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1
Carbone, Ilaria <1984>. "Human herpes virus and Alzheimer’s disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5255/.
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Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder and according to the WHO it is estimated that 36 millions of people worldwide currently suffer from AD. Genetic and environmental factors interact in a complex interplay that might affect pathogenic mechanisms leading to age-related neurodegeneration. The hypothesis is that the presence of allelic polymorphisms in selected genes affecting individual brain susceptibility to infection by the herpes virus family during aging, may contribute to neuronal loss, inflammation and amyloid deposition. Herpes virus family show features relevant to AD, since they infect a large proportion of human population, develop a latent form persisting for several years, are difficult to eliminate by immune responses especially when latency has been established and are able to infect neurons. The association between AD and herpes viruses infection has been investigated. In particular the investigation focused on CMV, EBV and HHV-6 in DNA samples from peripheral blood of a large cohort of patients with clinical diagnosis of AD and age matched CTR, from a longitudinal population study, and DNA samples from brain tissue of patients with neuropathological diagnosis of definitive AD. An association between the presence of EBV and HHV-6 DNA from PBL positivity with the cognitive deterioration and progression to AD has been focused. Moreover, IgG plasma levels in CTR and AD to these viruses were tested. CMV and EBV IgG plasma levels were higher in elderly subjects that developed clinical AD at the end of the five year follow up. Our findings support the notion that persistent cycles of latency and reactivation of herpes viruses may contribute to impair systemic immune response and induce altered inflammatory process that in turn affect cognitive decline during aging.
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Halawi, Mustafa. "Immune responses against human herpes virus 6." Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2012959/.
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Human herpes virus 6 (HHV6) infects the majority of individuals in childhood, followed by a lifelong asymptomatic latent infection. However, in immunosuppressed individuals reactivation of HHV6 can cause significant clinical pathology. Recent successes with adoptive T cell therapy against other viral infections, notably the human herpes viruses Epstein-Barr virus (EBV) and Human cytomegalovirus (HCMV), suggest that this may be a useful therapeutic approach for HHV6-driven disease in immunosuppressed individuals. However, very few studies have been carried out analysing the immune response to HHV6 in any detail. This thesis was aimed at characterising the CD8+ T cell response to HHV6 in a group of healthy individuals, with the aim of mapping and characterising novel CD8+ T cell epitopes. Initial studies included four HHV6B antigens (U11, U39, U54 and U90), predicted to be immunogenic based on their HCMV homologues. Whole antigen peptide mixes (pepmixes) were used to stimulate peripheral blood mononuclear cells (PBMC) from healthy subjects. T cell responses were analysed by intracellular cytokine staining (ICS) after overnight stimulation and/or by interferon-γ (IFN-γ) ELISpot assay after 10 days of stimulation. For responses to U11 and U90, peptides libraries were used to map minimum CD8+ restricted epitopes. Further characterisation of HHV6B-specific T cells was carried out by identifying the HLA restriction elements and determining whether these T cells were capable of killing HHV6B-infected cells. PBMC from 30 healthy donors were stimulated with pepmixes corresponding to HHV-6B antigens U11, U39, U54 and U90. A weak CD8+ response (0.02-0.2%) to U90 and U54 was observed in a number of donors. Short-term in-vitro reactivations of PBMC (in 25 healthy donors) with HHV6B pepmixes followed by analysis of antigen and peptide specific response were performed by IFN-γ ELISpot assay. T cell responses to U54, U90, U11 and U39 were observed in 88%, 84%, 76% and 72% of the donors, respectively. Subsequently, the breadth of epitope specificity within U90 and U11 was screened for 9 healthy donors; with successful identification of 10 CD8+ T cells specific (9-mer) epitopes within these antigens. Seven of them were within U90 antigens and three of them were within U11 antigens. Allelic association of the U90 epitopes were; VEESIKEIL - B40 (60), FESLLFPEL - B40 (60), NLITAAKNI - A2, ITAAKNIGI - A2, LNIDPSESI - A1, PSKSKKIKL - A29, NHCFINHFV - B39. Allelic association of the 2 U11 epitopes were LKTQRRHKF - B37 and GILDFGVKL - A2; the HLA association for FNAVYSQRV was not identified. CD8+ T cell populations specific to some of these epitopes were also able to kill HHV6B infected cells. HHV6B T cells responses are detectable in healthy donors. Peptide specific responses against U11 and U90 have been mapped and characterised. These findings are relevant to the development of T cell mediated immunotherapy of HHV6-associated diseases.
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Sayers, Charlotte. "Herpes simplex virus type 1 infection of human keratinocyte cells." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11112.
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Infection of herpes simplex virus type 1 (HSV-1) begins at the epidermis, a stratified layer composed primarily of keratinocytes. The physiologically relevant cell type for the study of HSV-1 assembly is therefore the human keratinocyte. Nonetheless, relatively little is known about the replication of HSV-1 in this natural host cell. Comparison of virus growth in monolayers of keratinocyte cells and Vero cells, a routinely used cell line for HSV-1 studies, revealed that these keratinocytes support a more productive virus replication than Vero cells. Furthermore, newly assembled virus is produced more rapidly in keratinocytes and this enhancement occurs prior to, or upon the initiation of immediate early gene transcription. This augmented replication in keratinocytes can be at least partially attributed to the method of entry of the virus. We have found by penetration assays and electron microscopy that the virus is able to penetrate keratinocyte cells much more rapidly than Vero cells. We have also shown that the virus entry mechanism is more efficient at lower temperatures in nTERT cells, with virus entering cells at temperatures as low as 7°C. Additionally preliminary work implies that depletion of one of the herpes virus entry receptors, Nectin-1, does not affect entry into nTERT cells, whereas entry is reduced up to 65% in HeLa cells. Taken together, these results imply a role for other entry receptors, possibly as yet unidentified, in the entry of human keratinocyte cells. This work also identifies a role for cellular Rab proteins, GTPases essential for the regulation of vesicle trafficking, in HSV-1 infection of keratinocytes. In particular Rab6, which was also found to play a role in infected HeLa cells (Elliott Group), appears to have a similar function in both these cells and together support a model for HSV-1 morphogenesis involving Rab-regulated vesicle trafficking of viral glycoproteins to the cell surface. Several other Rabs identified by this screen now provide interesting opportunities to elucidate further roles of Rab proteins in HSV-1 infection of keratinocyte cells. This project has broadly characterised the replication of HSV-1 in keratinocyte cells and explored the role of Rab GTPases in virus trafficking within keratinocytes - a cell type that is physiologically relevant to infection.
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Simmonds, Peter. "Detection of antibody responses to infection with herpes simplex virus and human immunodeficiency virus." Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/26933.
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Thellman, Nichole Nikki M. "A human neuronal model for herpes simplex virus latency and reactivation." Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10284545.
