Transcriptome analysis of Burkitt lymphoma cells treated with anti-convulsant drugs that are inhibitors of Epstein-Barr virus lytic reactivation.

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.

Clinical laboratory Analysis of EB Virus Associated Hemophagocytic Lymphohistiocytosis in Children.

Objective: Epstein-Barr virus (EBV) is a common virus that infects a large portion of the world's population, with most people becoming infected during childhood or adolescence. The objective of this article is to analyze the clinical and laboratory examination results of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children, summarize its characteristics, identify critically ill children as soon as possible, and provide a basis for diagnosis and treatment. Method: The retrospective analysis in this study involved collecting data from 34 cases of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) admitted to Hebei Children's Hospital from January 2019 to December 2022. The inclusion criteria for the cases studied likely included confirmed diagnosis of EBV-HLH based on clinical symptoms, laboratory findings, and possibly viral testing results. Key parameters analyzed in the study may have included clinical manifestations, laboratory test results (e.g., levels of lactate dehydrogenase, sCD25, IL-10, calcium ions, glutathione aminotransferase, ferritin, alanine aminotransferase, D-dimer), survival rates, and other relevant indicators. Additionally, the cases were likely divided into high-risk groups (with multiple organ dysfunction or requiring ventilator-assisted ventilation) and non-risk groups for comparative analysis. Results: The results showed that 34 cases (100%) of EBV-HLH had elevated levels of lactate dehydrogenase, sCD25, IL-10, and decreased levels of calcium ions. 97.1% of the children had a fever and elevated levels of glutathione aminotransferase and ferritin, with an 8-week survival rate of 91.2%. The levels of alanine aminotransferase, alanine aminotransferase, lactate dehydrogenase, ferritin, D-dimer, and sCD25 in critically ill children were significantly higher than those in the non-critically ill group, with statistical significance (P < .05). The decreased levels of calcium ions in EBV-HLH patients suggest potential tissue damage and disruption of calcium homeostasis, contributing to the systemic manifestations of the disease. Compared with non-critical recombinant albumin, the decrease in critical recombinant albumin was statistically significant (P < .05). Conclusion: Significant changes in laboratory results can contribute to the early diagnosis and targeted treatment of EBV-HLH, especially for critically ill children. We should pay timely attention to laboratory examinations, diagnosis and treatment, and avoid or reduce the occurrence of adverse consequences. Based on the results of the study on Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children, specific strategies and criteria can be proposed to aid in the early identification of critically ill children with this condition in clinical practice: Clinical Screening, Risk Stratification, Early Intervention, Multidisciplinary Management and Educational Measures.

Revolutionizing gastric cancer treatment: The potential of immunotherapy.

Gastric cancer, a prevalent malignancy worldwide, ranks sixth in terms of frequency and third in fatality, causing over a million new cases and 769000 annual deaths. Predominant in Eastern Europe and Eastern Asia, risk factors include family medical history, dietary habits, tobacco use, Helicobacter pylori, and Epstein-Barr virus infections. Unfortunately, gastric cancer is often diagnosed at an advanced stage, leading to a grim prognosis, with a 5-year overall survival rate below 5%. Surgical intervention, particularly with D2 Lymphadenectomy, is the mainstay for early-stage cases but offers limited success. For advanced cases, the National Comprehensive Cancer Network recommends chemotherapy, radiation, and targeted therapy. Emerging immunotherapy presents promise, especially for unresectable or metastatic cases, with strategies like immune checkpoint inhi-bitors, tumor vaccines, adoptive immunotherapy, and nonspecific immunomodulators. In this Editorial, with regards to the article "Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review", we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Visceral leishmaniasis misdiagnosed as an upper respiratory infection and iron-deficiency anemia in a 20-month-old male patient: a case report.

