München, Techn. Univ., Diss., 2002.

Regensburg, Univ., Diss., 2002.

Orientador: Deilson Elgui Oliveira / Resumo: Presente em aproximadamente 95% da população mundial o Vírus de Esptein-Barr (Epstein-Barr Virus - EBV) está relacionado com 1,5% dos casos de câncer no mundo com destaque para o carcinoma de nasofaringe (Nasopharyngeal Carcinoma – NPC) o qual segundo a Organização Mundial da Saúde, 90% dos carcinomas indiferenciados estão associados ao EBV. Expresso durante o ciclo de latência III e II a proteína latente de membrana 1 (Latent Membrane Protein 1, LMP1), um dos principais produtos oncogênicos do EBV mimetiza o receptor CD40 e mantém-se constitutivamente ativa na célula. Com papel importantíssimo no desenvolvimento do carcinoma de nasofaringe, LMP1 atua na imortalização e proliferação de linfócitos B por meio da deflagração de vias de sinalização intracelular como NFkB e PI3K/AKT. Atualmente são conhecidas sete variantes do gene BNLF1 que codifica LMP1 e apresentam diferenças nas sequências nucleotídicas e aminoacídicas, ambas consideradas oncogênicas por conservarem os domínios CTARs. Essas diferenças encontradas nas variantes de LMP1 podem estar relacionadas à agressividade dos tumores. Entre as variantes de LMP1 foram avaliadas no presente estudo as variantes B95.8 e M81, ambas associadas ao desenvolvimento de NPC. As propriedades transformantes dessas variantes de LMP1 foram analisadas frente ao programa biológico transição epitelial- mesenquimal (Epithelial-Mesenckymal Transition – EMT) que está diretamente relacionado com a progressão dos carcinomas. A avaliação das v... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

