, key markers of the lytic cycle, along with increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, followed by the activation of caspases. These effects could also be confirmed in tumor tissue from mice implanted with C666.1 cells. Towards a mechanistic understanding of these events, we used siRNA-mediated knockdown of CHOP and inclusion of anti-oxidant compounds. Both approaches blocked lytic cycle induction by NEO212. Therefore, we established a sequence of events, where NEO212 caused reactive oxygen species (ROS) production, which triggered ER stress and elevated the levels of CHOP, which was required to stimulate the lytic cascade of EBV. Inclusion of the antiviral agent ganciclovir synergistically enhanced the cytotoxic impact of NEO212, pointing to a potential combination treatment for EBV-positive cancers which should be explored further. Overall, our study establishes NEO212 as a novel agent able to stimulate EBV's lytic cycle in NPC tumors, with implications for other virus-associated cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: The current standard of care for nasopharyngeal carcinoma (NPC) is predominantly guided by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumour-node-metastasis (TNM) staging system. This review aims to discuss the current strategies and development of new technologies to optimise NPC patients' stratification to ultimately provide better patient management and more targeted therapy. Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV) driven malignancy arising from the nasopharyngeal epithelium. Current treatment strategies depend on the clinical stage of the disease, including the extent of the primary tumour, the extent of nodal disease, and the presence of distant metastasis. With the close association of EBV infection with NPC development, EBV biomarkers have shown promise in predicting treatment outcomes. Among the omic technologies, RNA and miRNA signatures have been widely studied, showing promising results in the research setting to predict treatment response. The transformation of radiology images into measurable features has facilitated the use of radiomics to generate predictive models for better prognostication and treatment selection. Nonetheless, much of this work remains in the research realm, and challenges remain in clinical implementation. [ABSTRACT FROM AUTHOR]

Poly (β-amino ester) (PBAE) is an exceptional non-viral vector that is widely used in gene delivery, owing to its exceptional biocompatibility, easy synthesis, and cost-effectiveness. However, it carries a high surface positive charge that may cause cytotoxicity. Therefore, hydrophilic d-α-tocopherol polyethylene glycol succinate (TPGS) was copolymerised with PBAE to increase the biocompatibility and to decrease the potential cytotoxicity of the cationic polymer-DNA plasmid polyplex nanoparticles (NPs) formed through electrostatic forces between the polymer and DNA. TPGS-b-PBAE (TBP) copolymers with varying feeding molar ratios were synthesised to obtain products of different molecular weights. Their gene transfection efficiency was subsequently evaluated in HEK 293T cells using green fluorescent protein plasmid (GFP) as the model because free GFP is unable to easily pass through the cell membrane and then express as a protein. The particle size, ζ-potential, and morphology of the TBP2-GFP polyplex NPs were characterised, and plasmid incorporation was confirmed through gel retardation assays. The TBP2-GFP polyplex NPs effectively transfected multiple cells with low cytotoxicity, including HEK 293T, HeLa, Me180, SiHa, SCC-7 and C666-1 cells. We constructed a MUC2 (Mucin2)-targeting CRISPR/cas9 gene editing system in HEK 293T cells, with gene disruption supported by oligodeoxynucleotide (ODN) insertion in vitro. Additionally, we developed an LMP1 (latent membrane protein 1)-targeting CRISPR/cas9 gene editing system in LMP1-overexpressing SCC7 cells, which was designed to cleave fragments expressing the LMP1 protein (related to Epstein–Barr virus infection) and thus to inhibit the growth of the cells in vivo. As evidenced by in vitro and in vivo experiments, this system has great potential for gene therapy applications. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126, siERK1&2, or siCREB suppressed C6-Cer-induced EBV lytic replication and autophagy initiation. In contrast, siJUN transfection had no impact on BZLF1 expression. The use of 3-methyladenine (3-MA), an inhibitor targeting class III phosphoinositide 3-kinases (PI3Ks) to inhibit autophagy initiation, resulted in reduced beclin-1 expression, along with suppressed C6-Cer-induced BZLF1 expression and LC3B accumulation. Chloroquine, an inhibitor of autophagosome-lysosome fusion, increased BZLF1 protein intensity and LC3B accumulation. However, siLC3B transfection had minimal effect on BZLF1 expression. The results suggest the significance of ceramide-related sphingolipid metabolism in controlling EBV latency, highlighting the potential use of drugs targeting sphingolipid metabolism for treating EBV-positive gastric cancer. IMPORTANCE Epstein-Barr virus remains dormant in the host cell but occasionally switches to the lytic cycle when stimulated. However, the exact molecular mechanism of this lytic induction is not well understood. In this study, we demonstrate that Epstein-Barr virus infection leads to a reduction in ceramide levels. Additionally, the restoration of ceramide levels triggers lytic replication of Epstein-Barr virus with increase in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB. Our study suggests that the Epstein-Barr virus can inhibit lytic replication and remain latent through reduction of host cell ceramide levels. This study reports the regulation of lytic replication by ceramide in Epstein-Barr virus-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV) is detected in 40% of patients with Hodgkin lymphoma (HL). During latency, EBV induces epigenetic alterations to the host genome and decreases the expression of pro-apoptotic proteins. The present study aimed to evaluate the expression levels of mRNA molecules and the end product of proteins for the JAK/STAT and NF-κB pathways, and their association with clinicopathological and prognostic parameters in patients with EBV-positive and -negative classical Hodgkin lymphoma (CHL). Methods: A prospective cohort study was conducted from 2017 to 2022 at the Faculty of Medicine, Zagazig University Hospital (Zagazig, Egypt). Biopsy samples of 64 patients with CHL were divided into EBV-positive and EBV-negative groups. The expression levels of mRNA molecules (JAK2, STAT1, IRF-1, PD-L1, IFN-γ, NF-κB, Bcl-xL, COX-2) and the end product of proteins (PD-L1, Bcl-xL, COX-2) were determined and compared with clinicopathological and prognostic parameters. Data were analyzed using the Chi square test and Kaplan-Meier estimate. Results: EBV-positive CHL patients were significantly associated with positive expression of mRNAs molecules (P<0.001) and the end product of proteins (P<0.001) for the JAK/STAT and NF-κB pathways, B-symptoms (P=0.022), extra-nodal involvement (P=0.017), and advanced stage of CHL (P=0.018). These patients were more susceptible to cancer progression, higher incidence of relapse (P=0.008), poor disease-free survival rate (P=0.013), poor overall survival rate (P=0.028), and higher mortality rate (P=0.015). Conclusion: Through the activation of JAK/STAT and NF-κB signaling pathways, EBV-positive CHL is associated with poor clinicopathological parameters, higher incidence of disease progression, relapse, and poor overall survival. [ABSTRACT FROM AUTHOR]

