Search

Epstein-Barr virus (EBV) evolved an episomal system for maintaining life-long, latent infection of human B lymphocytes. Circular episomes engineered from EBV components required for this latent form of infection have the capacity to persist in most types of replicating mammalian cells without DNA integration and the pitfalls of insertional mutagenesis. EBV episomes are typically transduced using low-efficiency methods. Here we present a method for efficient delivery of EBV episomes to nuclei of hepatocytes in living mice using a helper-dependent adenoviral vector and Cre-mediated recombination in vivo to generate circular EBV episomes following infection. Cre is transiently expressed from a hepatocyte-specific promoter so that vector generation and transgene expression are tissue specific. We show long-term persistence of the circularized vector DNA and expression of a reporter gene in hepatocytes of immunocompetent mice. [ABSTRACT FROM AUTHOR]

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR-29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV)-related malignancies such as post-transplant lymphoproliferative disease (PTLD) are severe complications after allogeneic stem cell transplantation and solid-organ transplantation. In immunosuppressed transplant recipients, the activity of EBV-specific CTLs are often decreased or absent which leads to an increased risk of developing PTLD. If primary treatment modalities of PTLD fail, the most efficient way of treating the malignancy is adopting EBV-specific CTLs from the donor or, more recently, third-party donors. However, both are time consuming and expensive and often it is too late to administer cells to the patient. We have for the first time, using a rapid isolation protocol of EBV-specific T cells, treated and cured a patient suffering from PTLD with multiple-associated tissue lesions, using her haplo-identical mother as a donor. This treatment approach paves way for a new possibility to within-days treat patients with life-threatening EBV-associated malignancies. [ABSTRACT FROM AUTHOR]

The article cites the study of V. Saridakis and colleagues on the Epstein-Barr virus (EBV). The crystal structure of the human ubiquitin-specific protease 7 (USP7) N-terminal domain was solved by the researchers, both alone and when bound to an Epstein-Barr nuclear antigen 1 (EBNA1) peptide. Transfection experiments conducted have confirmed that EBNA1 interfered with the stabilization of p53 by USP7.

Spontaneous splenic rupture is a well known, yet very rare complication of infectious mononucleosis with an estimated incidence of 0.06% to 0.5%. It primarily affects teenagers and young adults and is the leading cause of death in infectious mononucleosis. There is a 9% mortality rate associated with spontaneous splenic ruptures; in all lethal cases a rupture occurs within the first 10 days of symptoms onset from infectious mononucleosis. The present case report concerns a young female, who presented with abdominal pain, vomiting and positive Kehr's sign two days after the onset of infectious mononucleosis symptoms. The patient was diagnosed with a spontaneous splenic rupture due to infectious mononucleosis and was treated operatively by laparotomy and splenectomy. The patient was successfully treated, and had no post operative complications. [ABSTRACT FROM AUTHOR]

A 45 year old female renal transplant recipient presented with headaches of 3 months duration. Clinical and radiological evaluation revealed an approximately 4x4cm rounded, enhancing mass at the left temporal pole. At surgery, the mass had dural attachment and clinically, radiographically, and macroscopically resembled a meningioma. Histopathological analysis revealed a leiomyoma. Epstein-Barr virus (EBV) DNA was demonstrated within the tumour cell nuclei by the in situ hybridisation technique. This is the first documentation of an EBV-associated primary intracranial leiomyoma in an organ transplant recipient and provides additional evidence of a possible relation between EBV infection and development of smooth-muscle tumours (SMT). With increasing numbers of individuals being on long-term immuno-suppression, EBV-associated SMTs may be encountered more frequently in the future. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) has been implicated in the pathogenesis of human malignancies, but its contribution to tumorigenesis is not well understood. EBV carriage is associated with increased genomic instability in Burkitt's lymphoma, suggesting that viral products may induce this tumor phenotype. Using a panel of transfected sublines of the B-lymphoma line BJAB expressing the viral genes associated with latent infection, we show that the EBV nuclear antigens, EBNA-1 and EBNA-3C, and the latent membrane protein 1, LMP-1, independently promote genomic instability, as detected by nonclonal chromosomal aberrations, DNA breaks and phosphorylation of histone H2AX. EBNA-1 promotes the generation of DNA damage by inducing reactive oxygen species (ROS), whereas DNA repair is inhibited in LMP-1-expressing cells through downregulation of the DNA damage-sensing kinase, ataxia telangiectasia mutated (ATM), reduction of phosphorylation of its downstream targets Chk2 and inactivation of the G2 checkpoint. EBNA-3C enhances the propagation of damaged DNA through inactivation of the mitotic spindle checkpoint and transcriptional downregulation of BubR1. Thus, multiple cellular functions involved in the maintenance of genome integrity seem to be independently targeted by EBV, pointing to the induction of genomic instability as a critical event in viral oncogenesis. [ABSTRACT FROM AUTHOR]