BACKGROUND: Visceral Leishmaniasis should be suspected in every patient with a history of splenomegaly, fever, and pancytopenia. It is one of the most dangerous forms of infection and prompt recognition is the key to positive outcome. CASE PRESENTATION: A 20-month-old Caucasian male patient was brought to our hospital as an outpatient with the complaint of persistent fever, which did not improve with empiric antibiotic treatment (> 96 hour after the initial dose). The antibiotic treatment had been prescribed by primary care physician at polyclinic, who also referred the patient to hematologist due to anemia, who prescribed iron supplement. Despite multiple subspecialist visits, bicytopenia was, unfortunately, left unidentified. Upon physical examination no specific signs were detected, however, spleen seemed slightly enlarged. Patient was admitted to the hospital for further work-up, management and evaluation. Abdominal ultrasound, complete blood count and c-reactive protein had been ordered. Hematologist and infectionist were involved, both advised to run serology for Epstein-Barr Virus and Visceral Leishmaniasis. The latter was positive; therefore, patient was transferred to the specialized clinic for specific management. CONCLUSION: Both in endemic and non-endemic areas the awareness about VL should be increased among the medical professionals. We also recommend that our colleagues take the same approach when dealing with bicytopenia and fever, just as with pancytopenia and fever. The medical community should make sure that none of the cases of fever and pancytopenia are overlooked, especially if we have hepatomegaly and/or splenomegaly.

Network Toxicology Prediction and Molecular Docking-based Strategy to Explore the Potential Toxicity Mechanism of Metformin Chlorination Byproducts in Drinking Water.

BACKGROUND: Metformin (MET), a worldwide used drug for treating type 2 diabetes but not metabolized by humans, has been found with the largest amount in the aquatic environment. Two MET chlorination byproducts, including Y and C, were transformed into drinking water during chlorination. However, the potential toxicity of the byproducts in hepatotoxicity and reproduction toxicity remains unclear. METHODS: The TOPKAT database predicted the toxicological properties of metformin disinfection by-products. The targets of metformin disinfection by-products were mainly obtained from the PharmMapper database, and then the targets of hepatotoxicity and reproductive toxicity were screened from GeneCards. The overlapping targets of toxic component targets and the hepatotoxicity or reproduction toxicity targets were regarded as the key targets. Then, the STRING database analyzed the key target to construct a protein-protein interaction network (PPI) and GO, and KEGG analysis was performed by the DAVID platform. Meanwhile, the PPI network and compound- target network were constructed by Cytoscape 3.9.1. Finally, Discovery Studio 2019 software was used for molecular docking verification of the two toxic compounds and the core genes. RESULTS: Y and C exhibited hepatotoxicity, carcinogenicity, and mutagenicity evaluated by TOPKAT. There were 22 potential targets relating to compound Y and hepatotoxicity and reproduction toxicity and 14 potential targets relating to compound C and hepatotoxicity and reproduction toxicity. PPI network analysis showed that SRC, MAPK14, F2, PTPN1, IL2, MMP3, HRAS, and RARA might be the key targets; the KEGG analysis indicated that compounds Y and C caused hepatotoxicity through Hepatitis B, Pathways in cancer, Chemical carcinogenesis-reactive oxygen species, Epstein-Barr virus infection; compound Y and C caused reproduction toxicity through GnRH signaling pathway, Endocrine resistance, Prostate cancer, Progesterone-mediated oocyte maturation. Molecular docking results showed that 2 compounds could fit in the binding pocket of the 7 hub genes. CONCLUSION: This study preliminarily revealed the potential toxicity and possible toxicity mechanism of metformin disinfection by-products and provided a new idea for follow-up research.

