A magnetic resonance imaging-based lymph node regression grading scheme for nasopharyngeal carcinoma after radiotherapy.

Background: Among patients with nasopharyngeal carcinoma (NPC), there is no established method to distinguish between patients with residual disease that may eventually progress and those who have achieved cured. We thus aimed to assess the prognostic value of magnetic resonance imaging (MRI)-based lymph node regression grade (LRG) in the risk stratification of patients with NPC following radiotherapy (RT). Methods: This study retrospectively enrolled 387 patients newly diagnosed with NPC between January 2010 and January 2013. A four-category MRI-LRG system based on the areal analysis of RT-induced fibrosis and residual tumor was established. Univariate analysis was performed using the Kaplan-Meier method, and comparisons were conducted via the log-rank test. Multivariate analyses were conducted using Cox regression models to calculate the hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted P values. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. Results: The sum of MRI-LRG scores (LRG-sum) was an independent prognostic factor for progression-free survival (PFS) (HR 2.50, 95% CI: 1.28-4.90; P<0.001). LRG-sum ≤9 and >9 showed a poorer 5-year PFS rate than did LRG-sum ≤2 (66.1%, 42.9%, and 77.6%, respectively; P<0.001). A survival clustering analysis-based decision tree model showed more complex interactions among LRG-sum and pretreatment and post-RT Epstein-Barr virus (EBV) DNA, yielding four patient clusters with differentiated disease progression risks (5-year PFS rates of 89.5%, 76.4%, 57.6%, and 27.8%, respectively), which showed better risk stratification than did post-RT EBV DNA alone (P<0.001). Conclusions: The MRI-LRG system adds prognostic information and is a potentially reliable, noninvasive means to stratify treatment modalities for patients with NPC.

Modified SMILE (mSMILE) is active in the treatment of pediatric Epstein-Barr virus-associated natural killer/T-cell lymphoma: a single center experience, case series.

Background: The Epstein-Barr virus-associated natural killer (NK) and T-cell lymphoma (EBV + NK/T cell lymphoma) is a severe illness mainly affecting children and young adults, often resulting in a poor prognosis. To date, there is no consensus on an established treatment strategy. This study aims to evaluate the efficacy and safety of the mSMILE (modified steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen in treating EBV+ NK/T-cell lymphoma and to provide insights into potential treatment outcomes. Methods: In this study, we conducted a retrospective analysis of the clinical data and treatment outcomes for patients with EBV + NK/T cell lymphoma treated at Children's Hospital of Nanjing Medical University between July 2017 and January 2022. These patients received at least two cycles of the mSMILE chemotherapy, in which a single dose of pegaspargase was substituted for 7 doses of L-asparaginase per cycle. Results: Eight patients were included in the study: one with extranodal NK/T-cell lymphoma, one with primary nodal NK/T-cell lymphoma, and six with Systemic EBV+ NK/T cell lymphoma of childhood. The results showed that five patients achieved complete remission, two achieved partial remission, and one showed progressive disease, resulting in a complete remission rate of 62.5% and an overall response rate of 87.5%. The 3-year overall survival (OS) and event-free survival (EFS) rates were 87.5% and 75%, respectively. The most common adverse reactions associated with chemotherapy were hematologic toxicities of stages III to IV. Nonhematologic adverse reactions mainly included impaired liver function, infections, and oral mucositis, which were resolved with aggressive anti-infective therapy. Conclusions: Based on our clinical experience, the mSMILE appears to be a safe and effective treatment option for EBV + NK/T-cell lymphoma, meriting further investigation in late-phase clinical trials.

Challenges in overcoming advanced-stage or relapsed refractory extranodal NK/T-cell lymphoma: meta-analysis of individual patient data.

Introduction: Extranodal NK/T-cell lymphoma (ENKTCL), a non-Hodgkin lymphoma, is known for its destructive local impact on nasal structures and systemic induction of inflammatory cytokines. Concurrent treatment with radiation and nonanthracycline- based chemotherapy has improved survival rates in patients with localized disease stages. However, survival outcomes vary significantly in advanced-stage and relapsed or refractory (R/R) cases. Methods: Therefore, we conducted a meta-analysis using random effects models to assess prognostic factors in advanced or R/R ENKTCL, employing a digital extractor on Kaplan-Meier graphs owing to the scarcity of published prospective trials for these patients. Results: We observed that patients with advanced ENKTCL treated with Lasparaginase had a median progression-free survival (PFS) of 14.3 months and an overall survival (OS) of 19 months. In R/R ENKTCL, PFS and OS were 11.7 and 15.6 months, respectively. Additionally, OS outcomes in advanced-stage ENKTCL were better in the asparaginase group than that in the non-asparaginase group, with PEG-asparaginase showing superior results compared with that using Lasparaginase. Epstein-Barr Virus (EBV)-DNA positivity in the bloodstream prior to treatment was associated with poor outcomes in advanced-stage ENKTCL, and similar trends were observed in patients with R/R ENKTCL and post-treatment EBV viremia. Discussion: Collectively, these findings suggest that chemotherapy with Lasparaginase or PEG-asparaginase can enhance survival in advanced or R/R ENKTCL. However, future strategies must be developed to effectively suppress EBV viremia and achieve a deep response toward tumor eradication.