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A defining characteristic of alphaherpesviruses is the establishment of lifelong latency in host sensory ganglia with occasional reactivation causing recurrent lytic infections. Much remains unknown regarding the cellular and viral mechanisms involved in HSV exit from latency. We hypothesize that VP16 recruits chromatin-remodeling enzymes to immediate early gene promoters on compact-latent chromatin as a necessary step for reactivation. In order to test this hypothesis, a robust in vitro assay in which HSV latency can be established in neurons was required. In this dissertation, I explored the use of a human sensory neuron cell line as a novel in vitro model of HSV-1 latency and reactivation. HD10.6 cells were derived from embryonic human dorsal root ganglia and immortalized by a tetracycline-regulated v-myc oncogene. HD10.6 cells mature to express a sensory neuron-associated phenotype when treated with doxycycline which suppresses proliferation mediated by the v-myc oncogene. Infection at a low MOI in the presence of acyclovir results in a quiescent infection resembling latency in matured cells. HD10.6 cells provide a novel context in which to study the host and viral mechanisms of HSV-1 latency establishment, maintenance, and reactivation.
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Brown, Elizabeth L. "Consequences of genital herpes simplex virus infection among vulnerable populations /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/10885.
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Held, Kathrin. "Control of herpes simplex virus type 1 latency in human trigeminal ganglia." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-142865.
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Baker, Kevin. "Investigations into the ocular involvement of human herpes and papilloma virus infections." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266252.
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Peat, D. S. "The effect of herpes simplex virus type 1 on chromosomes of human cells." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383841.
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O'Leary, John James. "Molecular analysis of Kaposi's sarcoma associated herpes virus (KSHV) in immunocompromised patients." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360468.
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Ellsmore, Victoria. "Human cytomegalovirus origin-dependent DNA synthesis." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340332.
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Ansari, Azeem. "Functional studies on the U69 protein kinase encoded by human herpes virus 6." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321937.
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Jalouli, Jamshid. "Human Papilloma Virus, Epstein-Barr Virus, and Herpes Simplex Virus Type-1 in Oral Squamous Cell Carcinomas from Three Populations." Doctoral thesis, Uppsala universitet, Käkkirurgi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128912.
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Most oral squamous cell carcinoma (OSCC) is believed to develop via a multistep process of cumulative gene damage in epithelial cells. Increasing incidence of OSCC and evidence that traditional risk factors may not be responsible directed us to investigate the prevalence of virus in pre- and malignant samples.The integration of the DNA from human papillomavirus (HPV), Epstein-Barr virus (EBV), and Herpes simplex (HSV) into the human genome is associated with the expression of oncogenes and the down-regulation of tumor-suppressor genes in OSCC carcinogenesis. This thesis compared samples from India and Sudan, two countries on two continents having a documented high incidence of oral cancer, with specimens from Sweden, with its known low incidence of oral cancer. Each region has, in addition to smoking, a unique non-smoked tobacco habits with documented carcinogenic effects. These countries also typify areas of low and high socioeconomic living conditions with their expected impact on disease development. The study populations were selected from tobacco users and nonusers with OSCC, oral sub-mucous fibrosis (India), oral lichen planus (Sweden), oral leukoplakia with and without dysplasia and snuff-induced lesions (Sweden and Sudan). An expedient method was developed for extracting DNA from old formalin-fixed and paraffin-embedded biopsies. The prevalence of HPV, EBV, and HSV was investigated using PCR/DNA sequencing and southern blot hybridization analysis. We found HPV and EBV to be most prevalent in samples of tissue characterized as normal, with decreasing prevalence in dysplastic and malignant lesions. This intriguing finding that prevalence decreases as neoplastic development proceeds warrants further investigation. Our data do not at first sight support the conclusion that viruses and tobacco use jointly interact with cell mechanisms in the development of oral cancer.
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Cartier, Anna. "Inhibition of apoptosis by the Us3 protein kinase of herpes simplex virus 1 /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-022-2/.
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Loiacono, Christina Marie. "Mechanism of herpes simplex virus type 1 latency in transgenic mouse models." MU has, 2002. http://wwwlib.umi.com/cr/mo/fullcit?p3052194.
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Mitterreiter, Johanna Gracia [Verfasser]. "Virus and Host Factors Involved in Herpes Simplex Virus Infection of the Human Nervous System / Johanna Gracia Mitterreiter." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2017. http://d-nb.info/1150336951/34.
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Garland, Russell John. "The ex-vivo expansion of human CD8'+ cytotoxic T lymphocytes to herpes simplex virus." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324367.
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Wade-Martins, Richard. "Developing Epstein-Barr virus-based stable episomes for gene expression from large genomic inserts to complement cell phenotypes." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301648.
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Dasari, Vijayendra. "Designing a Polyepitope Prophylactic Vaccine against Human Cytomegalovirus." Thesis, Griffith University, 2012. http://hdl.handle.net/10072/367769.
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Human cytomegalovirus (CMV) is a ubiquitous β human herpes virus that establishes lifelong infection. Primary CMV infection in immunocompetent individuals is generally asymptomatic, but in congenitally infected children and in transplant patients CMV causes significant morbidity and mortality. Based on the life-time cost to the health care system and its impact on human suffering, development of a vaccine to prevent congenital human cytomegalovirus (CMV) infection has been assigned the highest priority by the Institute of Medicine of the National Academy of Sciences (US) and US National Vaccine Program Office. Therefore there is an emerging need for the development of an effective CMV vaccine. The main objective of vaccine development against CMV is to reduce the risk of CMV associated injury to the developing fetus and in immunocompromised individuals such as recipients of solid organ and hematopoietic stem cell transplants. In immunocompetent individuals CMV infection is maintained under strict control by the immune system by a combination of humoral and cellular immune responses. Thus, an effective CMV vaccine should be designed to induce virus-specific antibody, and CD4+ and CD8+ T cell responses. In spite of extensive efforts over the last 30 years, a clinically licensed vaccine formulation with convincing clinical efficacy remains elusive.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Thapa, Manoj. "Chemokines and chemokine receptors that mediate immune defense to genital herpes simplex virus type 2 (HSV-2) infection." Oklahoma City : [s.n.], 2008.
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Hu, Nai-Chung. "Co-occurrence of shedding Herpes Simplex Virus type-2 (HSV-2), Human Papilloma Virus (HPV) and Human Immunodeficiency Virus 1 (HIV-1) in the female genital tract among HIV-infected women." Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31250.