OLIVEIRA, Emanuele Silva de. Frequência do vírus Epstein-barr (ebv) em pacientes com câncer de mama do serviço de mastologia de um hospital do estado do Ceará. 2015. 84 f. Dissertação (Mestrado em Microbiologia Médica) – Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2015. / Submitted by denise santos (denise.santos@ufc.br) on 2015-10-26T13:25:54Z No. of bitstreams: 1 2015_dis_esoliveira.pdf: 1176281 bytes, checksum: 2f8b26f6c2f881e2d69d6ff40545a894 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2015-10-26T13:28:26Z (GMT) No. of bitstreams: 1 2015_dis_esoliveira.pdf: 1176281 bytes, checksum: 2f8b26f6c2f881e2d69d6ff40545a894 (MD5) / Made available in DSpace on 2015-10-26T13:28:26Z (GMT). No. of bitstreams: 1 2015_dis_esoliveira.pdf: 1176281 bytes, checksum: 2f8b26f6c2f881e2d69d6ff40545a894 (MD5) Previous issue date: 2015 / Breast cancer is the leading cause of cancer death among women worldwide. Despite having good prognosis when diagnosed and treated properly, breast cancer mortality rates remain high in Brazil. The etiology of breast cancer is multifactorial and some risk factors are described, such as age, family and personal history of cancer, factors linked to endocrine aspects , among others. However, by 50 to 80% of cases none of these factors is identified, suggesting the existen ce of another one . S tudies point to an association of breas t cancer with the Epstein - Barr V irus (EBV), but the studies are controversial. Thus, this study aimed to verify the presence of EBV, using in situ hybridization in 75 patients diagnosed with invasi ve breast carcinoma, from the Mastology Clinic of the Maternity School Assis Chateaubriand. For molecular classification, E R , PR, HER2, Ki67, TP 53, CK5/ 6 and CK8 /18 markers were detected by immunohistochemistry. In this study, the median age of patients wa s 55 years, of which 28% were aged up to 45 years. Only 8,7 % of the tumors were diagnosed early. More advanced stage of degrees and lymph node involvement characterized this sample. Most tumors express luminal cytokeratins markers, hormone receptors and ma rker of cell proliferation (Ki67). Moreover, TP53 and HER2 were present in a minor fraction of tumors. EBV was positive in only 6.67% of the cases in which the presence of the virus was restricted to a few nuclei of tumor cells. The luminal B subtype was t he most common, followed by luminal A. TP53 was more frequent in tumors of the basal - like subtype (75%), significantly differing from the luminal A tumors ( 16,7 %) (p = 0.0 3 ) regardless of age. Among the patients up to 45 years, all triple negative (b asal - l ike and n ormal - like) subtype tumors were T P53 positive, while a low frequency was found in luminal A and B subtypes with a statistical difference between triple negative (100%) and luminal A ( 14,3 %) (p = 0.0 2 ), triple negative and luminal B (1 6 . 7 %) (p = 0. 0 2 ) , between basal - like (100%) and luminal A (p = 0.0 4 ) and basal - like and luminal B (p = 0.04) . The TP53 frequency did not differ significantly between the molecular subtypes in patients over 45 years. Comparing the age groups, it is interesting to note t hat in triple negative subtype tumors in patients under 45 years old TP53 was statistically more frequent than in patients over 45 years old compared with luminal B, while in luminal B tumors, TP53 was more frequent in patients over 45 years old. In conclu sion, despite the presence of EBV observed, the small number of cases and the weak positivity does not allow to say that this is an etiological factor for the development of breast cancer n either the association of their presence with some molecular subtyp e. However, it is important to note that the virus was investigated based on your profile latency considering the EBER expression and these data raise the addition of other targets for studying the real participation of the virus. Furthermore, it is intere sting to note the importance of TP53 as a marker of differential triple negative tumors in women below 45 years. / O câncer de mama representa a maior causa de mortalidade por câncer entre as mulheres em todo o mundo. Apesar de possuir bom prognóstico quando diagnosticado e tratado adequadamente, as taxas de mortalidade continuam elevadas no Brasil. A etiologia do câncer de mama é multifatorial e alguns fatores de risco são descritos, como: idade, história familiar e pessoal de câncer, fatores ligados a aspectos endócrinos, entre outros. Entretanto, em 50 a 80% dos casos, nenhum desses fatores é identificado, sugerindo a existência de outros. Estudos apontam a associação do câncer de mama com o Vírus Epstein-Barr (EBV), entretanto, os estudos são controversos. Assim, o presente estudo teve como objetivo verificar a presença de EBV, utilizando a técnica de Hibridação in situ, em 75 pacientes diagnosticadas com carcinoma mamário invasivo, provenientes do Ambulatório de Mastologia da Maternidade Escola Assis Chateaubriand. Para a classificação molecular, os marcadores RE, RP, HER2, Ki67, TP53, CK5/6 e CK8/18 foram detectados pela técnica de imunohistoquímica. Neste estudo, a mediana da idade das pacientes foi de 55 anos, das quais 28% tinham até 45 anos. Apenas 8,7% dos tumores foram diagnosticados precocemente. Graus de estadiamento mais avançados e comprometimento de linfonodos caracterizaram essa amostra. A maioria dos tumores expressaram marcadores de citoqueratinas luminais, receptores hormonais e marcador de proliferação celular (Ki67). Por outro lado, TP53 e HER2 estiveram presentes em uma fração menor dos tumores. EBV foi positivo em apenas 6,67% dos casos nos quais a presença do vírus foi restrita a poucos núcleos de células tumorais. O subtipo luminal B foi o mais frequente, seguido do luminal A. TP53 foi mais frequente nos tumores do subtipo basal símile (75%), diferindo significativamente dos tumores luminais A (16,7%) (p= 0,03) independente da idade. Entre as pacientes com até 45 anos, todos os tumores do subtipo triplo negativo (basal símile e normal símile) foram TP53 positivos, enquanto uma baixa frequência foi encontrada nos subtipos luminal A e luminal B com uma diferença estatística entre triplo negativo (100%) e luminal A (14,3%) (p = 0,02), triplo negativo e luminal B (16,7%) (p = 0,02), entre basal símile (100%) e luminal A (p = 0,04) e basal símile e luminal B (p = 0,04). As frequências de TP53 não diferiram significativamente entre os subtipos moleculares nas pacientes acima de 45 anos. Comparando-se os grupos de idade, é interessante notar que os tumores do subtipo triplo negativo nas pacientes de até 45 anos de idade tiveram TP53 estatisticamente mais frequente do que em pacientes acima de 45 anos quando comparados com luminal B, enquanto nos tumores do subtipo luminal B, TP53 foi mais frequente em pacientes acima de 45 anos de idade. Em conclusão, apesar da presença de EBV observada, o pequeno número de casos e a fraca positividade não permitem afirmar ser este um fator etiológico para o desenvolvimento do câncer de mama e nem a associação da sua presença com algum subtipo molecular. Entretanto, é importante ressaltar que o vírus foi pesquisado com base no seu perfil de latência considerando a expressão de EBER e esses dados suscitam a adição de outros alvos para a pesquisa da real participação do vírus. Por outro lado é interessante ressaltar a importância do TP53 como marcador diferencial dos tumores triplo negativos em mulheres abaixo de 45 anos.