Epstein-Barr Virus (EBV) diseases, including EBV-associated post-transplant lymphoproliferative disorder (PTLD) remain important causes of morbidity and mortality in children undergoing solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Despite progress in the prevention of EBV disease including PTLD (EBV/PTLD) in HCT, key questions in the prevention, and management of these infectious complications remain unanswered. The goal of this manuscript is to highlight key points and recommendations derived from the consensus guidelines published by the International Pediatric Transplant Association and the European Conference on Infections in Leukemia for children undergoing SOT and HCT, respectively. Additionally, we provide background and guidance on the use of EBV viral load measurement in the prevention and management of these children. [ABSTRACT FROM AUTHOR]

Simple Summary: Following infection with HIV, individuals are immunocompromised. Their weakened immune system puts them at a higher risk of certain cancers like Kaposi sarcoma and lymphoma. Even with antiretroviral therapy for HIV infection, these cancers remain common in developing countries, while in developed countries, there is a decline in some cancers but an increase in deaths from others. This review explores why these cancers happen in people with HIV and finds that the current treatment is not enough to prevent them. Understanding these reasons is crucial to improving the diagnosis and treatment of both HIV and its associated cancers, highlighting the need for more research to tackle this ongoing health issue. The immune deficiency associated with human immunodeficiency virus (HIV) infection causes a distinct increased risk of developing certain cancer types. Kaposi sarcoma (KS), invasive cervical cancer and non-Hodgkin's lymphoma (NHL) are the prominent malignancies that manifest as a result of opportunistic viral infections in patients with advanced HIV infection. Despite the implementation of antiretroviral therapy (ART), the prevalence of these acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) remains high in developing countries. In contrast, developed countries have experienced a steady decline in the occurrence of these cancer types. However, there has been an increased mortality rate attributed to non-ADMs. Here, we provide a review of the molecular mechanisms that are responsible for the development of ADMs and non-ADMs which occur in HIV-infected individuals. It is evident that ART alone is not sufficient to fully mitigate the potential for ADMs and non-ADMs in HIV-infected individuals. To enhance the diagnosis and treatment of both HIV and malignancies, a thorough comprehension of the mechanisms driving the development of such cancers is imperative. [ABSTRACT FROM AUTHOR]

Background. Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein–Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR). Methods. A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality. Results. Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R−), and 4 (1%) were low risk (D−/R−). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3–60). The highest proportion of DNAemia was observed in D+/R− subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia (p < 0.001). All patients with PTLD were managed with RIS and rituximab. Conclusion. We observed that EBV D+/R− serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR. [ABSTRACT FROM AUTHOR]