Although frequently expressed in Epstein–Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)α and IFNγ, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNγ-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting ‘globally’ on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus-positive post-transplant lymphoproliferative disease (PTLD) is a potentially lethal complication of iatrogenic immunosupression after transplantation. Predicting the development of PTLD allowing early and effective intervention is therefore of importance. Polymorphisms within cytokine genes are implicated in susceptibility to, and progression of, disease however the published data are often conflicting. We undertook investigation of polymorphic alleles within cytokine genes in PTLD and non-PTLD transplant cohorts to determine risk factors for disease.Methods: SSP-PCR was used to analyse single nucleotide polymorphism within tumour necrosis factor (TNF)-alpha, interleukin- 1, -6, -10 and lymphotoxin-alpha genes. The TNF-alpha levels were measured by standard enzyme-linked immuno-absorbant assay.Results: We show an association between variant alleles within the TNF-alpha promoter (-1031C (P=0.005)); -863A (P=0.0001) and TNF receptor I promoter regions (-201T (P=0.02)); -1135C (P=0.03) with the development of PTLD. We also show an association with TNF-alpha promoter haplotypes with haplotype-3 significantly increased (P=0.0001) and haplotype-1 decreased (P=0.02) in PTLD patients compared to transplant controls. Furthermore, we show a significant increase (P=0.02) in the level of TNF-alpha in PTLD patient plasma (range 0-97.97 pg ml(-1)) compared to transplant controls (0-8.147 pg ml(-1)), with the highest levels found in individuals carrying the variant alleles.Conclusion: We suggest that genetic variation within TNF-alpha loci and the level of plasma cytokine could be used as a predictive risk factor for the development of PTLD. [ABSTRACT FROM AUTHOR]

p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(-) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(-) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(-) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21(WAF1) which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21(WAF1) restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21(WAF1)-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients. [ABSTRACT FROM AUTHOR]

Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-gamma, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-beta (beta isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target. [ABSTRACT FROM AUTHOR]

Background Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive lymphoreticular proliferation, which usually involves the lungs, but may also involve the central nervous system (CNS). Unique involvement of the CNS has been reported rarely. We report our experience with LYG confined to the brain and review the pertinent literature. Patients and Methods From January 1995 to September 2007, we identified patients with isolated brain LYG through a search of the histopathology database of the Catholic University of Rome; medical and radiological data were analyzed. Immunophenotype, in situ hybridization analysis of EBV-encoded small RNAs (EBER ISH) and immunoglobulin rearrangement studies were performed on the pathological specimens. Results Four patients with brain-LYG (male/female 1:1, mean age 44 years) underwent surgery in the study period. Subsequent therapy was tailored according to LYG grading. At the latest follow-up (range from 18 to 221 months), patient conditions had improved in all cases. EBER ISH was negative in all cases. Study of the IgH chain gene documented a monoclonal pattern in two cases. Conclusions CNS-LYG is a rare disease that should be considered in the differential diagnosis of both diffuse and space-occupying cerebral lesions. Primary cerebral LYG seems not to be associated with EBV and appears to have a better prognosis than systemic LYG with CNS localization, which is frequently EBV positive. [ABSTRACT FROM AUTHOR]

Lymphomas are a heterogeneous group of immune-cell malignancies. Immunology-related conditions are among the few factors for which consistent evidence exists relating them to lymphoma risk. We used the data from the European case–control study Epilymph on 2,362 lymphoma cases and 2,458 controls to investigate associations between a medical history of infectious and non-infectious diseases with overall and subentity-specific lymphoma risk. As key results, we observed an increased odds ratio (OR) for self-reported infections with hepatitis B virus (HBV, OR = 1.91, 95% CL = 1.24–2.94) and a null result for rheumatoid arthritis. Additionally, we found an increased OR for infectious mononucleosis (OR = 1.68, 95% CL = 1.14–2.48), an inverse association to frequency of sickness in childhood (OR = 0.68, 95% CL = 0.55–0.84), and—as casual finding—an increased OR with acetaminophen intake (OR = 2.29, 95% CL = 1.49–3.51). Our results are consistent with the current knowledge about the association with mononucleosis as indicator of Epstein–Barr-virus infection, suggest serological study of the association to HBV infection and do not support the view of a positive association between rheumatoid arthritis and lymphoma risk. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) with onset in childhood offers a unique opportunity to study the infectious background of this disease but the immune reactions against infectious agents in such children have only recently been investigated. These and other epidemiological studies strongly implicate involvement of one or more infectious agents in the aetiology of MS, with Epstein-Barr virus (EBV) being the prime candidate. Rather than being the actual cause of MS, it is more probable that these agents are involved in the development of immunoregulatory pathways. These pathways, if disturbed by hygiene-related factors including an altered sequence of infections, may generate and maintain a deficit within the immunological network that facilitates, to particular early events in the development of MS, preceding the onset of MS disease by years or a decade. A framework that can serve as a guide for further epidemiological, immunologic and molecular biologic investigations is formulated. This approach may shed light on the complex natural history of MS and may lead to rational preventive and therapeutic strategies. It is possible that, in the future, MS could be prevented by vaccination against EBV in early childhood; the framework is of relevance to the design of an appropriate type of vaccine. [ABSTRACT FROM AUTHOR]