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Introduction: Human Immunodeficiency Virus remains as one of the largest pandemics in the world, with the prevalence of more than 70% of HIV-infected individual reside in Sub-Saharan Africa. Moreover, other sexually transmitted viral infection such as Human Papillomavirus and Herpes Simplex Virus also show a high prevalence in Sub-Saharan Africa. Recent studies show the presence of other viral STI in the genital region may have increased HIV shedding in the genital region. However, it not clearly known if the presence of ART or HIV may affect the shedding of other viral STI in the genital region and if the combination of other viral STI treatment and ART is necessary to treat an individual with multiple STI infection. Methods: This is a secondary data analysis study, based on analysing the data collected from a single-site, double-blinded randomized control study (2-IUD study). The research site was the Gugulethu Community Health Centre, Cape Town, South Africa and samples were collected between 2014 and 2018. Analysis was conducted on genital tract specimens of study participants obtained via the Menstrual Cup (MC) and Endocervical Swabs (ECS), collected at baseline, 3 and 6 months’ follow up visit from randomly selected 52 ART-Naïve participants and 56 age-matched women from the ART-Using group of the primary study. Logistic regression models were constructed to measure the associations between possible risk factors and viral STIs. Results are presented as odds ratios (OR) with 95% confidence intervals (CI). Results: ART-Naïve women had higher rates of HIV shedding in the genital tract at each visit. However, more than half of women using ART, most of them virally suppressed, had detectable genital HIV at one or more visits. Most of the participants showed pre-exposure to HSV-2, but shedding of HSV-2 was substantially less common. HPV was detected in 72% of the participants, with no significant difference by ART status. Overall, 70.3% of samples had at least one viral pathogen detected - 60.4% among ART-Using women compared to 82.8% in ART-Naïve women (P<0.001). Compared to ART-Naïve women, ART-Using women were significantly less likely to have co-occurrence of viral shedding overall. However, ART-Using women with higher VL had levels of viral co-occurrence similar to those of ART-Naïve women. Conclusion: Our analysis demonstrated that the ART-Using women were less likely to shed HIV, HSV-2, HPV and viral STI co-infection in the genital tract compared to ART-Naïve women. This may be be driven by plasma VL levels where ART-Using women with lower VL are less likely to shed these viruses compared to women with elevated VL, including those not on ART.
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Ye, Shanli. "DNA Sequences Involved in the Regulation of Human c-myc Gene Expression by Herpes Simplex Virus Type 1 (HSV-1)." PDXScholar, 1995. https://pdxscholar.library.pdx.edu/open_access_etds/5221.
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The human c-myc gene is a cellular proto-oncogene composed of three exons and two introns. Transcription of c-myc is controlled by two promoters, Pl and P2. The activity of these promoters is regulated by many factors, such as cellular transcription factors E2F, YYl, and HSV-1 immediate-early proteins, ICPO, ICP4. Many regulatory elements located both upstream of and between P 1 and P2 have been identified, and some of these are required for optimum expression of c-myc. In this thesis research, a region downstream from P2 in the c-myc exon 1 was identified by its response to transactivation by HSV-1 immediate-early proteins, ICPO and ICP4. The purpose of this research was to examine this region for regulatory sites that respond to HSV-1 infection. I hypothesized that after HSV-1 infection, ICPO and ICP4 activate c-myc expression, in part, through regulatory sequences present in exon 1. To test for this hypothesis, reporter plasmids containing (I) the c-myc promoter (from - 101 bp relative to Pl) and exon 1 coupled to the bacterial CAT gene were constructed. (ii) The c-myc exon sequences used were either intact (wild-type) or they were constructed with various deletions. The activities of these plasmids were examined in transient expression assays. To analyze protein binding, electrophoretic mobility shift assay (EMSA) and completion EMSAs were carried out. The results from these experiments lead to the following conclusions: (i) ICP4 and ICPO serve as activators, whereas ICP27 inhibits c-myc gene expression. (ii) The region from +332 to +513 within the c-myc exon 1 contains an important element required for transactivation of the c-myc gene by HSV-1 proteins. (iii) Cellular proteins, including factor YYl, bind to the region from +332 to +513 in the c-myc exon 1. Although the exact mechanism by which HSV-1 immediate-early proteins regulate cmyc gene expression is still not clear, it gives rise to a possibility that this regulation is caused by turning on or activation of the cellular regulatory proteins by ICP4 and ICPO. The cellular proteins in turn activate the c-myc gene expression by interacting with the ciselement downstream from P2.
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Held, Kathrin [Verfasser], and Hans [Akademischer Betreuer] Straka. "Control of herpes simplex virus type 1 latency in human trigeminal ganglia / Kathrin Held. Betreuer: Hans Straka." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1022523740/34.
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Chen, Fu. "Epstein-Barr virus (EBV) latent membrane protein LMP2A /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-589-5/.
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Solaroli, Nicola. "Investigation of antiviral and anticancer nucleoside analog substrate recognition of drosophila melanogaster and herpes virus deoxyribonucleoside kinases /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-922-X/.
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Nishikawa, Masaya, Yasushi Hayashi, Noriyuki Yamamoto, Takafumi Fukui, Hirokazu Fukuhara, Kenji Mitsudo, Iwai Tohnai, Minoru Ueda, Masaaki Mizuno, and Jun Yoshida. "Cell Death of Human Oral Squamous Cell Carcinoma Cell Line Induced by Herpes Simplex Virus Thymidine Kinase Gene and Ganciclovir." Nagoya University School of Medicine, 2003. http://hdl.handle.net/2237/5397.
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Yamamoto, Noriyuki, Yasushi Hayashi, Hideaki Kagami, Takafumi Fukui, Hirokazu Fukuhara, Iwai Tohnai, Minoru Ueda, Masaaki Mizuno, and Jun Yoshida. "Suicide gene therapy using adenovirus vector for human oral squamous carcinoma cell line In vitro." Nagoya University School of Medicine, 2005. http://hdl.handle.net/2237/5408.
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Reyes-Goddard, Janelle Maria. "The use of surface enhanced raman scattering to differentiate between a human tear film model with and without Herpes Simplex virus." Thesis, Cranfield University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405624.
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Eleuterio, Junior Jose. "Marcadores biomoleculares de lesões epiteliais escamosas genitais pre-invasivas." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309413.