(1) Background: the purpose of the study was to assess the relationship between cancer stage, selected immunological parameters, Epstein–Barr virus (EBV) infection, and total serum content of iron, zinc, and copper in patients with laryngeal cancer (LC). (2) Methods: serum Fe, Zn, and Cu were measured in 40 LC patients and 20 controls. Immunophenotyping of peripheral blood lymphocytes was performed by flow cytometry using fluorescent antibodies against CD3, CD4, CD8, CD19, CD25, CD69, and PD-1. Tumor and lymph node lymphocytes were analyzed by flow cytometry. EBV DNA was quantified by real-time PCR, targeting the EBNA-1 gene. Associations between serum elements, immune markers, and cancer grade/stage were evaluated using ANOVA and appropriate nonparametric tests. (3) Results: levels of Fe, Cu, and Zn were lower, while Cu/Zn was statistically higher, in patients with LC than in the control group. Correlation analysis showed a statistically significant association between the levels of these elements and parameters of the TNM (Tumor, Node, Metastasis) staging system, immunophenotype, and the amount of EBV genetic material in patients with LC who survived for more than 5 years. (4) Conclusion: the results suggest that the total serum levels of the determined micronutrients may significantly affect the immunopathogenesis and progression of LC. [ABSTRACT FROM AUTHOR]

Background The 2 cofactors in the etiology of Burkitt lymphoma (BL) are Epstein-Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and controls. Age was analyzed as a covariate because immunity to malaria in endemic regions is age dependent. Methods Children (2–10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative polymerase chain reaction, and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes. Results Regardless of the compartment, we detected EBV more frequently in malaria cases compared to controls, although the difference was not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (P <.05), indicating increased EBV lytic replication. In younger children before development of immunity to malaria, there was a significant effect of malaria on EBV load in peripheral blood mononuclear cells (P =.04). Conclusions These data suggest that malaria can directly modulate EBV persistence in children, increasing their risk for BL. [ABSTRACT FROM AUTHOR]

Simple Summary: Unlike NPC, there is little research concerned with the role of EBV in the development of OPSCC. Therefore, it is necessary to search for new markers enabling the early diagnosis and prognosis of this disease. The aim of this study was to evaluate the diagnostic utility of anti-Zta and anti-LMP1 antibodies in EBV positive OPSCC patients. For this purpose, experiments were carried out to determine both the prevalence and level of anti-Zta and anti-LMP1 antibodies in serum patients with OPSCC in relation to grading and TNM classification. The highest level of tested antibodies was observed in more advanced clinical stages. The diagnostic accuracy of anti-Zta antibodies was confirmed using ROC analysis. We showed that the determination of both types of antibodies may be useful in the diagnosis of OPSCC. Moreover, anti-LMP1 antibody may be a diagnostic as well as prognostic biomarker. Background: The role of the Epstein–Barr virus (EBV), the first known human oncogenic virus, in the development of nasopharyngeal cancer (NPC) is already well documented. There are few studies in the available scientific literature on oropharyngeal cancer associated with EBV infection. Due to the lack of an effective vaccine against EBV, it is necessary to search for new markers for the early diagnosis and prognosis of this disease. The aim of current study was to determine the usefulness of anti-Zta and anti-LMP1 antibodies as diagnostic and prognostic markers in EBV positive OPSCC patients. Methods: For this purpose, experiments were carried out to determine both the prevalence and level of EBVCA, EBNA1, EA, Zta, and LMP1 antibodies in serum patients depending on histological differentiation-grading and TNM classification (ELISA assay). Results: Based on the obtained results, we showed that OPSCC EBV positive patients are characterized by a higher level of anti-Zta antibodies than in the EBV negative group. Their level depended on the clinical stage. Moreover, a ROC analysis confirmed the diagnostic accuracy of anti-Zta antibodies. Conclusions: Anti-Zta and anti-LMP1 antibodies may be useful in the diagnosis of OPSCC. It seems that combined antibody testing should be performed to increase diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer (PCa) is a serious men's health problem worldwide. Some authors report the occurrence of the Epstein–Barr virus (EBV), a well-known oncovirus, in PCa. Therefore, in this study, PCa tissues were screened for the presence of EBV. Then, the frequency and titer of antibodies against EBV in the serum of EBV-positive and EBV-negative patients were compared. The results obtained showed a higher frequency and level of Epstein–Barr virus capsid antigen (EBVCA) and Epstein–Barr nuclear antigen 1 (EBNA1) antibodies in patients with EBV-positive PCa. Higher levels of tested antibodies were observed in more advanced stages of the disease (high-risk group, high Gleason score (GS) and stage T2). These observations may suggest a role for EBV in the development and/or progression of PCa. Prostate cancer (PCa) is the fourth most frequently diagnosed cancer worldwide, accounting for 7.3% of all cancers. PCa mortality is the fifth most common cause of cancer death. Despite well-known factors influencing the development of PCa, such as age, race/ethnicity and family history, many researchers have raised the possibility of persistent infections with oncogenic viruses. Therefore, we aimed to assess the frequency of Epstein–Barr virus (EBV) DNA in tissue collected from PCa patients. Next, the frequency and the level of Epstein–Barr virus capsid antigen (EBVCA) and Epstein–Barr nuclear antigen 1 (EBNA1) antibodies in both IgA and IgG classes were measured. The antibody titer was also analyzed depending on the risk group, Gleason score (GS) and tumor, node, metastasis (TNM) classification. Serum samples were analyzed using the Microblot-Array EBV IgM, IgA and IgG test kits. The study group consisted of 115 patients diagnosed and histopathologically confirmed with PCa. In 49% of patients included in the study, EBV DNA was detected in the tumor tissue. The studies showed both higher seroprevalence and higher antibody titers in patients with EBV-positive PCa compared to patients with EBV-negative PCa. We also observed a dependence of antibody titer on pathological features, such as GS, risk group and T stage. [ABSTRACT FROM AUTHOR]