Hodgkin's lymphoma was first described in 1832. The aetiology of this lymphoma, however, remained enigmatic for a long time. Only within the past 10 years has the B-cell nature of the pathognomonic Hodgkin and Reed-Sternberg (HRS) cells been revealed, along with several recurrent genetic lesions. The pathogenetic role for Epstein-Barr virus infection has also been substantiated. HRS cells in classical Hodgkin's lymphoma have several characteristics that are unusual for lymphoid tumour cells, and the Hodgkin's lymphoma microenvironment is dominated by an extensive mixed, potentially inflammatory cellular infiltrate. Understanding the contribution of all of these changes to the pathogenesis of this disease is essential for the development of novel therapies. [ABSTRACT FROM AUTHOR]

Splenic infarction is a common cause of left upper quadrant pain and must be suspected in patients with hematologic or thromboembolic conditions and signs of localized or systemic inflammation. Although several mechanisms have been proposed for splenic infarction in patients with various hematologic disorders, hereditary spherocytosis (HS) is usually not associated with an increased risk for thromboembolic events. We report a 13-year-old male with HS who was referred to our hospital with a 4-day history of fever and left upper quadrant pain. Ultrasound scans and magnetic resonance imaging showed lesions suggestive of splenic infarction. Initially, antibiotic treatment was started because secondary infection was suspected. However, 1 week after admission the patient developed typical clinical signs of acute infectious mononucleosis. Further laboratory work up confirmed the diagnosis of acute Epstein-Barr virus infection and additionally revealed protein C deficiency. This association has not been reported previously and may have contributed to the development of splenic infarction. Since infectious mononucleosis is a common cause for clinical consultations in adolescence, physicians caring for children with hematologic disorders should be particularly aware of those possible complications. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) associated central nervous system (CNS) infection is a rare disease. We report an atypical manifestation of EBV encephalitis initially presenting with a tumor-like lesion of the optic tract in an immunocompromised patient 8 years after a combined kidney and pancreas transplantation had been performed. Polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) and antibody testing confirmed the diagnosis of EBV encephalitis, most likely as a consequence of a reactivated persistent EBV infection. After cessation of the immunosuppressive therapy and induction of treatment with ganciclovir, clinical and magnetic resonance imaging (MRI) findings rapidly improved. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor–associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor–associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells. [ABSTRACT FROM AUTHOR]

Latent membrane protein 1 (LMP1) of the Epstein-Barr virus is a constitutively activated analog of the tumor necrosis factor receptor TNF-R1. LMP1 serves as a viral oncogen able to transform human B-ymphocytes and rodent fibroblasts via activation of numerous cellular signal cascades. Two specific motifs within LMP1 are responsible for interaction of this viral protein with the receptor protein β-TrCP/HOS SCF of the ubiquitin ligase E3 complex, playing an important role in degradation of numerous cellular proteins including NF-κB inhibitor IκBα. In this study, we demonstrate for the first time the importance of point mutations affecting HOS-recognizing motifs of LMP1 for activation of NF-κB, AP1, and PI3K/Akt signaling pathways. It has also been shown that rat fibroblast cell lines (Rat-1) expressing different HOS mutants of LMP1 produce different amounts of reactive nitrogen species. Our data confirm the hypothesis that point mutations in the C-terminal region of the LMP1 cytoplasmic domain can influence the transforming potential of the Epstein-Barr virus. [ABSTRACT FROM AUTHOR]

Nasal NK/T-cell lymphoma (NKTCL) is an uncommon disease, but usually shows a highly aggressive clinical course. The disease is much more frequent in Asian and Latin American countries than in Western countries, and is universally associated with Epstein-Barr virus (EBV) infection. Analyses of gene mutations, especially p53 and c-KIT, revealed the different frequencies by district. Epidemiological studies revealed the changes of the disease frequency in Korea during the period from 1977-1989 to 1990-1996. Case-control study showed that the exposure to pesticides and chemical solvents could be causative of NKTCL. Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism. [ABSTRACT FROM AUTHOR]