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Orientador: Paulo Cesar GiraldoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Objetivos: Estudar a importância de determinados marcadores de diagnóstico e prognóstico de lesões escamosas genitais, com ênfase nos estudos de p16INK4a e HPV de alto risco. Material e Métodos: Marcadores tumorais foram revisados em 21 estudos publicados entre 1994 e 2005, no sentido de identificar aqueles que teriam melhor valor diagnóstico e/ou prognóstico das lesões intra-epiteliais escamosas. Revisão mais apurada avaliou os marcadores p16INK4a e HPV de alto risco em lesões do colo uterino (36 publicações entre 1994 e 2006). Estudou-se a associação do p16INK4a e HPV de alto risco em 96 amostras de colo utenno (13 casos de lesão intra-epitelial escamosa de alto grau (HSIL), 26 casos de lesão intra-epitelial escamosa de baixo grau (LSIL) e 57 biópsias normais. O p16INK4a foi identificado por imuno-histoquímica, usando-se o p16INK4a kit (E6H4 clone, DakoCytomation, Carpinteria, CA) e o DNA-HPV foi classificado por captura híbrida (Digene®). Associações foram avaliadas pelo índice KAPPA. No artigo foram envolvidos 54 homens, parceiros sexuais assintomáticos de mulheres com lesão intra-epitelial escamosa de baixo grau associada com HPV de alto risco, com a finalidade de verificar se a presença do HPV de alto risco poderia ajudar a identificar os casos com maior risco de ter lesões intra-epiteliais penianas, devendo submeter-se à biópsia. O DNA-HPV foi testado por captura híbrida (Digene®) em raspados do pênis. Peniscopia identificou lesões suspeitas que resultaram em biópsias. Resultados: As revisões demonstraram uma clara potencialidade clínica no uso da associação do p16INK4a e do HPV de alto risco no diagnóstico das SIL do colo uterino, e um possível uso como fator prognóstico. O p16INK4a foi detectado em 92,3% das HSIL, em 15,4% das LSIL e em nenhum caso de histologia normal. Encontrou-se respectivamente sensibilidade, especificadade, valor preditivo positivo e valor preditivo negativo de 92,3%, 100%, 100% e 98,3%, de p16INK4a para HSIL e 100%, 70,42%, 43,3% e 100% do HPV de alto risco para HSIL. No segundo estudo o HPV de alto risco estava presente em 25,9% dos parceiros. A peniscopia levou a 13 biópsias (24,07%) com os seguintes diagnósticos: condiloma (2 casos), PIN I (2 casos), PIN II (1 caso) e histologia normal (8 casos). O teste de HPV de alto risco revelou 80% de sensibilidade, 100% de especificidade, 100% de valor preditivo positivo e 88,9% de valor preditivo negativo para identificação de lesões penianas, mostrando que homens com HPV de alto risco positivo têm maior chancer de ter lesões escamosas penianas em biópsias guiadas pela peniscopia que aqueles com lesões aceto-brancas com teste de HPV negativo, (p = 0.007); OR = 51 (Cl 1.7-1527.1). Conclusões: Marcadores como o HPV de alto risco têm um potencial muito grande para aumentar o poder diagnóstico das HSIL e, principalmente, supor o prognóstico da evolução destas lesões, principalmente quando associado ao p16INK4a
Abstract: Objectives: To study the importance of the diagnostic and prognostic markers of genital squamous lesions, meanly p16INK4a and high risk HPV. Material And Methods: Squamous intra-epithelial lesion tumoral markers were revised in 21 publications between 1994 and 2005 to identify those with diagnostic and prognostic value. More accurate revision assessed the markers p16INK4a and high risk HPV (36 publications between 1994 and 2006). The p16INK4a and high-risk Human papillomavirus were investigated in 96 samples of the cervix (13 cases of high grade squamous intraepithelial lesions, 26 cases of low grade intraepithelial lesions and 57 normal tissues). The p16INK4a was identified by immunohistochemistry using the p16INK4a kit (E6H4 clone, DakoCytomation, Carpinteria, CA). and Human papillomavirus DNA was classified by hybrid capture (Digene®). Associations were evaluated by the KAPPA index. In the other report fifty four asymptomatic male sexual partners of women with low grade squamous intraepithelial lesions (LSIL) associated to high risk HPV were examined, between April 2003 and June 2005, to verify if the high risk HPV could help to identify those with more risk to have a squamous penile lesion. The DNA-HPV was tested by second generation Hybrid Capture (Digene ®) in penile scraped samples. Peniscopy identified suspicious lesions leading to biopsy. Results: The revisions showed the clinical potentiality of the concomitant use of high risk HPV and p16INK4a in diagnosis of cervical SIL and a possible utility in prognosis of genital squamous intra-epithelial. In 96 cervical biopsies, p16INK4a was detected in 92.3% of the high-grade squamous intraepithelial lesions, in 15.4% of the low-grade and in none of the normal tissues. The sensitivity, specificity, positive predictive value and negative predictive value for high-grade lesion were 92.3%, 100%, 100%, and 98.3%, respectively when considering p16INK4a expression, and 100%, 70.2%, 43.3% and 100%, respectively when considering high-risk HPV. In the male partner study high risk HPV was present in 25.9% (14/54) of the cases. Peniscopy led to 13 biopsies (24.07%). Condyloma (2 cases), PIN I (2 cases), PIN II (1 case) and normal tissue (8 cases) were found. The high risk HPV test presented 80% sensitivity, 100% specificity, 100% positive predictive value and 88.9% negative predictive value for the identification of penile lesions. So, there was a greater chance in finding HPV lesions in the biopsy in the positive cases for high risk HPV with abnormal peniscopy than in the negative cases for high risk HPV with anormal peniscopy (p = 0.007); OR = 51 (CI 1.7-1527.1). Conclusions: Markers as high risk HPV have a potential to increase the diagnostic of HPV induced lesions and maybe indicate the evolution, meanly associated with p16INK4a
Doutorado
Tocoginecologia
Doutor em Tocoginecologia
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West, Andrew. "Investigations by mass spectrometry of the interactions of novel serine protease inhibitors with herpes simplex virus type 2 and human cytomegalovirus proteases." Thesis, University of Warwick, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343830.
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Chatterjee, Koushik. "A study of host genetic determinants of human papillomavirus (HPV) infection, cervical cancer and herpes simplex virus type-2 (HSV-2) infection." Doctoral thesis, University of Cape Town, 2010. http://hdl.handle.net/11427/3160.
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Winters, Thomas Andrew. "Identification, purification, and characterization of two chromatographically distinct species of uracil-DNA glycosylase from herpes simplex virus type 2 infected human cells /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487686243821847.
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Chang, Eddie. "The role of perforin and chemokines in the pathogenesis of chronic corneal inflammation induced by herpes simplex virus type-1 infection." free to MU Campus, others may purchase, 2003. http://wwwlib.umi.com/cr/mo/fullcit?p3091911.
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Bonnafous, Pascale. "Etude des mécanismes moléculaires de la résistance du sixième herpèsvirus (HHV-6) aux antiviraux." Paris 6, 2007. http://www.theses.fr/2007PA066398.