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10−6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10−8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10−6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control. A study of 4,645 children in four countries in East Africa, 800 with Burkitt lymphoma (BL), identifies an association between HLA-DQA1*04:01 and variant rs2040406(G) and elevated risk of BL in Africa. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft‐versus‐host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin‐like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non‐relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo‐HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo‐HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied. [ABSTRACT FROM AUTHOR]

Background and Aim: Infection with Epstein-Barr virus (EBV) ranks as one of the most substantial risk factors associated with Glioblastoma multiforme (GBM). At the core of this intricate relationship lies the EBV nuclear antigen-1 (EBNA1) protein, a central figure with a remarkable ability to regulate the expression of both cellular and viral genes. This research delves into the impact of EBNA1 on the expression patterns of four cellular genes - MDMX, MDM2, MYC, and BIRC5 in the U87MG cell line. Materials and Methods: We divided U87MG cells into two distinct groups. The first group involved cells that were transfected with a plasmid containing the EBNA1 gene, while the second group consisted of cells that were transfected with a control plasmid. To evaluate the transcriptional activity of MDMX, MDM2, MYC, and BIRC5 genes in both sets of cells, we employed a real-time PCR technique. Any observed differences were considered statistically significant if the associated Pvalues were less than 0.05. Results: Our findings demonstrated a substantial three-fold increase in the expression of the MDMX gene when U87MG cells were transfected with EBNA1 plasmid (P=0.02). Although the cells transfected with EBNA1 plasmid displayed great elevations in the expression levels of MDM2, MYC, and BIRC5 genes, these alterations were not statistically significant. Conclusion: The outcomes of this investigation have unveiled that EBNA1 has the ability to trigger the expression of four crucial cellular genes, which wield substantial influence in the genesis of GBM within glioblastoma astrocytoma cells. This underscores the potential impact of EBNA1 on the evolution of GBM, particularly in individuals harboring EBV. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein Barr virus (EBV) is a constant companion of humans with more than 95% of the adult population being persistently infected. Fortunately, this companionship is mostly asymptomatic, but in around 300,000 new patients every year, EBV-associated cancers emerge. These medical cases are mostly caused by environmental or genetic conditions that either increase EBV-associated tumorigenesis or weaken its immune control. In this review, I will discuss co-infections as important environmental risk factors for EBV-associated malignancies and how both EBV infection but also the respective co-infections could be targeted to reduce the associated disease load. The oncogenic and persistent Epstein Barr virus (EBV) is carried by more than 95% of the human adult population. While asymptomatic in most of these, EBV can cause a wide variety of malignancies of lymphoid or epithelial cell origin. Some of these are also associated with co-infections that either increase EBV-induced tumorigenesis or weaken its immune control. The respective pathogens include Kaposi-sarcoma-associated herpesvirus (KSHV), Plasmodium falciparum and human immunodeficiency virus (HIV). In this review, I will discuss the respective tumor entities and possible mechanisms by which co-infections increase the EBV-associated cancer burden. A better understanding of the underlying mechanisms could allow us to identify crucial features of EBV-associated malignancies and defects in their immune control. These could then be explored to develop therapies against the respective cancers by targeting EBV and/or the respective co-infections with pathogen-specific therapies or vaccinations. [ABSTRACT FROM AUTHOR]