The Epstein Barr virus (EBV) is causally associated to several tumors of epithelial and lymphoid origin. The cancerogenic role in other than B cells has not been proven. This virus has been considered as a target in the effective diagnosis of EBV-associated tumors. For this purpose, molecular biology methods to measure EBV DNA load in the circulation of patients suffering from EBV-related cancers have been recently developed. In this review, we discuss the role of EBV DNA determination, the technical limitations of molecular assays measuring viral load and their impact on the clinical management of patients with EBV-associated tumors arising in the immunocompetent host. Several studies have recently clarified the biological and clinical characteristics of herpesvirus-associated tumors. However, some additional issues must be clarified before introducing viral load determinations into clinical practice. Firstly, since the various EBV-related tumors have different etiopathological and clinical characteristics, the most appropriate biological samples and analytical cut off values must be clearly defined in each group of patients. Secondly, a standardization of the assay, including the definition of the gene segment to be amplified, the use of an international reference for the standard curve and disease-related cut-off values, is strongly required. Thirdly, the interpretation of laboratory data may benefit from an improved design of the studies and obtaining an aggregrate of patients from different institutions, pooling these together, in order to have a sample size that is adequate to reinforce the statistical power of the studies. [ABSTRACT FROM AUTHOR]

The introduction of single-agent rituximab has markedly changed the approach to therapy of patients with post-transplantation lymphoproliferative disorder (PTLD), but response to treatment varies substantially between patients. In the current report, we analyze long-term efficacy of single-agent rituximab in 60 patients and present factors predictive of progression-free and overall survival. Twelve months after completing first-line treatment, 34 of 60 patients (57%) had progressive disease, resulting in a median progression-free survival of 6.0 months at a median follow-up of 16.3 months. Using multivariate Cox regression analysis, the following factors were identified as significantly predictive of overall survival: age at diagnosis, performance status, lactate dehydrogenase (LDH), and time from transplantation to PTLD. Stage of disease and Epstein–Barr virus association of PTLD did not influence overall survival. LDH and time from transplantation to PTLD were also predictive of progression-free survival. The international prognostic index was shown to be of limited predictive value in these patients, but a PTLD-specific prognostic index separated low-, intermediate-, and high-risk patients with high significance: 2-year overall survival rates after first-line treatment with single-agent rituximab were 88, 50, and 0%, respectively. Thus, prognostic indices can be useful tools for prediction of treatment outcome and for the development of risk-adapted treatment strategies in patients with PTLD and may also provide the basis for interstudy comparisons. [ABSTRACT FROM AUTHOR]

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. [ABSTRACT FROM AUTHOR]

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13–19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were 16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index 0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy±radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome.British Journal of Cancer (2007) 97, 29–36. doi:10.1038/sj.bjc.6603809 www.bjcancer.com Published online 29 May 2007 [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumors where it plays an essential role in the maintenance, replication and transcription of the EBV genome. Transcriptional profiling of EBNA1-expressing carcinoma cells demonstrated that EBNA1 also influences the expression of a range of cellular genes including those involved in translation, transcription and cell signaling. Of particular interest was the ability of EBNA1 to enhance expression of STAT1 and sensitize cells to interferon-induced STAT1 activation with resultant enhancement of major histocompatibility complex expression. A negative effect of EBNA1 on the expression of TGFβ1-responsive βig-h3 and PAI-1 genes was confirmed at the protein level in EBV-infected carcinoma cells. This effect resulted from the ability of EBNA1 to repress TGFβ1-induced transcription via a reduction in the interaction of SMAD2 with SMAD4. More detailed analysis revealed that EBNA1 induces a lower steady-state level of SMAD2 protein as a consequence of increased protein turnover. These data show that EBNA1 can influence cellular gene transcription resulting in effects that may contribute to the development of EBV-associated tumors.Oncogene (2007) 26, 4135–4147; doi:10.1038/sj.onc.1210496; published online 7 May 2007 [ABSTRACT FROM AUTHOR]

It was proposed that Epstein–Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC); however, the molecular mechanisms involved in the effect of EBV on NPC host genes have not yet been well defined. For this study, two sets of microarray experiments, NPC (EBV-free) vs normal epithelial cells and EBV+ vs EBV− NPC arrays, were analyzed and the datasets were cross-compared to identify any correlation between gene clusters involved in EBV targeting and the NPC host gene expression profiles. Statistical analysis revealed that EBV seems to have a preference for targeting more genes from the differentially expressed group in NPC cells than those from the ubiquitously expressed group. Furthermore, this trend is also reflected in log ratios where the EBV target genes of the differentially expressed group origin showed greater log ratios than genes with an origin from the ubiquitously expressed NPC group. Taken together, the genome-wide comparative scanning of EBV and NPC transcriptomes has successfully demonstrated that EBV infection has an intensifying effect on the signals involved in NPC gene expression both in breadth (the majority of the genes) and in depth (greater log ratios). [ABSTRACT FROM AUTHOR]