Submitted by CLEITON SILVA MARQUES null (biocleitond2@yahoo.com.br) on 2017-06-14T16:42:05Z No. of bitstreams: 1 MS 201513939-9 Dissertação Cleiton Silva Marques.pdf: 1951878 bytes, checksum: 324f65b41f0660609ec022c77b81f85e (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-06-19T13:53:05Z (GMT) No. of bitstreams: 1 marques_cs_me_bot.pdf: 1951878 bytes, checksum: 324f65b41f0660609ec022c77b81f85e (MD5) / Made available in DSpace on 2017-06-19T13:53:05Z (GMT). No. of bitstreams: 1 marques_cs_me_bot.pdf: 1951878 bytes, checksum: 324f65b41f0660609ec022c77b81f85e (MD5) Previous issue date: 2017-05-15 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Presente em aproximadamente 95% da população mundial o Vírus de Esptein-Barr (Epstein-Barr Virus - EBV) está relacionado com 1,5% dos casos de câncer no mundo com destaque para o carcinoma de nasofaringe (Nasopharyngeal Carcinoma – NPC) o qual segundo a Organização Mundial da Saúde, 90% dos carcinomas indiferenciados estão associados ao EBV. Expresso durante o ciclo de latência III e II a proteína latente de membrana 1 (Latent Membrane Protein 1, LMP1), um dos principais produtos oncogênicos do EBV mimetiza o receptor CD40 e mantém-se constitutivamente ativa na célula. Com papel importantíssimo no desenvolvimento do carcinoma de nasofaringe, LMP1 atua na imortalização e proliferação de linfócitos B por meio da deflagração de vias de sinalização intracelular como NFkB e PI3K/AKT. Atualmente são conhecidas sete variantes do gene BNLF1 que codifica LMP1 e apresentam diferenças nas sequências nucleotídicas e aminoacídicas, ambas consideradas oncogênicas por conservarem os domínios CTARs. Essas diferenças encontradas nas variantes de LMP1 podem estar relacionadas à agressividade dos tumores. Entre as variantes de LMP1 foram avaliadas no presente estudo as variantes B95.8 e M81, ambas associadas ao desenvolvimento de NPC. As propriedades transformantes dessas variantes de LMP1 foram analisadas frente ao programa biológico transição epitelial- mesenquimal (Epithelial-Mesenckymal Transition – EMT) que está diretamente relacionado com a progressão dos carcinomas. A avaliação das variantes de LMP1 foi feito por meio de transfecção transiente de células HEK293 e NP69. Células expressando as variantes de LMP1 apresentaram maior capacidade de migração e invasão em relação ao grupo controle. Ainda, células expressando as variantes de LMP1 demonstraram alteração para alguns genes relacionados ao processo de EMT. No entanto, as variantes de LMP1 não apresentam diferenças significativas na regulação do programa de EMT. / FAPESP: 2015/13939-9