Mammalian cells repress expression of repetitive genomic sequences by forming heterochromatin. However, the consequences of ectopic repeat expression remain unclear. Here we demonstrate that inhibitors of EZH2, the catalytic subunit of the Polycomb repressive complex 2 (PRC2), stimulate repeat misexpression and cell death in resting splenic B cells. B cells are uniquely sensitive to these agents because they exhibit high levels of histone H3 lysine 27 trimethylation (H3K27me3) and correspondingly low DNA methylation at repeat elements. We generated a pattern recognition receptor loss‐of‐function mouse model, called RIC, with mutations in Rigi (encoding for RIG‐I), Ifih1 (MDA5), and Cgas. In both wildtype and RIC mutant B cells, EZH2 inhibition caused loss of H3K27me3 at repetitive elements and upregulated their expression. However, NF‐κB‐dependent expression of inflammatory chemokines and subsequent cell death was suppressed by the RIC mutations. We further show that inhibition of EZH2 in cancer cells requires the same pattern recognition receptors to activate an interferon response. Together, the results reveal chemokine expression induced by EZH2 inhibitors in B cells as a novel inflammatory response to genomic repeat expression. Given the overlap of genes induced by EZH2 inhibitors and Epstein–Barr virus infection, this response can be described as a form of viral mimicry. Synopsis: Expression of repetitive genomic elements can activate inflammatory signaling via binding of pattern recognition receptors. Here, inhibition of PRC2 subunit EZH2 is shown to cause repeat element expression and activation of different cytokine or chemokine pathways in normal and transformed cells. EZH2 inhibition induces sterile inflammation and cell death selectively in resting splenic B cells.Cytosolic pattern recognition receptors are required to activate inflammation induced by EZH2 inhibition.Resting B cells respond to EZH2 inhibition by inducing NF‐kB pathway‐dependent chemokine expression, while cancer cells activate an interferon expression program. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a debilitating disease that causes inflammation of the central nervous system, resulting in myelin damage and axon degeneration. Although the cause of MS remains unknown, various factors such as sex, latitude, sun exposure, serum vitamin D levels, Epstein Barr Virus infection, diet, microbiota and ethnicity are being studied for their potential roles in the development of the disease. While chronobiological factors such as circadian rhythm and seasonality have been explored for their potential influence on the onset, exacerbation, and/or relapses of MS, the potential influence of the lunar cycle on MS has yet to be studied. Therefore, the authors of this letter call for future studies to investigate the possible effects of the lunar cycle on MS activity and course, given evidence suggesting that the lunar cycle may affect sleep, fatigue, melatonin secretion, and mood state in humans. A deeper understanding of the chronobiology of MS could have practical implications for the development of chronotherapeutic strategies and the prevention or mitigation of MS relapses, potentially improving the quality of life of MS patients. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is a prevalent herpesvirus that commonly infects a substantial proportion of the global population. Infection with the Epstein-Barr virus has been hypothesized to be one of the environmental factors that contribute to the development of systemic lupus erythematosus. Our objective was to investigate the correlation between Epstein-Barr virus (EBV) reactivation and the prognosis of systemic lupus erythematosus (SLE). The study conducted Specialized Center for Diseases and Kidney Transplant in AL-Sadder Medical City in Al-Najaf Governorate involved obtaining blood samples from 50 hemodialysis patients and 50 healthy control. The data collection period for the study was from January to December 2022. The study collected blood samples from 50 hemodialysis cases. The researchers used RT-qPCR technique to detect EBV infection. Among the 50 patients, 18 (36%) tested positive for EBV using RT-qPCR. The ELISA technique was also used in the study to detect systemic lupus erythematosus by detecting the level of Anti-ds-DNA in all samples. The results showed that 19 (36%) of the samples tested positive for anti-dsDNA. Remarkably, among those who tested positive for EBV, 13 individuals (72.2%) were simultaneously positive for both EBV and SLE. We also examined serum levels of IL-10 and IL-18 in hemodialysis patients with both EBV and SLE. IL-10 and IL-18 concentrations in co-positive samples (EBV+ SLE) in hemodialysis patients showed significant differences, with IL-10 increasing by (379±55.2) and IL-18 increasing by (26.4±8.86), respectively, in comparison to the control group's levels of (207±5.9) for IL-10 and (11.7±0.72) for IL-18. The study's findings lead to the conclusion that patients undergoing hemodialysis exhibit demonstrate a greater incidence of both Epstein-Barr virus (EBV) and systemic lupus erythematosus (SLE) in comparison to the control group. Furthermore, the study indicates a significant increase in IL10 and IL18 levels in comparison to the control group. [ABSTRACT FROM AUTHOR]

Objective: Primary Epstein‐Barr virus (EBV) infection is observed in 60% of children during the first year after liver transplantation as usage of imm‐unosuppressant. Finding predictive indicators of EBV infection is important to reduce the morbidity and mortality of EBV infection‐related diseases by suggesting a dose reduction of immunosuppressant. Methods: We compared and analysed the gut microbiome of EBV‐infected children with an asymptomatic virus‐carrying status and EBV‐uninfected children after liver transplantation using high‐throughput sequencing. Results: Significant differences in gut microbiome composition in two groups were detected. In detail, Firmicutes and Lactobacillus were increased in EBV‐infected group, while Clostridium was increased in EBV‐uninfected group. Furthermore, CD4 percentage in T cells of blood showed a significant positive correlation with the content of Clostridium sp. CAG: 127 in EBV‐uninfected group. Conclusion: Changes in the gut microbiome could predict and decrease the EBV infection risk of children after liver transplantation. [ABSTRACT FROM AUTHOR]