Cholestatic hepatitis in acute Epstein-Barr virus infection: A case report.

Cholestatic hepatitis is a rare complication of Epstein-Barr virus infection and is often self-limiting. Systemic signs, including viral prodrome and lymphadenopathy, can provide crucial diagnostic cues and avoid unnecessary invasive investigations or aggressive medical therapy unless indicated.

Cephalic and ocular manifestations of EBV-associated plasmablastic lymphoma: Clinical and radiological response to bortezomib, EPOCH, and intrathecal methotrexate.

Plasmablastic lymphoma (PBL) is a rare and aggressive type of lymphoma, particularly affecting HIV-positive and immunocompromised individuals, with a median diagnosis age of 49 years. Cases of this malignancy in HIV-negative individuals are less common and rarely involve the bone marrow. While traditional chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) were previously utilized in the management of such malignancy, the National Comprehensive Cancer Network currently recommends more intensive approaches. We present a rare stage IV Epstein-Barr virus (EBV)-positive PBL with a nasal cavity tumor extending into the left orbital sinus and encapsulating segments of the optic nerve in a 38-year-old young immunocompetent adult, without a significant past medical history. Treatment consisted of 6 cycles of Bortezomib in combination with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and intrathecal methotrexate which exhibited significant clinical and radiological improvement suggesting the potential efficacy of this regimen. Vision returned to baseline, the mass size reduced significantly, and headaches improved. Given this outcome, it is highly encouraged to emphasize the need for further exploration of this treatment in larger clinical trials.

Evaluating the role of interleukin-2 and interleukin-12 in pediatric patients with concurrent Mycoplasma pneumoniae and Epstein-Barr virus infections.

BACKGROUND: Mycoplasma pneumoniae (MP) frequently causes respiratory infections in children, whereas Epstein-Barr virus (EBV) typically presents subclinical manifestations in immunocompetent pediatric populations. The incidence of MP and EBV co-infections is often overlooked clinically, with the contributory role of EBV in pulmonary infections alongside MP remaining unclear. AIM: To evaluate the serum concentrations of interleukin-2 (IL-2) and interleukin-12 (IL-12) in pediatric patients with MP pneumonia co-infected with EBV and assess their prognostic implications. METHODS: We retrospectively analyzed clinical data from patients diagnosed with MP and EBV co-infection, isolated MP infection, and a control group of healthy children, spanning from January 1, 2018 to December 31, 2021. Serum IL-2 and IL-12 levels were quantified using enzyme-linked immunosorbent assay. Logistic regression was employed to identify factors influencing poor prognosis, while receiver operating characteristic (ROC) curves evaluated the prognostic utility of serum IL-2 and IL-12 levels in co-infected patients. RESULTS: The co-infection group exhibited elevated serum IL-2 and C-reactive protein (CRP) levels compared to both the MP-only and control groups, with a reverse trend observed for IL-12 (P < 0.05). In the poor prognosis cohort, elevated CRP and IL-2 levels, alongside prolonged fever duration, contrasted with reduced IL-12 levels (P < 0.05). Logistic regression identified elevated IL-2 as an independent risk factor and high IL-12 as a protective factor for adverse outcomes (P < 0.05). ROC analysis indicated that the area under the curves for IL-2, IL-12, and their combination in predicting poor prognosis were 0.815, 0.895, and 0.915, respectively. CONCLUSION: Elevated serum IL-2 and diminished IL-12 levels in pediatric patients with MP and EBV co-infection correlate with poorer prognosis, with combined IL-2 and IL-12 levels offering enhanced predictive accuracy.

Epstein-Barr virus noncoding RNA EBER1 promotes the expression of a ribosomal protein paralog to boost oxidative phosphorylation.