Biosensor technologies based on optical readout are widely used in protein–protein interaction studies. Here we describe a fast and simple approach to the creation of oriented interfacial architectures for surface plasmon resonance (SPR) transducers, based on conventional biochemical procedures and custom reagents. The proposed protocol permits the oriented affinity-capture of GST fusion proteins by a specific antibody which is bound to protein A, which in turn has been immobilized on the transducer surface (after the surface has been modified by guanidine thiocyanate). The applicability of the method was demonstrated by studying the interaction between retinoblastoma tumor suppressor protein (pRb) and MRS18-2 proteins. The formation of the pRb–MRS18-2 protein complex was examined and the pRb binding site (A-box–spacer–B-box) was mapped. We have also shown that MRS18-2, which was detected as the Epstein–Barr virus-encoded EBNA-6 binding partner using the yeast two-hybrid system, binds to pRb in GST pull-down assays. [ABSTRACT FROM AUTHOR]

To detect the infection frequencies of different genotypes of Epstein-Barr virus (EBV) in subgingival samples from chronic periodontitis (CP) patients, and to discuss the correlation between infection with EBV and clinical parameters. Nested-PCR assay was used to detect EBV-1 and EBV-2 in subgingival samples from 65 CP patients, 65 gingivitis patients and 24 periodontally healthy individuals. The amplicons were further identified by restriction fragment length polymorphism analysis (RFLP) with endonucleases Afa I and Stu I. Clinical parameters mainly included bleeding on probing (BOP), probing depth (PD), attachment loss (AL) in six sites of the dentition. In CP patients, gingivitis and periodontally healthy individuals, the infection frequencies were 47.7%, 24.6% and 16.7% for EBV-1, and 15.4%, 7.7% and 0% for EBV-2, respectively. In 2 out of the 65 CP patients co-infection of EBV-1 and EBV-2 was found. The positive rate of EBV-1 in chronic periodontitis patients was higher than that in gingivitis patients ( P=0.01) and periodontally healthy individuals ( P=0.01). But no significant difference was shown in EBV-1 frequency between gingivitis patients and healthy individuals ( P>0.05) or in EBV-2 frequency among the three groups ( P>0.05). In CP patients, higher mean BOP value was found in EBV-1 or EBV-2 positive patients than that in EBV negative ones ( P<0.01), but with no statistical difference in the mean PD or AL value between EBV positive and negative patients ( P>0.05). After initial periodontal treatment, 12 out of the 21 EBV-1 positive CP patients did not show detectable EBV-1 in subgingival samples. nPCR plus RFLP analysis is a sensitive, specific and stable method to detect EBV-1 and EBV-2 in subgingival samples. Subgingival infection with EBV-1 is closely associated with chronic periodontitis. Infection of EBV in subgingival samples was correlated with BOP. [ABSTRACT FROM AUTHOR]

A baculoviral mammalian-cell vector was constructed to express Rta, a protein of Epstein-Barr virus (EBV) responsible for the transition from latent infection to lytic replication. EBV lytic replication and cell-growth inhibition was observed in infected D98/HR1 cells. The baculovirus caused little cytotoxicity in the non-targeted HeLa cells, compared to an adenovirus vector. It is concluded that recombinant baculovirus might have the potential as a vector for the therapy of EBV-related cancer. [ABSTRACT FROM AUTHOR]

Immunocompromised individuals are at high risk for life-threatening diseases, especially those caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus. Conventional therapeutics are primarily active only against CMV, and resistance is frequent. Adoptive transfer of polyclonal cytotoxic T lymphocytes (CTLs) specific for CMV or EBV seems promising, but it is unclear whether this strategy can be extended to adenovirus, which comprises many serotypes. In addition, the preparation of a specific CTL line for each virus in every eligible individual would be impractical. Here we describe genetic modification of antigen-presenting cell lines to facilitate the production of CD4+ and CD8+ T lymphocytes specific for CMV, EBV and several serotypes of adenovirus from a single cell culture. When administered to immunocompromised individuals, the single T lymphocyte line expands into multiple discrete virus-specific populations that supply clinically measurable antiviral activity. Monoculture-derived multispecific CTL infusion could provide a safe and efficient means to restore virus-specific immunity in the immunocompromised host. [ABSTRACT FROM AUTHOR]

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein–Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse. [ABSTRACT FROM AUTHOR]