Infectious mononucleosis (IM) often results from late primary infection with Epstein–Barr virus (EBV). Exposure to EBV at ages 0–2 years from, e.g., siblings therefore protects against IM. Using Danish registers, we therefore followed children born in 1997 through 2015 from age 3 years for a hospital contact with an IM diagnosis as outcome with the number of antimicrobial prescriptions filled before age 3 years as a proxy of infection pressure and the main exposure in stratified Cox regressions. The main analyses used sibships as strata primarily to adjust for health-seeking behaviour with further possible adjustments for age, sex, calendar period and sibship constellation. In these analyses we followed 7087 children, exposed on average to 3.76 antimicrobials prescriptions. We observed a crude hazard ratio for IM per unit increase in cumulative antimicrobial use of 1.00 (95% confidence interval 0.99, 1.02), with similar results in adjusted analyses. The hypothesis that children with the largest use of antimicrobials at ages 0–2 years would subsequently have the lowest risk of IM within a sibship was not corroborated by the data. Furthermore, sibship-matched analyses provided no support for some common early-life immune system characteristics being predictive of IM. [ABSTRACT FROM AUTHOR]

The significance of Epstein-Barr virus (EBV) detection in the cerebrospinal spinal fluid (CSF) in people living with HIV (PLWH) is not entirely understood. The detection of EBV DNA may represent active central nervous system (CNS) infection, reactivation in the setting of another CNS pathogen or due to impaired immunity, or detection of quiescent virus. We screened 470 adult PLWH in Zambia with neurological symptoms for the presence of EBV DNA in the CSF. We performed quantitative EBV PCR on the CSF and blood. We then performed quantitative EBV DNA PCR on the blood of controls with documented HIV viral suppression without CNS symptoms. The prevalence of EBV DNA in the CSF of patients with CNS symptoms was 28.9% (136/470). EBV DNA positivity was associated with younger age, shorter duration of HIV diagnosis, lower CSF glucose levels, higher CSF protein and white blood cell levels, and a positive CSF Mycobacterium tuberculosis result. The median EBV DNA load was 8000 cps/mL in both the CSF and blood with a range of 2000–2,753,000 cps/mL in the CSF and 1000 to 1,871,000 cps/mL in the blood. Molecular screening of CSF for other possible causes of infection identified Mycobacterium tuberculosis in 30.1% and cytomegalovirus (CMV) in 10.5% of samples. EBV DNA load in the blood and CSF was not associated with mortality. Our results suggest that even though EBV DNA was commonly detected in the CSF of our population, it appears to have limited clinical significance regardless of EBV DNA load. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite an in-depth understanding of Epstein–Barr virus-associated epithelial and lymphoid tumors, there is a paucity of knowledge concerning mesenchymal tumors associated with the Epstein–Barr virus. Our objective with this review article is to provide a comprehensive reference, offering current insights into the clinical features, pathological characteristics, pathophysiology, prognostic factors, and current therapeutic approaches of Epstein–Barr virus-associated mesenchymal tumors. The Epstein–Barr virus (EBV) is associated with various tumor types, including nasopharyngeal carcinoma and lymphoproliferative disorders. While much is known about EBV-related epithelial and lymphoid tumors, there is a paucity of knowledge concerning EBV-associated mesenchymal tumors. This review aims to provide a comprehensive overview of EBV-associated mesenchymal tumors, encompassing their clinical features, pathological characteristics, pathophysiology, prognostic factors, and current treatment approaches. Through an extensive literature search using the PubMed database, we were able to identify three distinct EBV-associated mesenchymal tumors: EBV-associated smooth muscle tumors, inflammatory pseudotumor-like follicular dendritic cell sarcomas, and EBV-associated osteosarcomas. Although this review extensively explored the different aspects of these mesenchymal tumors, our comprehension of the underlying pathophysiology in this context is still incomplete. Therefore, we hope that this review paper will not only serve as a valuable repository of information but also serve as a catalyst for prospective in vitro and in vivo research studies to bridge the existing knowledge gap surrounding pathophysiology, ultimately making an important contribution to shaping future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Infectious mononucleosis (IM) is a common infectious disease in children mainly caused by Epstein–Barr virus (EBV) infection, followed by abnormal immune response, and resulting in serious complications. However, there are few clinical analyses of immune responses in children with IM at different stages. Methods: This study combined EBV serological test and EBV DNA test to diagnose the infection status of children with IM, and the infection status was divided into primary acute IM infection (AIM), primary late IM infection (LIM) and reactivation IM infection (RIM). Results: The results revealed that the absolute numbers of leukocytes and CD8+ T lymphocytes in primary IM infection were significantly higher than those in reactivation infection, while the frequencies of CD4+ T lymphocytes and B cells were significantly lower than those in reactivation infection. In addition, the activities of ALT, AST, α‐HBDH and LDH in liver function indicators in primary infection were significantly increased compared with reactivation infection. Similarly, the EBV DNA levels of the primary infection were significantly higher than that of the reactivation infection. Conclusion: There are differences in immune response at different stages of infection, which can provide guidance for effective treatment in children with IM infection. [ABSTRACT FROM AUTHOR]