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Le sixième herpèsvirus humain ou HHV-6 appartient à la sous-famille des bêtaherpèsvirus, tout comme le cytomégalovirus humain (CMV), et peut être à l’origine d’infections graves nécessitant une chimiothérapie antivirale par ganciclovir (GCV), foscarnet (PFA) ou cidofovir (CDV). Nous nous sommes intéressés ici à la résistance du HHV-6 aux antiviraux. La quantification de la charge virale par PCR en temps réel a été utilisée pour suivre la cinétique de réplication de la souche HST sur lignée lymphocytaire MT4, et pour développer une nouvelle méthode d’étude de la sensibilité du HHV-6 aux antiviraux. La charge virale suit une phase exponentielle puis stationnaire, l’ADN persistant dans la culture cellulaire longtemps après la fin de l’infection lytique. Une quantification précoce pendant la réplication active est possible et nécessaire à une bonne interprétation des résultats de l’antivirogramme. Comparée à la cytométrie en flux, la PCR en temps réel permet de réduire le temps de lecture et est plus économe en cellules et en virus. Cette méthode a été utilisée pour tester de nouvelles molécules antivirales et pour caractériser de nouvelles souches. En particulier, parmi plusieurs médicaments utilisés dans le traitement de l’épilepsie dont l’étiologie du HHV-6 est discutée, la lamotrigine a montré une certaine activité anti-HHV-6, sur la souche HST comme sur d’autres souches virales. D’autre part, la culture in vitro des souches HST sauvage ou GCVR1 (dérivée d’HST, résistante au GCV), en présence de concentrations croissantes de PFA, a conduit à la sélection de deux nouvelles souches, 8 et 15 fois plus résistantes au PFA qu’HST. De nouvelles mutations ont été mises en évidence dans le gène U38 codant l’ADN polymérase, qui est l’enzyme cible des antiviraux : T435R , H507Y et C525S localisées dans le domaine conservé dC, et F292S en dehors des domaines conservés, détectée dans une souche qui n’a pu être isolée. Les mutations T435R et C525S sont en outre aux positions homologues respectivement des mutations N495K et S585A du gène UL54 codant l’ADN polymérase du CMV et associées à une résistance du CMV au PFA. Dans un test fonctionnel permettant de mesurer l’activité enzymatique de l’ADN polymérase du HHV-6, la présence des quatre mutations nouvellement décrites, seules ou en association, diminue significativement l’effet inhibiteur du PFA sur l’enzyme. Une troisième souche sélectionnée à partir d’HST en concentrations croissantes de CDV, s’est montrée 118 fois plus résistante à cet antiviral que la souche sauvage, et une seule mutation a été détectée dans l’ADN polymérase, R798I, localisée dans le domaine VII. Comme dans le cas de GCVR1, une résistance croisée au CDV et GCV a été observée. Enfin, pour mieux appréhender les interactions des antiviraux avec leur cible et comprendre les mécanismes moléculaires impliqués dans la résistance, la structure tridimensionnelle de l’ADN polymérase du HHV-6 a été modélisée. Deux modèles « ouvert » (enzyme seule) et « fermé » (enzyme en mode de polymérisation) ont été élaborés à partir des structures connues des ADN polymérases de l’herpèsvirus simplex 1 (HSV-1) et du bactériophage RB69. Dans les deux modèles, les acides aminés modifiés dans les souches mutantes sont situés dans les différents domaines structuraux de l’enzyme, et éloignés du site actif. L’implication de chaque mutation dans la résistance aux antiviraux pourrait alors s’expliquer, non pas par une modification du site actif lui-même, mais par une modification conformationnelle de l’enzyme limitant l’accès ou la fixation de l’antiviral. Ces résultats sont une première étape dans l’interprétation de mutations décrites dans l’ADN polymérase associées à une résistance du HHV-6 aux antiviraux et dans la compréhension des mécanismes moléculaires sous-jacents.
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Yang, Chin-An. "Characterization of differential Toll-like receptor function in human immune cells and association with susceptibility to recurrent HSV-1 reactivations and gastric cancer." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16268.
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Toll-like Rezeptoren (TLRs) sind essentielle angeborene Rezeptoren, die konservierte Strukturen von Krankheitserregern oder Gefahrsignale, die von beschädigten Zellen freigesetzt werden, erkennen können. Genetische Variationen in TLRs wie Einzel-Nukleotid-Polymorphismus (SNP) können die Funktion von TLRs beeinträchtigen und erste Studien zeigen, dass dies zu einer erhöhten Anfälligkeit gegenüber Virusinfektionen oder einem erhöhten Krebsrisiko führen kann. In dieser Studie haben wir einen Multicolor-Durchflußzytometrie-Test entwickelt, um die TLR-Funktionen in verschiedenen Subpopulationen unseparierter peripherer mononukleärer Blutzellen (PBMCs) simultan analysieren zu können. Wir konnten beobachten, dass das Ausmaß der TLR-Antworten zwischen den Probanden stark variierte, jedoch über einen Zeitraum von einem Monat gut reproduzierbar war. Zunächst untersuchten wir TLR Reaktionen bei Patienten mit rezidivierenden Herpes labilalis (HL). Im Vergleich zu asymptomatischen Personen war eine HL- Anamnese mit einer signifikant verminderten TLR3-IFN-Gamma-Antwort nach Stimulation mit poly(I:C) in NK Zellen assoziiert. Weitere molekulare Untersuchungen zeigten eine mögliche Beteiligung von TLR3 L412F SNP, welcher die oberflächliche TLR3 Expression und die IFN-Gamma-Antworten in NK-Zellen reduzierte. Einige Studien zeigen, dassTLR1 I602S, ein weiterer sehr verbreiteter SNP, in der Lage ist die TNF-Alpah-Antworten von Monozyten gegen den TLR2/1-Agonisten (Pam3Cys) zu verringern. In der hier vorliegenden Arbeit konnten wir zudem nachweisen, dass TLR1 I602S SNP auch die Funktion von NK-Zellen und CD8+ T-Zellen beeinträchtigt. Wir konnten keine Assoziation zwischen TLR2/1-Defizienz und reaktivierendem HL feststellen. Jedoch konnten wir an einer großen Kohorte von über 326 Patienten zeigen, dass der TLR1 SNP sowohl ein Risikofaktor für Magenkarzinomentstehung als auch für die Metastasierung ist. Zusammenfassend weisen unsere Ergebnisse darauf hin, dass genetische Polymorphismen von TLRs die Funktion von NK-Zellen beeinträchtigen und zu einer erhöhten Anfälligkeit für HSV-1 Erkrankung und Magenkarzinom führen können.Toll-like Receptors (TLRs) are essential innate receptors which recognize conserved structures of pathogens, or danger signals released from damaged cells. Alterations of TLR responses might result in severe viral infections or a higher risk of cancer. Therefore, development of clinical assays to evaluate TLR functions could provide personalized information about susceptibility to these diseases. Since TLRs are differentially expressed on different subsets of human peripheral blood mononuclear cells (PBMCs), a multi-color flow cytometry-based assay was developed to detect TLR responses of individual cell types simultaneously. We observed that the magnitude of TLR responses largely varied between human subjects, but was highly reproducible over one month. To evaluate the potential role of differences in natural killer (NK) cell TLR response we studied the association of NK cell TLR function and TLR single nucleotide polymorphisms (SNPs) with susceptibility to recurrent herpes labialis (HL) and gastric cancer. Using our assay, impaired TLR3 response of NK cells was found in people with recurrent HL. In addition, we have identified enhanced levels of homozygous TLR3 L412F SNP in people with recurrent HL, which results in lower surface expression and reduced NK cell response to poly(I:C). TLR1 I602S, another common SNP, has been reported to decrease TNF-Alpha responses of monocytes toward TLR2/1 agonist, Pam3CSK4 (Pam3Cys), stimulation. In our study, we found that TLR1 I602S homozygosity also contributes to impaired IFN-Gamma responses of NK cells and CD8+T cells. Although we did not observe an association of TLR2/1 deficiency with recurrent HL, association of TLR1 I602S with risk for primary as well as metastatic gastric cancer was found in a cohort of 326 patients. To sum up, our results suggest that genetic polymorphisms of TLRs can impair TLR function of NK cells, which contribute to the increased susceptibility to HSV-1 diseases and gastric cancer.