Unraveling the mechanism of Yiqi Jiedu formula against nasopharyngeal carcinoma: An investigation integrating network pharmacology, serum pharmacochemistry, and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Yiqi Jiedu formula (YQJDF), rooted in the traditional Chinese medicinal principle of "tonifying qi and detoxifying", is remarkably efficacious in the clinical treatment of nasopharyngeal carcinoma (NPC). Previous studies have shed light on some of its anti-NPC effects and mechanisms, but the responsible pharmacological substances and their precise mechanisms of action remain unclear. AIM OF THE STUDY: The purpose of this study was to identify components of YQJDF that entered the bloodstream and to investigate their mechanisms of action against NPC through network pharmacology and serum metabolomics. MATERIAL AND METHODS: Components of YQJDF in serum were identified using liquid chromatography-tandem mass spectrometry. With these serum species as the focus of our research, network pharmacology analysis was used to identify active compounds and target genes that might mediate the efficacy of YQJDF in the treatment of NPC. Following establishment of an NPC xenograft model in nude mice, a non-targeted metabolomics approach was adopted to identify significant serum metabolites and metabolic pathways influenced by YQJDF. RESULTS: Thirty-six components of YQJDF were identified, primarily consisting of alkaloids, phenylpropanoids, and flavonoids. Notably, pathways such as PI3K/AKT, factors associated with Epstein-Barr virus infection, IL-17 signaling, and lipid metabolism, were highlighted as potential therapeutic targets of YQJDF during NPC treatment. Additionally, our findings suggested that YQJDF modified the metabolism of arginine and proline in the serum of mice bearing nasopharyngeal tumor grafts. CONCLUSIONS: This study identified the primary active components of YQJDF, highlighting its holistic role in the treatment of NPC through multiple targets and pathways. Furthermore, our findings provided a roadmap for future research into the mechanism of YQJDF in the therapy of NPC, setting the stage for its clinical application.

Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to Clinical Practice.

Long COVID symptoms typically occur within 3 months of an initial COVID-19 infection, last for more than 2 months, and cannot be explained by other diagnoses. The most common symptoms include fatigue, dyspnea, coughing, and cognitive impairment. The mechanisms of long COVID are not fully understood, but several hypotheses have been put forth. These include coagulation and fibrosis pathway activation, inflammatory and autoimmune manifestations, persistent virus presence, and Epstein-Barr virus reactivation. Hyperbaric oxygen therapy (HBOT) is a therapeutic method in which a person inhales 100% oxygen under pressure greater than that of the atmosphere. HBOT has some therapeutic effects, including improvement of microcirculation, inhibition of cytokine release leading to a reduction in inflammatory responses, inhibition of autoimmune responses, and promotion of neurological repair. Several clinical trials have been carried out using HBOT to treat long COVID. The results suggest that HBOT helps to improve symptom severity, reduce symptom duration, and enhance patients' quality of life. It is believed that HBOT is an effective option for patients with long COVID, which is worth actively promoting.

Integrating Baseline Nutritional and Inflammatory Parameters with Post-Treatment EBV DNA Level to Predict Outcomes of Patients with De Novo Metastatic Nasopharyngeal Carcinoma Receiving Chemotherapy Combination PD-1 Inhibitor.

OBJECTIVES: To develop and validate a prognostic nomogram based on baseline nutritional and inflammatory parameters for risk stratification in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) receiving chemotherapy combination programmed death-1 (PD-1) inhibitor. METHODS: This retrospective study analyzed 131 patients with dmNPC (88 and 43 in the training and validation cohorts, respectively) between March 2017 and November 2020. All these patients received chemotherapy combined with PD-1 inhibitor treatment. We identified independent risk factors using univariate and multivariate Cox regression analyses and established a nomogram to predict the progression-free survival (PFS). The predictive accuracy of the nomogram was evaluated and independently validated. RESULTS: Baseline nutritional risk index (NRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), uric acid (UA), and post-treatment Epstein-Barr virus (EBV) DNA were used to develop a nomogram that could divide patients into favorable- and unfavorable-prognosis groups. The median PFS (mPFS) was significantly longer in the favorable-prognosis group compared to the unfavorable-prognosis group (35.10 months [95% CI: 27.36-42.84] vs. 7.23 months [95% CI: 6.50-7.97]; p = 0.001). All results were confirmed in the validation cohort. CONCLUSIONS: The proposed model improved the prognostic risk stratification for patients with dmNPC undergoing chemotherapy combined with PD-1 inhibitor treatment.

Perceived income inadequacy is associated with Epstein-Barr Virus latency and mental health outcomes in informal caregivers who are also employed in the healthcare industry.