The clinical characteristics, risk factors and survival prognosis of pericardial effusion (PE) after haematopoietic stem cell transplantation (HSCT) in children were investigated. Clinical data of children who underwent HSCT at the Children's Hospital Affiliated with Chongqing Medical University from January 2016 to December 2022 were analysed retrospectively. Cox proportional hazards regression and the Kaplan-Meier method were used to analyse the risk factors for post-HSCT PE and its impact on outcomes, respectively. We enrolled 452 patients with HSCT: 307 males and 145 females, with a median age of 3.4 (1.8 to 6.5) years at transplantation. Forty-five patients (10%) had PE within a median time of 25 (10.5 to 44) days, 42 (93%) within 100 days. Three patients with large PE were treated with pericardiocentesis and drainage, while the others were treated conservatively. Of the 45 patients with PE, 24 survived, and their PE disappeared after treatment. Graft-versus-host disease (GVHD) grade, abnormal pre-HSCT electrocardiogram, hepatic veno-occlusive disease (HVOD), pulmonary infection and Epstein–Barr virus (EBV) infection were risk factors for PE. The overall survival (OS) rates at 1, 3, and 5 years were 86.0%, 84.2%, and 82.3%, respectively. PE had a significant negative effect on OS after HSCT (P < 0.0001). Particularly, one patient with large PE died of pericardial tamponade. Post-HSCT PE usually occurred within 100 days. GVHD grade, abnormal pre-HSCT electrocardiogram, HVOD, pulmonary infection and EBV infection were closely related to PE. PE had a significant negative effect on OS rate. [ABSTRACT FROM AUTHOR]

Background and Objective. Multiple sclerosis (MS) is a progressive disease of the nervous system that leads to demyelination of the nerves and is more common in young adults, especially women. Environmental factors that trigger MS pathogeneses are genetic susceptibility and viral infections. The viral infections are considered to be of particular relevance. Along with viruses belonging to the Herpesviridae family such as varicella zoster virus (VZV), human herpes virus-6 (HHV-6), and particularly Epstein–Barr virus (EBV), the expression of the env gene of human endogenous retrovirus (HERV-W) like MSRV is expected to be one of the risk factors for bringing up MS and disease progression. The present study aimed to investigate the correlation between EBV infection and HERV-W env in a case group (MS patients) and a control group (healthy individuals). Materials and Methods. 130 subjects were enrolled in a case-control study at two tertiary university hospitals from Tabriz (Imam and Razi), Iran. Of these, 65 subjects were MS patients serving as the case group, and 65 subjects were healthy individuals serving as the control group. After DNA extraction from all samples, the EBER region of EBV genome was used as the primer for the detection of EBV. RNA was extracted from PBMCs, and cDNA synthesis was performed by using Sina Gene kit. Subsequently, each sample was analysed by RT-PCR with two sets of primers to detect specifically multiple sclerosis retroviruses (MSRV) env, and RT-PCR was repeated for each HERV-W env. Positive sample was used in order to confirm the result. Results. In the case group, 19 (29.2%) patients were male and 46 (70.8%) patients were female. Nevertheless, in the control group, 21 (32.3%) subjects were male and 44 (67.7%) subjects were female. No significant difference was found between groups in gender (p = 0.70). The mean range in control and case groups was 33/38 ± 9/85 and 33.18 ± 8.65, respectively. No significant difference was found between groups in age (p = 0.902). 4 (6.2%) patients in case groups were found to be positive for EBV DNA (p = 0.119). Expression of the env gene of HERVs was observed in 10 (15.38%) and two (3.07%) specimens in the case and control groups (p = 0.030), separately. A comparison of the prevalence of the HERV ENV genome between the two study groups showed a significant difference (p = 0.005). Conclusion. The results of this study failed to show any difference between MS patients and healthy controls in the rate of EBV infection. It can be concluded that the expression of HERV-W/env genes may be involved in the development of MS in these patients. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV) infection is a major global threat; its manifestations range from the absence of symptoms to multiorgan malignancies and various gastrointestinal diseases. Analyzing the composition and metabolomic profile of gut microbiota during acute EBV infection might be instrumental in understanding and controlling EBV. Methods: Six tree shrews were inoculated with EBV by intravenous injection. Blood was collected at regular intervals thereafter from the femoral vein to detect EBV and inflammatory biomarker. At the same time, tree shrew faeces were collected for 16 S rRNA gene sequencing and Non-targeted metabolomics analysis. Results: 16 S rRNA gene characterization along with β diversity analysis exhibited remarkable alterations in gut microflora structure with a peak at 7 days post-infection(dpi). Some alterations in the relative richness of bacterial taxon were linked to infectious indicators. Of note, Butyricicoccus relative richness was positively linked to EBV presence in the blood and plasma, the opposite correlation was seen with Variovorax and Paramuribaculum. Non-targeted metabolomics indicated the fecal metabolome profile altered during EBV infection, particularly 7 dpi. The relative abundance of geranic acid and undecylenic acid in stool samples was positively linked to systemic inflammatory biomarkers, and an inverse relationship was reported with the estrone glucuronide, linoleic acid, protoporphyrin IX and tyramine. Conclusion: Collectively, EBV infection in this model correlated with changes in the composition and metabolome profile of the gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Cancer, as a complex, heterogeneous disease, is currently affecting millions of people worldwide. Even if the most common traditional treatments, namely, chemotherapy (CTx) and radiotherapy (RTx), have been so far effective in some conditions, there is still a dire need for novel, innovative approaches to treat types of cancer. In this context, oncoviruses are responsible for 12% of all malignancies, such as human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), as well as hepatitis B virus (HBV) and hepatitis C virus (HCV), and the poorest in the world also account for 80% of all human cancer cases. Against this background, nanomedicine has developed nano-based drug delivery systems (DDS) to meet the demand for drug delivery vectors, e.g., extracellular vesicles (EVs). This review article aimed to explore the potential of engineered small EVs (sEVs) in suppressing human oncovirus-associated cancers. Methods: Our search was conducted for published research between 2000 and 2022 using several international databases, including Scopus, PubMed, Web of Science, and Google Scholar. We also reviewed additional evidence from relevant published articles. Results: In this line, the findings revealed that EV engineering as a new field is witnessing the development of novel sEV-based structures, and it is expected to be advanced in the future. EVs may be further exploited in specialized applications as therapeutic or diagnostic tools. The techniques of biotechnology have been additionally utilized to create synthetic bilayers based on the physical and chemical properties of parent molecules via a top-down strategy for downsizing complicated, big particles into nano-sized sEVs. Conclusion: As the final point, EV-mediated treatments are less toxic to the body than the most conventional ones, making them a safer and even more effective option. Although many in vitro studies have so far tested the efficacy of sEVs, further research is still needed to develop their potential in animal and clinical trials to reap the therapeutic benefits of this promising platform. [ABSTRACT FROM AUTHOR]