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Al-Otaibi, Luba M. "Studies into the disparity in extent of human herpes virus 8 infection in Saudi Arabian general population, chronic renal failure patients and renal allograft recipients." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444092/.
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Transplantation-associated Kaposi's sarcoma (KS), causatively associated with human herpes virus 8 (HHV-8), is particularly prevalent in Saudi Arabia, although the prevalence rate of HHV-8 infection in the general population there is comparable to that in other geographical regions. The serologic and genomic prevalences of HHV-8 in samples representing the general population (n=238), patients with end-stage renal disease (n=78), and renal allograft recipients (n=66) were investigated. To evaluate if oral shedding of HHV-8 might play a role in transplantation KS, the extent of HHV-8 shedding in the mouth compared to other anatomical compartments, and the presence of multiple HHV-8 infection were also studied. PCR protocols were applied to amplify 3 fragments of the viral genome (from open reading frames 26 and K1) from whole-mouth saliva, parotid saliva, buccal and palatal exfoliates, plasma, sub sets of peripheral blood cells, and KS lesional tissue, and to quantify the salivary viral load. Demographic and clinical data were analysed to identify risk factors for HHV-8 infection. A higher HHV-8 seroprevalence was observed in patients with renal disease compared to the general population, but no significant difference in HHV-8 DNA detection rates in CD45+ cells was found. The oral cavity was identified as a major site of HHV-8 shedding in renal disease patients regardless of a previous history of KS. In patients with end-stage renal disease, HHV-8 DNA was more frequently detectable in oral samples than in blood. They and renal allograft recipients showed evidence of being multiply infected by HHV-8. These findings suggest that iatrogenic, salivary HHV-8 transmission between patients with renal disease prior to transplantation accounts for the relatively high prevalence of HHV-8 infection. Implementation of measures to minimise contamination of oral fluid between renal disease patients may play a role in controlling HHV-8 transmission and reduce the incidence of transplantation-associated KS.
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Krainz, Thomas Edward. "An Analysis of Heat Shock Protein Production in Human Retinal Pigment Epithelial Cells After Different Stress-Induced States." Walsh University Honors Theses / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=walshhonors1524248740945083.
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Khoja, Suhail. "HSV-1 amplicon system for human artificial chromosome formation in human ES/iPS cells and pluripotency induction." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6b04170b-f2d9-4114-9511-05a1a98ccfec.
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Development of safe and efficient approaches for gene delivery in human embryonic stem cells (hESc) and particularly in human induced pluripotent stem (hiPS) cells, which can be derived in a person-specific manner, is considered to be imperative for harnessing their full potential in both the basic and applied research. The aim of this study was to evaluate the potential of human artificial chromosome (HAC) for gene delivery and expression in hESc and hiPS cells. HAC offers many potential advantages including the provision for carrying large genes with corresponding regulatory elements to obtain long-term regulated gene expression. In addition, they can replicate and segregate independently without integration into the host cell genome. To develop HAC in hiPS cells, the first part of the study was aimed at generating hiPS cells utilising the Herpes Simplex Virus (HSV)-1 amplicon system. With the use of EBNA-1/OriP retention elements incorporated into the HSV-1 amplicon vectors, hiPS cells completely free of vector and transgenes sequences were successfully derived from human embryonic fibroblasts. The hiPS cells exhibited proliferation and differentiation potential similar to that of hESc. In the second part of the study, development of HAC in hESc and hiPS cells was assessed by utilising the HSV-1 amplicon system to deliver the HAC DNA. Analysis of the hESc confirmed the presence of functional HAC which replicated the behaviour of the host chromosomes. Additionally, HAC generation did not lead to impairment in the developmental potential and pluripotency of hESc. The hiPS cells supported HAC at low frequency but DNA also integrated into the host chromosomes. The HAC system, therefore, needs further refinements to improve the frequency of HAC formation and reduce the chromosomal integration of HAC constructs in hiPS cells. Overall, these findings provide a simple and safe way of pluripotency induction and genetic modification of pluripotent stem cells using the HSV-1 amplicon system and represent an important advance towards patient specific gene and cell therapy.
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Vogel, Karin [Verfasser], and Barbara [Akademischer Betreuer] Schmidt. "Role of plasmacytoid dendritic cells and other accessory cells in the activation of human natural killer cells by herpes simplex virus type 1 / Karin Vogel. Gutachter: Barbara Schmidt." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2015. http://d-nb.info/1075837367/34.
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Lontchi, Yimagou Eric. "Infection par le virus de l'herpès humain de type 8 (HHV8) et inflammation : implications dans le diabète de type 2 cétonurique." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066207/document.