Epstein-Barr virus (EBV) is a highly successful pathogen that infects ~95% of the adult population and is associated with diverse cancers and autoimmune diseases. The most abundant viral factor in latently infected cells is not a protein but a noncoding RNA called EBV-encoded RNA 1 (EBER1). Even though EBER1 is highly abundant and was discovered over forty years ago, the function of EBER1 has remained elusive. EBER1 interacts with the ribosomal protein L22, which normally suppresses the expression of its paralog L22-like 1 (L22L1). Here we show that when L22 binds EBER1, it cannot suppress L22L1, resulting in L22L1 being expressed and incorporated into ribosomes. We further show that L22L1-containing ribosomes preferentially translate mRNAs involved in the oxidative phosphorylation pathway. Moreover, upregulation of L22L1 is indispensable for growth transformation and immortalization of resting B cells upon EBV infection. Taken together, our results suggest that the function of EBER1 is to modulate host gene expression at the translational level, thus bypassing the need for dysregulating host gene transcription.

Association of partial infections with the risk of psoriasis: A two-sample Mendelian randomization study.

BACKGROUND: As a common chronic recurrent inflammatory skin disease, psoriasis is characterized by erythema and scaly skin lesions, with infection as an integral part of the pathogenesis of many diseases. Many previous cases reported the impact of psoriasis on infection. However, the existing research fails to completely clarify the infection factors associated with the potential of these diseases and causality. MATERIALS AND METHODS: Thirteen kinds of pathogens and their immune responses and psoriasis in the phenotype of 46 species of SNPs data were respectively obtained from the GWAS catalog database and the UK biobank database. With the help of R software, three methods of inverse variance weighted (IVW), weighted median (WME), and MR-Egger regression were used to analyze the causality of the dataset. RESULTS: According to the results of IVW analysis, there is a causal relationship between anti-Epstein Barr virus antibody and psoriasis (OR: 1.003, 95% CI: 1.001∼1.006, P = 0.046) with a positive correlation. CONCLUSION: Based on the results of MR analysis, there is a causal relationship between psoriasis and EBV infection, which indicates that EBV infection can increase the risk or severity of psoriasis. Therefore, in clinical scenarios, patients afflicted with psoriasis should be prevented from contracting the infection and recurrence of EBV as well as symptoms of psoriasis. The underlying immunological mechanism also provides a new perspective for experimental research.

Enhancing diagnostic precision in EBV-related HLH: a multifaceted approach using 18F-FDG PET/CT and nomogram integration.

BACKGROUND: The hyperinflammatory condition and lymphoproliferation due to Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) affect the detection of lymphomas by 18F-FDG PET/CT. We aimed to improve the diagnostic capabilities of 18F-FDG PET/CT by combining laboratory parameters. METHODS: This retrospective study involved 46 patients diagnosed with EBV-positive HLH, who underwent 18F-FDG PET/CT before beginning chemotherapy within a 4-year timeframe. These patients were categorized into two groups: EBV-associated HLH (EBV-HLH) (n = 31) and EBV-positive lymphoma-associated HLH (EBV + LA-HLH) (n = 15). We employed multivariable logistic regression and regression tree analysis to develop diagnostic models and assessed their efficacy in diagnosis and prognosis. RESULTS: A nomogram combining the SUVmax ratio, copies of plasma EBV-DNA, and IFN-γ reached 100% sensitivity and 81.8% specificity, with an AUC of 0.926 (95%CI, 0.779-0.988). Importantly, this nomogram also demonstrated predictive power for mortality in EBV-HLH patients, with a hazard ratio of 4.2 (95%CI, 1.1-16.5). The high-risk EBV-HLH patients identified by the nomogram had a similarly unfavorable prognosis as patients with lymphoma. CONCLUSIONS: The study found that while 18F-FDG PET/CT alone has limitations in differentiating between lymphoma and EBV-HLH in patients with active EBV infection, the integration of a nomogram significantly improves the diagnostic accuracy and also exhibits a strong association with prognostic outcomes.

Epidemiologic Associations Between Inflammatory Bowel Disease and Hodgkin Lymphoma or Multiple Sclerosis.