We present the case of a 70-year-old woman presenting with nausea, diarrhoea and a generalised rash. Initial blood tests revealed obstructive deranged liver function tests and low haemoglobin. A haemolysis screen revealed raised reticulocytes, low haptoglobin and a positive direct antiglobulin test. 6 days into her admission, she developed lower limb weakness and loss of sensation. MRI spine showed no significant findings. Cerebrospinal fluid showed raised white blood cell count and raised protein. Nerve conduction studies were normal. The clinical picture was in keeping with transverse myelitis. Autoimmune and viral screens were negative except for a single result which provided the unifying diagnosis: Epstein--Barr virus (EBV). She responded to high dose intravenous corticosteroids and her rehabilitation is ongoing. EBV should be considered even in the older population. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, along with uncontrolled proliferation of activated macrophages and lymphocytes. The clinical features of HLH often overlap with the clinical features of other severe inflammatory conditions such as sepsis, hindering accurate and timely diagnosis. In this study, we performed a data-independent acquisition mass spectrometry-based plasma proteomic analysis of 33 pediatric patients with HLH compared with four control groups: 39 healthy children, 43 children with sepsis, 39 children hospitalized in the pediatric intensive care unit without confirmed infections, and 21 children with acute Epstein-Barr virus infection. Proteomic comparisons between the HLH group and each of the control groups showed that HLH was characterized by alterations in complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. We identified eight differentially expressed proteins in patients with HLH, including plastin-2 (LCP1), vascular cell adhesion protein 1, fibrinogen beta chain, fibrinogen gamma chain, serum amyloid A-4 protein, extracellular matrix protein 1, apolipoprotein A-I, and albumin. LCP1 emerged as a candidate diagnostic marker for HLH with an area under the curve (AUC) of 0.97 in the original cohort and an AUC of 0.90 (sensitivity = 0.83 and specificity = 1.0) in the validation cohort. Complement C1q subcomponent subunit B was associated with disease severity in patients with HLH. Based on comparisons with multiple control groups, this study provides a proteomic profile and candidate biomarkers of HLH, offering researchers novel information to improve the understanding of this condition. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common leukemia in adults in Western countries. Transformation of CLL/SLL to plasmablastic lymphoma (PBL) is exceedingly rare and often has an extremely poor response to treatment. A thorough molecular workup may help in determining clonality-relatedness and prognosis. We describe two cases of CLL/SLL that transformed into PBL, with an extensive molecular workup in one case, and a review of the literature. [ABSTRACT FROM AUTHOR]