2,500 research outputs found
Lymphoid hyperplasia and lymphoma in transgenic mice expressing the small non-coding RNA, EBER1 of Epstein-Barr virus
No full textBackground. Non-coding RNAs have critical functions in diverse biological processes, particularly in gene regulation. Viruses, like their host cells, employ such functional RNAs and the human cancer associated Epstein-Barr virus (EBV) is no exception. Nearly all EBV associated tumours express the EBV small, non-coding RNAs (EBERs) 1 and 2, however their role in viral pathogenesis remains largely obscure.Methodology/Principal FindingsTo investigate the action of EBER1 in vivo, we produced ten transgenic mouse lines expressing EBER1 in the lymphoid compartment using the mouse immunoglobulin heavy chain intronic enhancer E++. Mice of several of these E++EBER1 lines developed lymphoid hyperplasia which in some cases proceeded to B cell malignancy. The hallmark of the transgenic phenotype is enlargement of the spleen and mesenteric lymph nodes and in some cases enlargement of the thymus, liver and peripheral lymph nodes. The tumours were found to be of B cell origin and showed clonal IgH rearrangements. In order to explore if EBER1 would cooperate with c-Myc (deregulated in Burkitt's lymphoma) to accelerate lymphomagenesis, a cross-breeding study was undertaken with E++EBER1 and E++Myc mice. While no significant reduction in latency to lymphoma onset was observed in bi-transgenic mice, c-Myc induction was detected in some E++EBER1 single transgenic tumours, indicative of a functional cooperation. Conclusions/SignificanceT his study is the first to describe the in vivo expression of a polymerase III, non-coding viral gene and demonstrate its oncogenic potential. The data suggest that EBER1 plays an oncogenic role in EBV associated malignant disease
Immunodominance of lytic cycle antigens in Epstein-Barr virus-specific CD4+ T cell preparations for therapy.
No full textEpstein-Barr virus (EBV) is associated with a number of human malignancies. EBV-positive post-transplant lymphoproliferative disease in solid organ and hematopoietic stem cell transplant recipients has been successfully treated by the adoptive transfer of polyclonal EBV-specific T cell lines containing CD4+ and CD8+ T cell components. Although patients receiving T cell preparations with a higher CD4+ T cell proportion show better clinical responses, the specificity of the infused CD4+ component has remained completely unknown.
We generated LCL-stimulated T cell lines from 21 donors according to clinical protocols, and analyzed the antigen specificity of the CD4+ component in EBV-specific T cell preparations using a genetically engineered EBV mutant that is unable to enter the lytic cycle, and recombinantly expressed and purified EBV proteins. Surprisingly, CD4+ T cell lines from acutely and persistently EBV-infected donors consistently responded against EBV lytic cycle antigens and autoantigens, but barely against latent cycle antigens of EBV hitherto considered principal immunotherapeutic targets. Lytic cycle antigens were predominantly derived from structural proteins of the virus presented on MHC II via receptor-mediated uptake of released viral particles, but also included abundant infected cell proteins whose presentation involved intercellular protein transfer. Importantly, presentation of virion antigens was severely impaired by acyclovir treatment of stimulator cells, as currently performed in most clinical protocols.
These results indicate that structural antigens of EBV are the immunodominant targets of CD4+ T cells in LCL-stimulated T cell preparations. These findings add to our understanding of the immune response against this human tumor-virus and have important implications for the improvement of immunotherapeutic strategies against EBV
On unitary convex decompositions of vectors in a -algebra
No full textsummary:By exploiting his recent results, the author further investigates the extent to which variation in the coefficients of a unitary convex decomposition of a vector in a unital -algebra permits the vector decomposable as convex combination of fewer unitaries; certain -algebra results due to M. Rørdam have been extended to the general setting of -algebras
Validation of the Contemporary Epstein Criteria for Insignificant Prostate Cancer in European Men
No full textObjectives: The Epstein criteria represent the most widely used scheme for prediction of clinically insignificant prostate cancer (PCa). However, they were never validated in European men. We assessed the rate of unfavorable prostate cancer (Gleason 7-10 or non-organ-confined disease) in a cohort of 366 men who fulfilled the Epstein clinically insignificant PCa criteria. Methods: Between 1996 and 2006, 2580 men underwent radical prostatectomy at a single academic European institution. Of those, 366 fulfilled the contemporary Epstein clinically insignificant PCa criteria. Analyses targeted the rate of pathologically unfavorable prostate cancer, defined as either Gleason sum 7-10 or non-organ-confined disease, or a combination of these characteristics in patients with clinically insignificant PCa. Results: Gleason 7-10 prostate cancer at radical prostatectomy was found in 88 patients (24%) with clinically insignificant PCa. In addition, 30 (34.1%) of the 88 patients harboured non-organ-confined disease. Consequently, the contemporary Epstein criteria for clinically insignificant PCa were inaccurate in 24% of patients. Conclusions: The Epstein clinical insignificant PCa criteria may underestimate the true nature of prostate cancer in as many as 24% of European patients. Therefore, caution is advised when treatment decisions are based solely on these criteria. (C) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved
A new mucoadhesive dosage form for the management of oral lichen planus: Formulation study and clinical study
No full textThe work aimed at studying a new mucoadhesive prolonged release tablet containing 24μg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n=16) who received three applications-a-day over 4weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123μg/application) extemporary mixed with OrabaseTM (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n=2) and taste alteration (n=4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24μg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment. © 2010 Elsevier B.V.The work aimed at studying a new mucoadhesive prolonged release tablet containing 24μg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n=16) who received three applications-a-day over 4weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123μg/application) extemporary mixed with OrabaseTM (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n=2) and taste alteration (n=4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24μg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment. © 2010 Elsevier B.V
Cervical cancer with Human Papilloma Virus and Epstein Barr Virus positive
No full textThe Early-7 (E7) protein of HPV binds to the underphosphorelated form of the tumor suppressor
protein – pRb and displaces the E2F transcription factor that is normally bound by pRb. The latent
membrane protein-1 (LMP-1) of EBV prevents apoptosis of B cells by up regulating the expression
of bcl-2, and it activates growth promoting pathway that are normally triggered by T cell – derivate
signal. The aims of this study to know that in cervical cancer stay HPV and EBV.