The efficient gene transfer of immunostimulatory cytokines into autologous tumor cells or the transfer of tumor-associated antigens into professional antigen-presenting cells is a prerequisite for many immunotherapeutic approaches. In particular with B cells, the efficiency of gene uptake is one of the limiting factors in cell-based vaccine strategies, since normal and malignant human B cells are commonly refractory to transducing gene vectors. Due to its natural tropism for human B cells, Epstein–Barr virus (EBV), a human herpes virus, might be an option, which we wanted to explore. EBV efficiently infects human B cells and establishes a latent infection, while the viral genome is maintained extrachromosomally. Although these characteristics are attractive, EBV is an oncogenic virus. Here, we present a novel EBV-derived vector, which lacks three EBV genes including two viral oncogenes and an essential lytic gene, and encodes granulocyte-macrophage colony-stimulating factor (GM-CSF) as a cytokine of therapeutic interest. We could show that EBV vectors efficiently transduce different B-cell lines, primary resting B cells, and tumor cells of B-cell lineage. Vector-derived GM-CSF was expressed in sufficient amounts to support the maturation of dendritic cells and their presentation of model antigens to cognate T-cell clones in autologous settings and an allogeneic, HLA-matched assay. We conclude that the EBV vector system might offer an option for ex vivo manipulation of B cells and gene therapy of B-cell lymphomas.Gene Therapy (2006) 13, 150–162. doi:10.1038/sj.gt.3302602; published online 1 September 2005 [ABSTRACT FROM AUTHOR]

Unlabelled: We analysed data of 96 infants (under 1 year of age) with haemophagocytic lymphohistiocytosis (HLH) from the registry of an HLH study conducted during 1986-2002 in Japan. The cases were classified into five groups. The diagnosis of familial HLH (FHL) as group 1 (n = 27) was made with positive family history and/or recent molecular test for perforin and Munc13-4 mutations. Neonatal enterovirus- or herpes simplex virus-associated HLH as group 2a (n = 7), Epstein-Barr virus-associated HLH (n = 12) as group 2b, adenovirus- or cytomegalovirus-associated HLH as group 3 (n = 9) were mostly diagnosed by viral isolation or by the detection of viral genome. Juvenile rheumatoid arthritis-associated macrophage activation syndrome was classified as group 4 (n = 4) and the remaining without known triggers as group 5 (n = 37). The peak onset age was 1-2 months for group 1, 1-2 weeks for group 2a, 12 months for group 2b, none for group 3, 9 months for group 4 and 2 months for group 5. Future novel diagnostic measures are required to define the precise nature of HLH in group 5.Conclusion: These data may provide useful information for neonatologists/ paediatricians in the differential diagnosis of haemophagocytic lymphohistiocytosis in early infancy. [ABSTRACT FROM AUTHOR]

Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein-Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.Oncogene (2005) 24, 1711-1717. doi:10.1038/sj.onc.1208367 Published online 17 January 2005 [ABSTRACT FROM AUTHOR]

Endemic Burkitt's lymphoma is the most common childhood cancer in equatorial Africa. Two ubiquitous human pathogens are thought to be responsible for the aetiology of this disease: Epstein–Barr virus and Plasmodium falciparum malaria. New data suggest how these two pathogens might interact to result in disease and provide insights into the emerging concepts of polymicrobial disease pathogenesis. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) was discovered 40 years ago from examining electron micrographs of cells cultured from Burkitt's lymphoma, a childhood tumour that is common in sub-Saharan Africa, where its unusual geographical distribution-which matches that of holoendemic malaria-indicated a viral aetiology. However, far from showing a restricted distribution, EBV-a?-herpesvirus-was found to be widespread in all human populations and to persist in the vast majority of individuals as a lifelong, asymptomatic infection of the B-lymphocyte pool. Despite such ubiquity, the link between EBV and 'endemic' Burkitt's lymphoma proved consistent and became the first of an unexpectedly wide range of associations discovered between this virus and tumours. [ABSTRACT FROM AUTHOR]

Background: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after organ transplantation associated with a high mortality, and is often caused by a primary or reactivated Epstein-Barr virus (EBV) infection. The incidence of PTLD ranges from 1% to 10%, depending on the type of organ transplanted and the immunosuppressive regimens used.Methods: In this retrospective study from a single center, 12 (2.4%) of 500 consecutive recipients of liver grafts developed lymphoma. Patient data were obtained by chart review. All diagnostic biopsies were reviewed by two hematopathologists.Results: The median time between transplantation and the diagnosis of lymphoma was 19.5 (1.5-148) mo. Nine of the patients had been treated with OKT-3 and/or ATG after the transplantation. Two patients had a pretransplant diagnosis of lymphoma. The PTLD was of high grade in all patients, and was associated with EBV in 6 of 9 examined cases. No relation with human herpesvirus-8 could be detected. In all patients, immunosuppression was reduced at the time of lymphoma diagnosis. Chemotherapy was used in all patients, mostly upfront but in one patient after lymphoma progression after reduction of immunosuppression. Nine patients also got antiviral therapy. Immunotherapy with the monoclonal antibody rituximab was used in one patient. Half of the patients are alive, in complete continuous remission, more than 4 yr after the lymphoma diagnosis. Two patients died of neutropenic sepsis, three of persistent lymphoma, and one of recurrent cirrhosis while in complete remission.Conclusions: PTLD is a significant complication in liver-transplanted patients. Intensive chemotherapy can induce long-term remissions in a substantial number of patients. The role for monoclonal antibodies in this setting should be investigated further. [ABSTRACT FROM AUTHOR]