Finances are a prevalent source of stress. In a sample of 799 nursing home workers measured multiple times over 18 months, we found that higher perceived income inadequacy, the perception that one's expenses exceeds one's incomes, was associated with poorer self-reported mental health indicators and Epstein-Barr Virus antibody titers (a marker of cell-mediated immune function). Perceived income inadequacy predicted outcomes over and above the role of other socioeconomic status variables (objective household income and education). Mental health variables were not related to Epstein-Barr Virus antibody titers. Additionally, we found an interaction between perceived income inadequacy and informal caregiver status on our mental health outcomes; informal caregivers with higher perceived income inadequacy had poorer mental health than non-caregivers with the same perceived income inadequacy. Our findings may add nuance to the reserve capacity model, which states that those at lower socioeconomic levels are at higher risk of adverse health outcomes partly because they have fewer resources to address demands and strain. Perceived income inadequacy may significantly predict mental and physical well-being beyond other socioeconomic status variables, especially among lower-income employees. Caregiving stress and perceived income inadequacy may have synergistic effects on mental health.

PD-1 blockade and radiotherapy combination for advanced Epstein-Barr virus-associated intrahepatic cholangiocarcinoma: a case report and literature review.

Advanced intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor of biliary epithelial cells, known for its extremely unfavorable prognosis. In the absence of intervention, patients typically survive for less than 5 months. Current guidelines from the Chinese Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology (ESMO) recommend chemotherapy-based systemic therapy as the standard treatment for advanced ICC. However, the first-line regimen, consisting of gemcitabine in combination with cisplatin, generally results in a median survival of approximately one year, which is considered suboptimal. Significant progress has been made in radiotherapy techniques, molecular diagnostics, and tumor immune microenvironments. The integration of immune and radiation therapies has revolutionized treatment strategies for cholangiocarcinoma. Moreover, combined therapeutic regimens have shown promising results in improving survival rates among patients with advanced ICC. In this study, we present a case report of a 70-year-old male patient diagnosed with stage IV ICC, featuring metastases to the retroperitoneal, left adrenal, and left supraclavicular lymph nodes. The patient exhibited a high tumor mutational load, significant microsatellite instability, and hyper-expression of PD-L1 (90%), along with positive Epstein-Barr virus-encoded RNA (EBER). Pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, was administered in conjunction with radiotherapy. As a result, considerable shrinkage and inactivation of the primary foci were observed, accompanied by the disappearance of metastases. Ultimately, the patient achieved complete remission and maintained progression-free survival for 41 months following the initial treatment. To the best of our knowledge, this represents the longest case of complete remission using a combination of immunotherapy and radiotherapy as a first-line regimen for the high tumor mutational load, microsatellite instability, and PD-L1 expression (90%) subtype of Epstein-Barr virus-associated ICC (EBVaICC). These findings suggest that the combination of PD-1 inhibitors with radiotherapy may serve as a promising therapeutic strategy for treating this particular cancer subtype.

Investigating the potential link between lunar cycle and multiple sclerosis relapses: a call for further studies.

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.

Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Exploring underlying mechanism of artesunate in treatment of acute myeloid leukemia using network pharmacology and molecular docking.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous hematological cancer. The current diagnosis and therapy model of AML has gradually shifted to personalization and accuracy. Artesunate, a member of the artemisinin family, has anti-tumor impacts on AML. This research uses network pharmacology and molecular docking to anticipate artesunate potential mechanisms of action in the therapy of AML. METHODS: Screening the action targets of artesunate through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), PubChem, and Swiss Target Prediction databases; The databases of Online Mendelian Inheritance in Man (OMIM), Disgenet, GeneCards, and Drugbank were utilized to identify target genes of AML, and an effective target of artesunate for AML treatment was obtained through cross-analysis. Protein-protein interaction (PPI) networks are built on the Cytoscape platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the relevant targets using R software. Finally, using molecular docking technology and Pymol, we performed verification of the effects of active components and essential targets. RESULTS: Artesunate 30 effective targets for treating AML include CASP3, EGFR, MAPK1, and STAT3, four targeted genes that may have a crucial function in disease management. The virus infection-related pathway (HeptatisB (HBV), Human papillomavirus (HPV), Epstein-Barr virus (EBV) infection and etc.), FoxO, viral carcinogenesis, and proteoglycans in cancer signaling pathways have all been hypothesized to be involved in the action mechanism of GO, which is enriched in 2044 biological processes, 125 molecular functions, 209 cellular components, and 106 KEGG pathways. Molecular docking findings revealed that artesunate was critically important in the therapy of AML due to its high affinity for the four primary disease targets. Molecular docking with a low binding energy yields helpful information for developing medicines against AML. CONCLUSIONS: Consequently, artesunate may play a role in multi-targeted, multi-signaling pathways in treating AML, suggesting that artesunate may have therapeutic potential for AML.