Background and Aims: Epidemiologic evidence suggests that Hodgkin lymphoma (HL) and multiple sclerosis (MS) share a common set of risk factors with Crohn's disease (CD) and ulcerative colitis (UC). It was hypothesized that such shared risk factors would lead to similar geographic distributions of these 4 diagnoses and their concurrence in identical patients. Methods: All subjects with HL, MS, CD, or UC were identified in the complete Inpatient Standard Analytic File of the Centers for Medicare and Medicaid Services from 2018. In a cross-sectional study, we evaluated whether the frequencies of HL, MS, CD, and UC occurrences among different US states were statistically correlated with each other. In a case-control study, the observed concurrences of each 2 of the 4 diagnoses were compared with their expected frequencies in the overall Medicare population by calculating odds ratios with their 95% confidence intervals. Results: The total Centers for Medicare and Medicaid Services population comprised 6,462,321 unique patients, of whom 8027 presented with HL, 42,934 with MS, 40,623 with CD, and 32,521 with UC. Statistically significant positive correlations (r) with P < .001 were found between HL and MS (r = 0.50), HL and CD (0.46), HL and UC (0.68), MS and CD (0.66), MS and UC (0.72), and CD and UC (0.68). Any inflammatory bowel disease was significantly associated with a diagnosis of concurrent HL (odds ratio: 1.22, 95% confidence interval: 1.01-1.48) or MS (1.35, 1.25-1.46). Conclusion: The epidemiologic associations of inflammatory bowel disease with HL or MS may reflect a common pathway in the etiology or pathogenesis of these diseases.

Hemophagocytic Lymphohistiocytosis in the Context of Hematological Malignancies and Solid Tumors.

Hemophagocytic lymphohistiocytosis (HLH) has been described for decades in association with malignancies (M-HLH). While its mechanism is unknown, M-HLH has a poor prognosis, ranging from 10% to 30% overall survival. Mature T-cell lymphomas, diffuse large B-cell lymphoma, and Hodgkin lymphoma, with or without viral co-triggers such as Epstein-Barr virus, are among the most frequent underlying entities. Most M-HLH cases occur at the presentation of malignancy, but they may also occur during therapy as a result of immune compromise from chemotherapy (HLH in the context of immune compromise, IC-HLH) and (typically) disordered response to infection or after immune-activating therapies (Rx-HLH, also known as cytokine release syndrome, CRS). IC-HLH typically occurs months after diagnosis in the context of fungal, bacterial, or viral infection, though it may occur without an apparent trigger. Rx-HLH can be associated with checkpoint blockade, chimeric antigen receptor T-cell therapy, or bispecific T-cell engaging therapy. Until recently, M-HLH diagnosis and treatment strategies were extrapolated from familial HLH (F-HLH), though optimized diagnostic and therapeutic treatment strategies are emerging.

Etoposide Therapy of Cytokine Storm Syndromes.

Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.

The role of microbiota in nasopharyngeal cancer: Where do we stand?

Nasopharyngeal carcinoma (NPC) is a common head and neck cancer with a poor prognosis. One of the crucial challenges regarding NPC is its pathogenesis. Recent findings highlight the significance of host microbiota in the development of NPC, affected locally by nasopharyngeal microbiota or remotely by oral microbiota. The oral microbiota can migrate to the nasopharyngeal space, thereby impacting the composition of the nasopharyngeal microbiota. Specific bacterial strains have been linked to the development of nasopharyngeal cancer, including Neisseria, Staphylococcus, Leptotrichia, Staphylococcaceae, Granulicatella, Corynebacterium, Fusobacterium, and Prevotella. Several mechanisms have been proposed to elucidate how microbiota dysbiosis contributes to the development of NPC, including triggering tumor-promoting inflammation, reactivating the Epstein-Barr virus (EBV), inducing oxidative stress, weakening the immune system, and worsening tumor hypoxia. In addition, the composition of nasopharyngeal microbiota and the number of tumor-infiltrating microbiota can influence the prognosis and treatment response in patients with NPC. To the best of our knowledge, this is the first review discussing the impacts of the host microbiota on nasopharyngeal cancer pathogenesis, progression, and treatment response.

Evodiamine suppresses endometriosis development induced by early EBV exposure through inhibition of ERß.