We report on identical twin brothers, one of whom presented at 14 months of age with fever and clinical, laboratory and histological evidence of Epstein-Barr virus-associated haemophagocytic syndrome (EBV-AHS) and 4 months later with typical signs and symptoms of Langerhans’ cell histiocytosis (LCH). The other twin, without previous symptoms, also displayed at that time LCH associated with signs of recent EBV infection, but without symptoms of haemophagocytic syndrome. No mutation in the SH2D1A gene, as observed in X-linked lymphoproliferative disease, or in the perforin gene as observed in some cases of hereditary haemophagocytic syndrome, was found. Conclusion:the occurrence of haemophagocytic syndrome and Langerhans’ cell histiocytosis, although genetically based, can be triggered by environmental agents and viruses, in particular Epstein-Barr virus. [ABSTRACT FROM AUTHOR]

Herpesviruses are present in most species throughout the animal kingdom and are classified into three subfamilies, α, β and γ, on the basis of their biological properties and genome sequences. A striking feature that is shared by many of the γ-herpesviruses is their ability to induce neoplastic disease in the host. This review focuses on three γ-herpesviruses: Epstein–Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) and herpesvirus saimiri (HVS), and discusses the diverse array of EBV, KSHV and HVS viral genes that are involved in transformation, cell signalling, episomal maintenance and cell proliferation. [ABSTRACT FROM AUTHOR]

Purpose. Allogeneic bone marrow transplantation (AlloBMT) can be curative for patients with leukemia. The most important anti-leukemic effect may be mediated by the T-cells contained within the graft; however, the allogeneic T-cells may also give rise to graft-vs-host disease (GVHD). One way to control GVHD might be to transduce the donor T-cells with a drug-inducible suicide gene. If a retrovirus vector is to be used for this transduction, activation of the T-cells is required for integration of the transgene to occur. The activation protocol should ensure expansion of a broad repertoire of donor T-cells. Notably, T-cells specific for herpes virus family antigens are important for adoptive immunoprotection. Methods. To define optimal activation conditions for retrovirus-mediated suicide gene transduction of donor T-cells, we examined the repertoire of CD8+ T-cells in general, and Epstein-Barr virus (EBV) specific T-cells in particular, following two different activation and expansion procedures. Results. We found that repeated CD3/CD28 stimulation resulted in a high level of activation-induced T-cell death, affecting in vivo expanded clones, some of which were specific for EBV, in particular. In contrast, initial CD3/CD28 activation followed by proliferation in interleukin-2 lead to expansion of EBV-specific clones over and above the expansion observed for CD8+ T-cells in general. Conclusion. These results should impact on protocols for ex vivo activation of T-cells prior to suicide gene transduction. [ABSTRACT FROM AUTHOR]

The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the ‘canonical’ NF-?B pathway that involves the phosphorylation and degradation of I?Ba downstream of the I?B kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-?B2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-?B subunits. LMP1-induced NF-?B transactivation is reduced in nf-kb2-/- mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-?B transcriptional effects. This pathway is likely to operate in vivo, as the expression of LMP1 in primary EBV-positive Hodgkin's lymphoma and nasopharyngeal carcinoma biopsies correlates with the nuclear accumulation of p52. Interestingly, while the ability of LMP1 to activate the canonical NF-?B pathway is impaired in cells lacking IKK?/NEMO, the regulatory subunit of the IKK complex, p100 processing remains unaffected. As a result, nuclear translocation of p52, but not p65, occurs in the absence of IKK?. These data point to the existence of a novel signalling pathway that regulates NF-?B in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.Oncogene (2003) 22, 7557-7569. doi:10.1038/sj.onc.1207120 [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is an extremely successful virus, infecting more than 90% of the human population worldwide. After primary infection, the virus persists for the life of the host, usually as a harmless passenger residing in B cells. However, EBV can transform B cells, which can result in the development of malignant lymphomas. Intriguingly, the three main types of EBV-associated B-cell lymphoma - that is, Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphomas - seem to derive from germinal-centre B cells or atypical survivors of the germinal-centre reaction in most, if not all, cases, indicating that EBV-infected germinal-centre B cells are at particular risk for malignant transformation. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease develops in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMC) from EBV[SUP+] individuals (SCID/hu mice). In this study, we investigated the contribution of EBV reactivation and de novo infection of B lymphocytes to tumor outgrowth in SCID/hu mice. Evaluation of BZLF-1, an early EBV activation transcript, in cells recovered from the mouse peritoneal cavity within 16 days following PBMC transfer did not reveal EBV reactivation, while BZLF-1 expression was only detected in tumor masses or in vitro established lymphoblastoid cell lines. To confirm these data by a different strategy, we coinjected PBMC from seropositive donors with purified B cells from seronegative donors of different sex. Fluorescence in situ hydridization analysis of the resulting tumor masses disclosed that the overwhelming majority of lymphoma cells originated from the seropositive donor, implying that no substantial in vivo production and transmission of virus had occurred. Further, treatment of SCID/hu mice with ganciclovir did not prevent lymphoma development. Our results suggest that in the SCID/ hu mouse, early EBV replication and secondary infection of bystander B cells does not occur, and that the direct outgrowth of the transformed B lymphocytes present within the PBMC inoculum is the predominant mechanism, which leads to lymphoma generation in this experimental model. [ABSTRACT FROM AUTHOR]