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Le Ketosis-Prone Diabetes (KPD) est un phénotype de diabète intermédiaire entre le diabète de type 1 et le diabète de type 2, fréquemment rencontré chez le sujet d’origine noire africaine. Cette forme de diabète suscite un intérêt certain de par son évolution clinique marquée notamment par la restauration de l’insulinosécrétion initialement altérée. Sobngwi et coll. en 2008 ont établi une association entre le virus HHV8 et le KPD chez des sujets Africains vivant en France. Nulle part ailleurs l’étude n’a été reproduite. L’objectif de cette thèse était de rechercher la potentielle association entre l’infection à HHV8 et le KPD ; puis d’évaluer l’impact de l’infection à HHV8 sur le profil inflammatoire des phénotypes du diabète de type 2. L’étude s’appuie sur une population de patients Africains vivant en Afrique admis consécutivement pour une décompensation hyperglycémique (glycémie à jeun≥2,5g/l) au Centre National d’Obésité de l’Hôpital Central de Yaoundé. Plus spécifiquement, il était question de :• étudier la fréquence du diabète non auto-immun à tendance cétosique (KPD); • étudier l’association entre le virus HHV8 et le KPD;• rechercher si l’infection à HHV8 est associée à un profil inflammatoire pouvant participer aux phénotypes de diabète. Etait inclus dans l’étude tout patient diabétique âgé de plus de 18 ans présentant un diabète aigu avec syndrome cardinal et cétonurie (KPD1), ceux ayant présenté un diabète inaugural aigu avec syndrome cardinal et cétonurie et en rémission depuis plus de trois mois et sans cétonurie à l’inclusion (KPD2), et ceux présentant un diabète de type 2 connu sans cétonurie (DT2). Etait exclu de l’étude tout patient présentant des stigmates d’auto-immunité du diabète de type 1 A, un diabète « MODY », une endocrinopathie, une maladie du pancréas, ou un diabète de type auto-immun. Chez l’ensemble des participants admis, nous avons collecté les données cliniques (le poids, la taille, l’IMC, le rapport tour de taille sur tour de hanche, la pression artérielle, et le pourcentage de graisse) et des prélèvements à jeun ont été effectués (sérum et cellules mononuclées du sang périphérique) pour les analyses biologiques : la glycémie par glucose oxydase, l’HbA1c par HPLC, les paramètres du profil lipidique par des methodes enzymatiques, les concentrations d’insuline et de peptide-C par électrochimiluminescence, les anticorps anti-HHV8 par immunofluorescence, l’ADN viral HHV8 par PCR en temps réel, et les marqueurs de l’inflammation par le Luminex. Les indices HOMA-β et HOMA-IR ont été utilisés pour évaluer l’insulinosécrétion et la sensibilité à l’insuline respectivement. Les marqueurs sérologiques de l’inflammation recherchés étaient : TNF-α, MCP-1, IL-8, MIP-1β, VEGF et MIP-1αKetosis-Prone Diabetes (KPD) is a diabetes phenotype intermediate between type 1 and type 2 diabetes, frequently encountered in populations of African origin. This form of diabetes arouses some interest because of its clinical course marked in particular by restoring the initial impaired insulin secretion. Sobngwi et al. in 2008 established an association between HHV-8 virus and KPD in African population living in France. Nowhere else has the study been replicated. The objective of this thesis was to investigate the potential association between HHV-8 infection and KPD; then evaluate the impact of HHV-8 infection on the inflammatory profile of type 2 diabetes phenotypes. The study is based on African patients living in Africa consecutively admitted for hyperglycemic decompensation (Fasting blood glucose≥2,5g/l) at the National Obesity Centre of the Yaounde Central Hospital. More specifically, the issue was:• study the frequency of non-immune ketosis-prone diabetes (KPD);• investigate the association between HHV8 and KPD;• investigate whether HHV-8 infection is associated with an inflammatory profile that may participate in diabetes phenotypes.Was included in this study all diabetic patients old more than 18 years with acute diabetes with syndrome cardinal and ketonuria (KPD1), those who presented with an acute inaugural cardinal syndrome and diabetes ketonuria and in remission for more than three months and without ketonuria at baseline (KPD2), and those with type 2 diabetes experienced without ketonuria (T2D). Was excluded from the study all patient with stigmata of autoimmunity of type 1 A diabetes, diabetes "MODY", endocrinopathy, pancreatic disease or an autoimmune diabetes.Among all participants admitted, we collected clinical data (weight, height, BMI, waist to hip ratio, blood pressure, and the percentage of fat) and levies fasting were made (serum and peripheral blood mononuclear cells) for biological testing: glyceamia by glucose oxidase, HbA1c by HPLC, lipid profile by enzymatic methods, the insulin and C-peptide concentrations by electrochemiluminescence, anti-HHV8 antibodies by immunofluorescence, HHV8 viral DNA by real-time PCR, and markers of inflammation by Luminex. HOMA-β and HOMA-IR indices were used to assess insulinsecretion and insulinsensitivity respectively. Serological markers of inflammation investigated were : TNF-α, MCP-1, IL-8, MIP-1β, MIP-1α and VEGF
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Mandegar, Mohammad Ali. "Analysis of artificial chromosomes in human embryonic stem cells." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:81d118c3-dd01-40e4-9fea-2c335d9f3101.
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The development of safe and efficient gene delivery systems in pluripotent human embryonic stem cells (hESc) is essential to realising their full potential for basic and clinical research. The purpose of this study was to develop an efficient, non-integrating gene expression system in pluripotent hESc using human artificial chromosomes (HAC). Similar to endogenous chromosomes, HAC are capable of gene expression, replication and segregation during cell division. Unlike retroviral-mediated gene delivery vectors, HAC do not integrate into the host genome and can encompass large genomic regions for the delivery of multiple genes. Despite the advantages HAC offer, their use has been limited due to laborious cloning procedures and poor transfection efficiencies, and thus only studied in immortalised and tumour-derived human cell lines. In this study, the high transduction efficiency of herpes simplex virus type-1 (HSV-1) amplicons was utilised to overcome the described difficulties and delivered HAC vectors into pluripotent hESc. Analysis of stable hESc clones showed that de novo gene-expressing HAC were present at high frequencies ranging from 10-70% of metaphases analysed, without integrating into the genome. The established HAC contained an active centromere, and were stably maintained without integration or loss in the absence of selection for 90 days. Stable HAC-containing hESc clones retained their pluripotency as demonstrated by neuronal differentiation, in vitro germ layer and teratoma formation assays. HAC gene expression persisted, with some variation, post-differentiation in the various deriving cell types. This is the first report of successful de novo HAC formation in hESc for gene expression studies. These findings show potential for delivering high-capacity genomic constructs safely and efficiently into pluripotent cells for the purpose of genetic manipulation and ultimately patient-specific somatic gene therapy.
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La, Bella Tiziana. "Adeno-associated virus in the liver : natural history of the infection and consequences in tumor development." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC263.