Network pharmacology and bioinformatics analysis on the underlying mechanisms of baicalein against oral squamous cell carcinoma.

BACKGROUND AND AIMS: This study performed a network pharmacology analysis to explore the potential anticancer activity of baicalein against oral squamous cell carcinoma (OSCC). METHODS: The differentially expressed genes in OSCC were identified by the OSCC, and the key module related to OSCC was acquired by the weighted gene co-expression network analysis from GSE30784. Baicalein targets were obtained from GeneCards, SwissTargetPrediction and TCMSP (the traditional Chinese medicine systems pharmacology database and analysis platform) databases. Apart from GSE30784, OSCC-related genes were acquired from the Comparative Toxicogenomics Database and DisGeNET platform. The baicalein targets and OSCC-related genes were overlapped to acquire the drug-disease interaction genes. We input the candidate drug-disease interaction genes into the STRING database and created the protein-protein interaction network. The hub genes in the network were identified by cytoHubba. The expression levels of hub genes between cancer tissues and normal tissues were evaluated based on The Cancer Genome Atlas. Moreover, we performed the cancer immune infiltration analysis and evaluated the association between the expression of HIF1A and the abundance of infiltrating immune cells. The molecular docking between HIFA and baicalein was also performed and visualized. Additionally, the enrichment analysis was performed based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database. RESULTS: After overlapping the candidate baicalein targets with OSCC-related genes, 34 candidate drug-disease interaction genes were obtained. cytoHubba identified the top 10 genes with high centrality measures from the network, including AKT1, CD44, EGFR, HIF1A, IGF1, MMP2, MYC, PTGS2, STAT3 and TP53. The enriched biological process terms included regulation of apoptotic signaling pathway, regulation of cysteine-type endopeptidase activity and cellular response to chemical stress. The top five enriched pathways comprised Kaposi sarcoma-associated herpesvirus infection, hepatitis C, p53 signaling pathway, Epstein-Barr virus infection and proteoglycans in cancer. The expression of HIF1A was positively associated with the infiltration levels of CD4 + T cells (cor = 0.131, p = 0.004) and dendritic cells (cor = 0.098, p = 0.03), whereas negatively associated with B cells (cor = -0.098, p = 0.03). CONCLUSION: Our results suggested that baicalein might be a candidate drug against OSCC. More studies are necessary to validate its anticancer effect and explore the underlying mechanisms.

From Mild Gait Difficulties to a Sudden Coma: A Rare Case of Marchiafava-Bignami Disease.