The presence and transcriptional expression of Epstein-Barr virus (EBV)-encoded genes, oestrogen receptor (ER) status and degree of lymphocyte infiltration were evaluated in 15 mastectomy-removed breast cancer samples, mostly of ductal origin. With regard to these parameters, the tumours were heterogeneous. Viral genes, including EBNA1 - a universal EBV marker - and others, selected in part on the basis of expression in other EBV-associated carcinomas and/or presence in an epithelial cell immortalising subfragment p31 of viral DNA, were detected in up to 40% of the breast malignancies. The small viral RNAs, EBERs, were not observed. In culture, p31 EBV DNA, alone among EBV fragments, stimulated the growth of human breast-milk epithelial cells. There was no correlation between viral and ER expression and tumours were heterogeneous with regard to their invasive lymphocytes: of three studied in detail, one contained none, another had (mainly) T-lymphocyte aggregates on the tumour periphery, and a third (BC 12) was infiltrated with both T- and B-lymphocytes. BC 12 differed in several aspects from other malignancies in expressing a transcriptional activator (BZLF1) associated with overcoming virus latency, and failing to express a viral oncogene, BARF1. Arguments are given for EBV as a protagonist cocarcinogen in some breast malignancies. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) is involved in the carcinogenesis of several human cancers such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). Given the consistent role of EBV in transformation and maintenance of malignant phenotype, antiviral strategies provide an attractive approach to target EBV-expressing cells. In that aim, we have tested the Cidofovir, which is an acyclic nucleoside phosphonate analog known to exert an antiproliferative activity in some human virus-related tumors. Here, we show that Cidofovir induces a downregulation of the EBV oncoprotein LMP1 associated with a decrease of the antiapoptotic Bcl-2 and an increase of the proapoptotic Bax protein in Raji (BL) and C15 (NPC) cells. Using BL cell line BL2 B95-8 (BL2 infected with the B95.8 strain of EBV), we addressed the relation between EBV genome expression and modulation of viral oncoproteins by Cidofovir and/or ionizing radiation (IR). Cidofovir was able to significantly reduce LMP1 and EBNA2 mRNA and protein expression. This effect was associated with inhibition of proliferation, stimulation of apoptosis, and decrease of Bcl-2 expression in BL2 B95.8 cells. In addition, Cidofovir enhanced the radiation-induced apoptosis and the radiosensitivity through the proteolytic cleavage of death effectors caspase-9 and -3, which was specifically induced by combined treatment in EBV-positive cells compared to their negative counterparts. Furthermore, the combined treatment in nude mice led to a complete tumor remission without increasing toxicity in two human EBV-related cancer xenografts (Raji and C15). These results provide the basis for a novel anticancer strategy to enhance the therapeutic ratio of IR in EBV-related cancers.Oncogene (2003) 22, 2260-2271. doi:10.1038/sj.onc.1206402 [ABSTRACT FROM AUTHOR]

Unlabelled: We report the case of a 12-year-old boy, who developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) 7 years after renal transplantation. He responded well to the reduced immunosuppressive therapy and treatment with ganciclovir. Two years later he developed severe pneumonia and hypogammaglobulinaemia related to EBV infection exacerbation. An X-ray film revealed persistent pneumonia in the right lung. Lung biopsy showed a large, diffuse EBV-associated B-cell lymphoma. This constellation suggested re-occurrence of the primary PTLD.Conclusion: We present a case of recurring Epstein-Barr virus-associated post-transplant lymphoproliferative disease with a remarkably late onset in addition to hypogammaglobulinaemia. [ABSTRACT FROM AUTHOR]

Presents a study which examined the resistance of fludarabine-induced apoptosis in Epstein-Barr virus infected B cells. Methodology; Results of the study; Conclusion.

Presents a study that examined hit and run immortalization of primate epithelial cells by a specific fragment of Epstein-Barr virus (EVB) DNA. Functions of EBV; Information on human papilloma viruses; Cellular transformation by human DNA viruses.