DNA was isolated from nineteen sample cervical cancer tissues frozen section. Diagnose related
with HPV and EBV was made by Polymerase Chains Reaction (PCR).
The result of this experiment showed that from 19 samples diagnosed as cervical cancer, 17
samples are positive HPV and 13 samples had HPV and EBV positive. The conclusion of this
experiment is 89% of cervical cancers are infected with HPV and 68% also infected with HPV and
EBV
Erratum: Half-supersymmetric solutions in five-dimensional supergravity (Journal of High Energy Physics (2007) 12 (025))
No full text[No abstract available]Gutowski JB, 2007, J HIGH ENERGY PHYS11
BARF1 AS A NEW THERAPEUTIC TARGET FOR EBV-ASSOCIATED MALIGNANCIES.
No full textWhile Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs) have been used successfully for the prophylaxis and treatment of the highly immunogenic post-transplant lymphoproliferative disorders, the clinical experience for other EBV-associated malignancies, such as Hodgkin's lymphoma and undifferentiated nasopharyngeal carcinoma (NPC), is limited and the results obtained so far indicate that EBV-CTLs are less effective in these settings. Decreased CTL efficacy most likely reflects immune evasion strategies by tumor cells, including down-regulation of immunodominant EBV proteins and the weak immunogenicity of the viral proteins expressed. One of the possible approaches to overcome these limitations is the identification of additional immunogenic viral proteins expressed by tumor cells that may serve as tumor-associated antigens to be targeted by improved CTL induction and expansion protocols. We have recently demonstrated that NPC patients show strong spontaneous CD4+ and CD8+ T cell responses specific for the EBV-encoded oncogenic protein BARF1. We also showed that BARF1 provides immunogenic HLA-A*0201-restricted epitopes, suggesting that exploitation of the immunogenic features of this viral antigen may help improve the current immunotherapeutic strategies for EBV-associated malignancies. On these grounds, we characterized more extensively the immunogenic properties of BARF1 with the final goal to develop improved protocols of adoptive immunotherapy based on the use of EBV-CTLs enriched in BARF1-specific effectors. In particular, we identified and validated additional BARF1 CTL epitopes presented in the context of common HLA class I alleles. These results strictly correlate to those deriving from a high-resolution HLA genotyping of a large series of NPC, giving a precise estimate of the immunogenicity of BARF1 in relation to the HLA class I profile of Italian NPC patients. To fully exploit the immunologic properties of BARF1, we are also developing and characterizing BARF1-specific monoclonal antibodies that may be of both diagnostic and therapeutic usefulness in these clinical settings. In future perspective, the proposed research may provide a strong rationale for the clinical application of improved adoptive immunotherapy protocols for the treatment of EBV-associated malignancies, particularly the less immunogenic forms, such as NPC and, possibly, Hodgkin’s lymphoma
Signal transduction by the Epstein-Barr virus oncogene latent membrane protein 1 (LMP1).
No full textThe latent membrane protein 1 (LMP1) of Epstein-Barr virus is a viral oncogene with the potential to antagonize apoptosis and senescence as well as to promote cellular survival and proliferation. LMP1 acts like a constitutively active receptor recruiting signalling molecules typically employed by the cellular tumour necrosis factor-receptor (TNF-R) and Toll-like/interleukin-1-receptor (TIR) families. LMP1 activates the classical and alternative NF-jB pathways, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), the JAK/STAT and phosphatidylinositol 3-kinase (PI3K) pathways. In this article, interactions of LMP1 with host cell signal transduction pathways and their role in LMP1-induced cell transformation are reviewed
Utilising proteomic approaches to understand oncogenic human herpesviruses
No full textThe γ‑herpesviruses Epstein-Barr virus and Kaposi's sarcoma‑associated herpesvirus are successful pathogens, each infecting a large proportion of the human population. These viruses persist for the life of the host and may each contribute to a number of malignancies, for which there are currently no cures. Large‑scale proteomic-based approaches provide an excellent means of increasing the collective understanding of the proteomes of these complex viruses and elucidating their numerous interactions within the infected host cell. These large‑scale studies are important for the identification of the intricacies of viral infection and the development of novel therapeutics against these two important pathogens
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