Made available in DSpace on 2014-06-12T18:04:23Z (GMT). No. of bitstreams: 2 arquivo6195_1.pdf: 1143920 bytes, checksum: 0d0ca55cd7599cecc0ad08a953f1ec9b (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2007 / O câncer apresenta-se como uma das grandes causa mortis na vida contemporânea, principalmente o de adulto que tem aumentado em função do aumento da expectativa de vida, mudança de hábitos alimentares e modo de vida. O câncer pediátrico está mais claramente relacionado a fatores genéticos herdados ou ligado a embriogênese. Os tipos mais prevalentes são as leucemias, os tumores do sistema nervoso e os linfomas. Os linfomas apresentam-se divididos em: doença de Hodgkin (HD) e linfomas não-Hodgkin (NHL), sendo o segundo responsável por mais da metade dos casos. Os NHL se destacam por várias características morfológicas, fenotípicas e por eventos moleculares que alteram a configuração cromossômica e a expressão de diversos genes, eventos moleculares estes que têm sido relacionados a vírus, porém de uma forma não muito clara e sem um modelo definitivo. No presente trabalho a relação entre a infecção por EBV, a transcrição de RNA do referido vírus e a superexpressão do proto-oncogene c-myc em amostras de linfoma foram estudadas. Analisamos biopsias de tumor de 49 pacientes, dos quais 34 (69,4%) eram do sexo masculino e 15 (31,6%) eram do sexo feminino. Os linfomas não-Hodgkin estudados eram de localização principalmente abdominal e em 63,4% o EBV foi detectado, com transcrição ativa do RNA viral em 29,3%. Já os linfomas de Hodgkin somaram apenas sete e em dois deles foi encontrada infecção por EBV. Nossos estudos indicam forte relação do EBV com o NHL, principalmente de localização abdominal, sendo necessários mais estudos da relação do vírus com a expressão elevada do proto-oncogene c-myc

The high incidence rate of Nasopharyngeal Carcinoma (NPC) in southern China, including Hong Kong, has attracted worldwide attention. According to the Center for Health Protection in Hong Kong, there were 841 new cases of NPC, with 655 cases of males and 186 cases of females in 2013. The development of NPC is highly associated with the infection of one human herpes virus, the Epstein-Barr virus (EBV). Given that the homodimerization of one of the EBV endogenous protein-Epstein-Barr Nuclear Antigen 1 (EBNA1) is essential for both viral genome maintenance and infected-cell survival, thus the interference of EBNA1 homodimerization would be a novel strategy for the inhibition of EBV-positive tumours. In this thesis we devote to conjugate several kinds of organic fluorophores with various EBV-specific peptides in order to achieve the highly responsive and selective imaging, as well as the effective inhibition of EBV-positive tumours in vitro and in vivo. The first research focused on the conjugation of a styrene pyridine fluorophore with two EBNA1-specific peptides, aiming to develop a dual-probe for the imaging and inhibition of EBV-positive tumour cells. Then we tried to introduce a Nuclear Localization Sequence into the EBNA1-specific peptide, and used an Intra-molecular Charge Transfer characterized fluorophore for the following second research, it showed an impressively responsive signal when the probe binds with EBNA1 both in vitro and in vivo, more importantly, only 4 μg probe can inhibit 92.8% of growth inhibition of an EBV-positive tumour. Along this line, our last research centred on the further improvement of the imaging by taking advantage of lanthanide.