Introduction: Endometriosis (EMS) is characterized as a prevalent gynecological inflammatory disorder marked by the existence of endometrial tissues situated beyond the uterus. This condition leads to persistent pelvic pain and may contribute to infertility. In this investigation, we explored the potential mechanism underlying the development of endometriosis (EMS) triggered by transient exposure to either latent membrane protein 1 (LMP1) or Epstein-Barr virus (EBV) in a mouse model. Additionally, we examined the potential inhibitory effect of evodiamine (EDM) on EMS. Methods: Immortalized human endometrial stromal cells (HESC) or epithelial cells (HEEC) were transiently exposed to either EBV or LMP1. The presence of evodiamine (EDM) was assessed for its impact on estrogen receptor ß (ERß) expression, as well as on cell metabolism parameters such as redox balance, mitochondrial function, inflammation, and proliferation. Additionally, a mixture of LMP1-treated HESC and HEEC was administered intraperitoneally to generate an EMS mouse model. Different dosages of EDM were employed for treatment to evaluate its potential suppressive effect on EMS development. Results: Transient exposure to either EBV or LMP1 triggers persistent ERß expression through epigenetic modifications, subsequently modulating related cell metabolism for EMS development. Furthermore, 4.0 µM of EDM can efficiently reverse this effect in in vitro cell culture studies. Additionally, 20 mg/kg body weight of EDM treatment can partly suppress EMS development in the in vivo EMS mouse model. Conclusion: Transient EBV/LMP1 exposure triggers permanent ERß expression, favoring later EMS development, EDM inhibits EMS development through ERß suppression. This presents a novel mechanism for the development of endometriosis (EMS) in adulthood stemming from early Epstein-Barr virus (EBV) exposure during childhood. Moreover, evodiamine (EDM) stands out as a prospective candidate for treating EMS.

Evidence of aberrant anti-epstein-barr virus antibody response, though no viral reactivation, in people with post-stroke fatigue.

BACKGROUND: Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. AIMS: We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. METHODS: In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F < 40) and low fatigue (FACIT-F > 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher's exact test for categorical data. RESULTS: We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). CONCLUSIONS: These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.

Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or alternate LT open reading frames (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1). Following activation, NF-κB dimers bind the MCPyV noncoding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB- and NTAR-dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.

New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis.

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as "progression independent of relapse activity" and "silent progression," now thought to take hold very early in the course, together argue that an underlying "cytodegenerative" process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein-Barr virus and B cells in this process is also discussed.

Clinicopathologic Insights and Molecular Oncogenesis: Understanding Epstein-Barr Virus-Induced B-cell Lymphoproliferations.

Epstein-Barr virus (EBV) is a highly prevalent virus among adults worldwide. In an immunocompetent individual, EBV infection generally results in lifelong latency of the virus and no sequelae. However, in the setting of immune dysfunction, EBV can induce the development of autoimmune disorders, hyperplastic proliferations, and cancers, including lymphoma. Here, we explore the pathogenic and oncogenic role of EBV in Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorders and lymphoproliferative disorders associated with immune deficiency and dysregulation. In addition to describing general mechanisms of EBV-associated oncogenesis, we also discuss EBV-associated oncogenesis in the context of each disorder, as well as their microscopic, phenotypic, and clinical presentations.

Aquaporin-3 is down-regulated by LMP1 in nasopharyngeal carcinoma cells to regulate cell migration and affect EBV latent infection.

Epstein-Barr virus (EBV) infection has a strong correlation with the development of nasopharyngeal carcinoma (NPC). Aquaporin 3 (AQP3), a member of the aquaporin family, plays an important role in tumor development, especially in epithelial-mesenchymal transition. In this study, the expression of AQP3 in EBV-positive NPC cells was significantly lower than that in EBV-negative NPC cells. Western blot and qRT-PCR analysis showed that LMP1 down-regulated the expression of AQP3 by activating the ERK pathway. Cell biology experiments have confirmed that AQP3 affects the development of tumor by promoting cell migration and proliferation in NPC cells. In addition, AQP3 can promote the lysis of EBV in EBV-positive NPC cells. The inhibition of AQP3 expression by EBV through LMP1 may be one of the mechanisms by which EBV maintains latent infection-induced tumor progression.

Left ventricular apical aneurysm in Takayasu arteritis and chronic active Epstein-Barr virus infection.

BACKGROUND: Takayasu arteritis (TA) is a chronic inflammatory disease of unknown etiology characterized by a large vessel vasculitis involving the aorta and its branches. Myocardial involvement is extremely unusual in TA and is mostly in the form of myocarditis, ventricular hypertrophy, and ventricular dysfunction secondary to coronary ischemia. Submitral aneurysms have been reported in TA and has been attributed to the chronic inflammatory process in TA. CASE PRESENTATION: We report a novel instance of left ventricular apical aneurysm in a 37-year-old lady with TA and normal epicardial coronaries. She was diagnosed with a left ventricular apical aneurysm, moderate aortic regurgitation, and moderate pericardial effusion. The coronary arteries were normal. The patient had concomitant chronic active Epstein-Barr virus infection complicating patient outcome. CONCLUSIONS: Left ventricular apical aneurysm with normal epicardial coronaries is a rare cause of heart failure in Takayasu arteritis. Concomitant chronic active Epstein-Barr virus infection can potentially accentuate the inflammatory process in Takayasu arteritis and complicate management and patient outcomes.