ABSTRACT: In this case report we describe the case of a 66-year old man with subacute gait difficulties, with a progression to confusion coma with multiple generalised epileptic seizures during the following days. Biochemical analysis showed hyperglycaemia, cerebrospinal fluid (CSF) testing showed a mild lymphocytic pleocytosis and an elevated protein and lactate. Broad-spectrum antibiotics and antiviral therapy where initiated. However, all other CSF testing remained negative. Magnetic resonance imaging of the brain showed remarkably symmetric hyperintense T2 white matter lesions most noticable in the corpus callosum. The lesion pattern was suggestive of a metabolic or toxic encephalopathy, the preponderance for the corpus callosum was furthermore suggestive for Marchiafava-Bignami disease (MDB), as was the clinical course since admission of the patient. A high dose IV substitution of vitamin B1, B6 and B12 was started and antibiotic and antiviral therapy was discontinued. After one day the patient showed progressive regaining of consciousness and he returned to premorbid functioning in a matter of 1-2 weeks. MRI of the brain after 1 week showed notable improvement of the white matter lesions. At routine follow-up two weeks later he presented with icterus and a diagnosis of Epstein-Barr virus (EBV) hepatitis was made, lymph node biopsies showed an EBV positive diffuse large cell B-cell lymphoma (DLCBL). MDB is mostly associated with severe alcoholism, with malnourishment being the second leading cause, however there are case reports describing MDB in patients with chronically poorly controlled diabetes mellitus. We hypothesize that his condition may have been precipitated by his poorly controlled diabetes mellitus. However it is also possible that weight loss (probably related to the DLCBL diagnosis) might have contributed to a state of malnourishment and therefore played a role in the aetiology as well.

Anti-Epstein-Barr Viral Agents from the Medicinal Herb-Derived Fungus Alternaria alstroemeriae Km2286.

Chromatographic separation on the liquid-state fermented products produced by the fungal strain Alternaria alstroemeriae Km2286 isolated from the littoral medicinal herb Atriplex maximowicziana Makino resulted in the isolation of compounds 1-9. Structures were determined by spectroscopic analysis as four undescribed perylenequinones, altertromins A-D (1-4), along with altertoxin IV (5), altertoxin VIII (6), stemphyperylenol (7), tenuazonic acid (8), and allo-tenuazonic acid (9). Compounds 1-6 exhibited antiviral activities against Epstein-Barr virus (EBV) with EC50 values ranging from 0.17 ± 0.07 to 3.13 ± 0.31 µM and selectivity indices higher than 10. In an anti-neuroinflammatory assay, compounds 1-4, 6, and 7 showed inhibitory activity of nitric oxide production in lipopolysaccharide-induced microglial BV-2 cells, with IC50 values ranging from 0.33 ± 0.04 to 4.08 ± 0.53 µM without significant cytotoxicity. This is the first report to describe perylenequinone-type compounds with potent anti-EBV and anti-neuroinflammatory activities.

Reducing Virus Infection Risk in Space Environments through Nutrient Supplementation.

Space exploration has brought many challenges to human physiology. In order to evaluate and reduce possible pathological reactions triggered by space environments, we conducted bioinformatics analyses on the methylation data of the Mars 520 mission and human transcriptome data in the experiment simulating gravity changes. The results suggest that gene expression levels and DNA methylation levels were changed under the conditions of isolation and gravity changes, and multiple viral infection-related pathways were found in the enrichment analysis results of changed genes including Epstein Barr virus (EBV) infection, Hepatitis B virus (HBV) infection, Herpes simplex virus (HSV) infection and Kaposi's sarcoma-associated herpesvirus (KHSV) infection. In this study, we found that Epigallocatechin-3-gallate (EGCG) and vitamin D are helpful in reducing viral infection risk. In addition, the causal associations between nutrients and viral infections were calculated using Two sample Mendelian Randomization (2SMR) method, the results indicated that vitamin D can reduce EBV infection and HBV infection risk. In summary, our study suggests that space environments increase the risk of human viral infection, which may be reduced by supplementing EGCG and vitamin D. These results can be used to formulate medical plans for astronauts, which have practical application value for future space exploration.

Case report: Cellular therapy for hydroa vacciniforme-like lymphoproliferative disorder in pediatric common variable immunodeficiency with chronic active Epstein-Barr virus infection.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a cutaneous form of chronic active Epstein-Barrvirus (EBV) infection, which can develop into the extremely rare systemic lymphoma. Patients with Inborn errors of immunity (IEI), such as common variable immunodeficiency (CVID), are at higher risk of developing a severe course of infections especially viral and malignancies than the general population. The aim of the study was to present complex diagnostic and therapeutic management of HV-LPD. The clinical diagnosis was confirmed at the histological and molecular level with next generation sequencing. HV-LPD was diagnosed in a patient with CVID and chronic active Epstein-Barr virus (CAEBV) infection. The patient was refractory to CHOP chemotherapy and immunosuppressive treatment in combination with antiviral drugs (prednisone, bortezomib, gancyclovir). The third-party donor EBV-specific cytotoxic T cells (EBV-CTL, tabelecleucel) were used, which stabilised the disease course. Finally, matched unrelated donor hematopoietic cell transplantation (MUD-HCT) was performed followed by another cycle of EBV-CTL.