A dissertation submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science in the branch of Anatomical Pathology. 21 July 2017. / Aims and objectives The study design aimed to assess and validate various laboratory techniques in the detection of EBV in HIV positive patients with diffuse large B cell lymphoma. The sensitivity and specificity of each technique was determined, as was the presence of an asymptomatic (latent) or lytic phase infection and the viral strain. DLBL samples occurring in HIV seropositive patients were used as a vehicle for these laboratory procedures which included chromogenic in situ hybridisation (EBER), immunohistochemistry (EBNA 2, LMP 1), real time PCR, (EBNA 1, LMP 2 and BZLF 1) and nested PCR (EBNA 2). Materials and Methods 46 cases of previously diagnosed DLBL from HIV positive individuals were identified and retrieved from the archives of the Department of Anatomical Pathology of the University of Witwatersrand and NHLS. All in-situ hybridisation, immunohistochemical and PCR laboratory procedures were carried out in accordance with the Standard Operating Procedures of the Anatomical Pathology Molecular Laboratory, using appropriate negative and positive controls throughout. Ethical clearance was obtained (M140273). Results/Conclusion A 20% frequency of EBV in HIV positive DLBL cases was established. All EBV infections were found to be in the lytic phase, with an almost equal distribution of latency patterns II and III and an equal distribution of EBV strains 1 and 2. EBER in situ hybridisation was confirmed to be the most sensitive and reliable method of viral detection, and the presence of the BZLF 1 gene determined by real time PCR was found to be a reliable indicator of a lytic infection. / LG2018

Immune evasion is an emerging hallmark of cancer. Dysregulation of the major histocompatibility complex class I (MHC-I) is a frequent mechanism of immune evasion utilized by tumor cells and is particularly relevant to the pathogenesis of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). A better understanding of MHC-I dysregulation in B-cell lymphomas is necessary to identify factors related to the risk, development, and progression of these tumors. In this thesis, we investigate the role of MHC-I dysregulation in DLBCL and cHL through the application of computational approaches to study genomic data. First, we introduce some background information about the normal function of MHC-I in the immune response to cancer and viral infection as well as the phenomenon of MHC-I dysregulation in the context of cancer. We provide an overview of how factors such as germline zygosity of HLA class I (HLA-I) genes and somatic alterations in the genes B2M and HLA-I that encode the protein subunits of MHC-I contribute to the development of DLBCL and cHL. Second, we present a study of the effects of HLA-I allele zygosity on survival in a cohort of 519 DLBCL patients treated with R-CHOP immunochemotherapy stratified by molecular subtype. Homozygosity in HLA-I was associated with a worse overall survival in patients whose tumors were classified in the “EZB” subtype, associated with somatic mutation in the epigenetic regulator EZH2. We find an association between the zygosity of the genes HLA-B and -C specifically and overall survival in EZB-DLBCL. These findings indicate that HLA-I zygosity may be a risk factor for worse clinical prognosis in patients with the EZB subtype of DLBCL. Third, we present a study of the genetic landscape of cHL tumors that are associated with infection with Epstein-Barr virus (EBV). We analyze inherited HLA-I allele types, somatic mutations, copy number changes, and mutational signatures in a cohort of 57 cHL patients (15 EBV-positive). We find that EBV-positive cHL is genetically distinct from EBV-negative cHL and is characterized by lower somatic mutation load and different activities of mutation signatures. Further, we find that cHL tumors are characterized by different patterns of MHC-I dysregulation depending on the EBV infection status. Germline homozygosity in HLA-I was associated with the EBV-positive subtype of cHL, while somatic alterations in HLA-I were associated with the EBV-negative subtype of cHL. These results suggest that inherited HLA-I homozygosity may be a risk factor for the EBV-positive subtype of cHL. Fourth, we expand our study of HLA-I in virus-associated cHL to perform a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We find that virus-positive tumors occur more frequently in males and show geographical disparities in incidence. Genomic analysis of 1,658 tumors reveals virus-positive tumors exhibit distinct mutation signatures, recurrent mutations in the RNA helicases DDX3X and EIF4A1, and a lower somatic mutation burden compared to virus-negative tumors of the same cancer type. We find that germline homozygosity in HLA-I is a potential risk factor for the development of EBV-positive cHL, but not other common virus-associated solid or hematological malignancies. Finally, we present in the Appendix a study of the genomic characterization of plasmablastic lymphoma (PBL), a rare EBV-associated B-cell lymphoma that occurs in the context of immunodeficiency caused by human immunodeficiency virus (HIV) infection. We find that PBL is characterized by mutations leading to constitutive activation of the JAK-STAT pathway. We additionally identify recurrent mutations in immune-related genes, such as B2M. These findings indicate a potential role for MHC-I and immune dysregulation in the pathogenesis of other B-cell lymphomas.

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