The immune microenvironment features and response to immunotherapy in EBV-associated lymphoepithelioma-like cholangiocarcinoma.

BACKGROUND AND AIMS: Limited data are available for tumor immune microenvironment (TIME) in Epstein-Barr virus (EBV)-associated lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a rare subtype of intrahepatic cholangiocarcinoma (IHCC). We aimed to investigate TIME features in EBV-LELCC and the correlation between the components of TIME and the clinical outcomes. METHODS: Tumor tissues from five EBV-LELCC cases confirmed through EBER in situ hybridization and five stage-matched conventional IHCC (non-EBV IHCC) cases were collected. These samples were used to evaluate genetic alterations, TIME composition, and PD-L1 expression through ion AmpliSeq comprehensive cancer panel, PanCancer immune profiling panel, immunohistochemistry, and immunofluorescence staining. The correlation between clinical outcomes and TIME components was analyzed in the two EBV-LELCC cases receiving anti-PD-1 treatment. RESULTS: The genetic mutations identified in EBV-LELCC were BARD1, CD19, CD79B, EPHA5, KDM5A, MUC6, MUC16, PTEN, RECQL4, TET1, and TNFAIP3. Both CD79B and TNFAIP3 mutations were involved in the NF-κB signaling pathway. PD-L1 was highly expressed in tumor-infiltrating immune cells, especially the T cells and macrophages. The TIME of EBV-LELCC displayed abundant immune cell infiltration with a stronger adaptive immune response. Increased Th1 cells, NK CD56dim cells, and M1 macrophages, decreased M2 macrophages, exhausted CD8 T cell infiltration, and increased T cell activation signatures in TIME were associated with longer survival. Two patients with metastatic EBV-LELCC had good disease control after anti-PD-1 antibody treatment. A significantly larger TIME component made EBV-LELCCs more sensitive to immune checkpoint blockade (ICB). CONCLUSION: A better understanding of the composition of TIME in EBV-LELCC is critical for predicting the clinical outcomes of ICB treatment.

How Epstein-Barr virus envelope glycoprotein gp350 tricks the CR2? A molecular dynamics study.

The connection of Epstein Barr virus (EBV) with diseases such as Burkitt Lymphoma, Hodgkin disease, multiple sclerosis, systemic lupus erythematosus and various B-cell lymphomas made EBV glycoproteins one of the most popular vaccine immunogens. As a protein being encoded by EBV, the viral membrane envelope protein gp350 is studied extensively due to its abundancy on the surface and its interaction with complementary receptor, CR2. The binding of CR2 and gp350 not only leads to the entrance of the virus to the B-cells, but also prevents CR2 and C3d protein interactions that are required for immune response. Thus, understanding the inhibition of gp350 activity is crucial for vaccine development. Although, the active residues on gp350 structure were determined by several mutational studies, the exact mechanism of CR2 binding is still not clear. To this end, we have performed molecular docking followed by molecular dynamics simulations and MM-PBSA on wildtype and several mutated gp350 and CR2 structures. Apart from identifying crucial amino acids, the results of per-residue decomposition energy analysis clarified the individual energy contributions of amino acids and were also found to be accurate in differentiating the active site residues in CR2 binding. Here, we highlight the role of binding region residues (linker-1) but more interestingly, the dynamic relation between the distant sites of gp350 (linker-2 and D3 residues) and CR2. These findings can lead further vaccine development strategies by pointing to the importance of computationally found novel regions that can be potentially used to modulate gp350 activity.