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Le virus adéno-associé (AAV) est un virus à ADN monobrin, défectif et endémique dans la population humaine. L'infection à AAV a longtemps été considérée comme non pathogénique. Cependant, il y a quelques années, nous avons identifié pour la première fois des insertions clonales récurrentes d'AAV2 impliquées dans la pathogenèse du carcinome hépatocellulaire humain (CHC) développé sur un foie normal. Ces insertions virales clonales ciblent des oncogènes et entraînent leur surexpression. À ce jour, peu de travaux ont étudié l'infection à AAV de type sauvage dans le foie humain. Dans ce travail, nous avons étudié l'histoire naturelle de l'infection virale dans les tissus hépatiques et ses conséquences sur le développement de tumeurs dans une vaste cohorte de patients (n = 1464). La présence de l'AAV est observée chez 21% des patients, plus fréquemment dans la contrepartie non-tumorale (18%) que dans la tumeur (8%) et significativement enrichie chez les femmes, les patients jeunes et non cirrhotiques. Deux sous-types d’AAV ont été identifiés dans le foie, l’AAV2 classique et un génotype hybride AAV2-AAV3-AAV13, avec une fréquence égale dans notre cohorte. Nous avons détecté la présence de formes épisomales d'AAV dans 27% des tissus non tumoraux positifs pour l'AAV, associée de manière significative à l'expression de l'ARN viral et à la co-infection par des virus auxiliaires, suggérant une infection active en cours. Nous avons identifié le virus de l'herpès humain de type 6 (HHV6) comme étant le virus auxiliaire naturel de l'AAV dans le foie. En revanche, l'ADN de l'adénovirus n'a été détecté que chez 0,5% des patients et aucune association avec l'AAV n'a été constatée. Nous avons confirmé la sélection positive des insertions d'AAV clonales au cours du développement du CHC chez les patients sans cirrhose dans 2% des tumeurs ciblant CCNA2, CCNE1, TERT, TNFSF10, KMT2B et INHBE / GLI1. De plus, les altérations de CCNA2 et de CCNE1 dues à des insertions virales d'AAV et de VHB ou à des réarrangements structurels ont défini une nouvelle sous-classe de CHC (CCN-HCC) et un nouveau mécanisme de développement du CHC sur le foie normal, améliorant nos connaissances sur l'hépatocarcinogénèse sur le foie non cirrhotique. Les CCN-HCC présentent également des caractéristiques moléculaires particulières qui pourraient être ciblées par un traitement spécifiqueAdeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population. AAV infection has long been considered as non-pathogenic, however few years ago we reported for the first time recurrent clonal AAV2 insertion in the pathogenesis of human hepatocellular carcinoma (HCC) developed on normal liver. These clonal viral insertions target cancer driver genes leading to their overexpression. To date, little is known about wild type AAV infection in human liver. In this work we investigated the natural history of the viral infection in the liver tissues and the consequences in tumor development in a large cohort of patients (n=1464). The presence of AAV was observed in 21% of patients, more frequently in the non-tumor counterpart (18%) than in tumor (8%) and significantly enriched in young, female and non-cirrhotic patients. Two AAV subtypes were identified in the liver, the classical AAV2 and a hybrid AAV2-AAV3-AAV13 genotypes, with an equal frequency in our cohort. We detected the presence of episomal AAV forms in 27% of AAV positive non-tumor tissues significantly associated with viral RNA expression and co-infection with helper viruses suggesting an ongoing active infection. We identified human herpes virus type 6 (HHV6) as the natural AAV helper virus in the liver. In contrast, adenovirus DNA was detected in only 0.5% of patients and no association with AAV was found. We confirmed the positive selection of clonal AAV insertions during HCC development in patients without cirrhosis in 2% of tumors targeting CCNA2, CCNE1, TERT, TNFSF10, KMT2B and INHBE/GLI1. Moreover, the alterations in CCNA2 and CCNE1 due to viral insertions of AAV and HBV or structural rearrangements defined a new subclass of HCCs (CCN-HCC) and a novel mechanism of HCC development on normal liver improving our knowledge on hepatocarcinogenesis on non-cirrhotic liver. CCN-HCCs display also peculiar molecular features that could be targeted by specific treatment
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Sehl-Ewert, Julia [Verfasser]. "Characterization of a Pseudorabies virus mutant lacking the pUS3 kinase and the tegument protein pUL21 in vitro and in vivo and the evaluation of an improved animal model for human Herpes Simplex Encephalitis / Julia Sehl." Gießen : Universitätsbibliothek, 2020. http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-154804.
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Sehl, Julia [Verfasser]. "Characterization of a Pseudorabies virus mutant lacking the pUS3 kinase and the tegument protein pUL21 in vitro and in vivo and the evaluation of an improved animal model for human Herpes Simplex Encephalitis / Julia Sehl." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1223461467/34.
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Gautheret-Dejean, Agnès. "Etude des interactions entre les sixieme et septieme herpesvirus humains (hhv-6, hhv-7) et le virus de l'immunodeficience humaine (hiv) chez l'homme." Paris 11, 1997. http://www.theses.fr/1997PA114842.
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Quintanilha, Falcão Deborah. "Étude de la composition chimique de Calceolaria chelidonioides Humb. Bonpl. & Kunth." Montpellier 1, 2007. http://www.theses.fr/2007MON13506.
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L’espèce Calceolaria chelidonioides, inconnue scientifiquement jusqu’à présent, a été choisie pour la réalisation de ce travail à partir des résultats obtenus au cours une étude ethnopharmacologique avec la communauté agricole de Alto de Macabú (RJ). Cette communauté est composée par des agriculteurs descendants, dans la plus grande partie, des italiens et allemands. Ils ont été interviewés dans le but de connaitre des espèces utilisées par la population dans des traitements dermatologiques. En effet, les interviews ont été structurées à partir d’un questionnaire préalablement élaboré envisageant exclusivement des pathologies dermatologiques. Ce travail a rendu quelques espèces dont Calceolaria chelidonioides, utilisées par la population pour le traitement des problèmes cutanées et différents types des cancers. Notre objectif a été d’isoler et caractériser les substances métabolisés par cette espèce, d’évaluer la toxicité et les propriétés pharmacologiques de l’extrait obtenu, jusqu’au développement de formulations galéniques topiques avec l’extrait comme actif, assurant sa sécurité et son efficacité. La partie phytochimie a été évaluée la composition de l’huile essentielle en montrant la présence de 5 substances: un sesquiterpène, hexahydrofarnesilone (I); un stéroïde, androstan-17b-ol-3-one (II) and trois diterpènes, biformene (III) le composant majoritaire, rimuene (IV) et 8-acetoxi-9-epi-ent-pimara-15-ene (V). C’est la première fois qu’on a été évaluée l’huile essentielle d’une espèce du genre Calceolaria. Cette composition, considérée un peu bizarre au début à cause du grand temps de rétention obtenu pour les substances, a été réévaluée sur les mêmes conditions, en assurant l’identité des métabolites. On a pu donc suggérer que l’espèce Calceolaria chelidonioides synthétise un type d’huile dans ses feuilles et ses tiges avec très bas volatilité et qu’il possède quelque activité de protection à cause de son aspect collant et la forte odeur, n’étant pas rare trouver quelques petits insectes attachés au végétal. La présence de biformene comme constitutif majoritaire est d’accord avec ça. Cette substance huileuse, synthétisé normalement par quelques espèces végétaux des familles Araucariaceae et Leguminoseae, est trouvé comme une résine responsable pour la protection des ces espèces contre différents pathogènes et animaux. Cette activité peut encore être reliée à l’huile présente dans les fleurs des espèces du genre Calceolaria que développent importante fonction d’attraction des abeilles pour la pollinisation. De toute fois, la composition riche en diterpènes est d’accord avec la phytochimie connue pour les espèces du genre. Il faut remarquer l’inexistence dans la littérature scientifique un travaille d’évaluation de la composition chimique d’huile essentielle des espèces du genre Calceolaria. En utilisant différentes techniques chromatographiques il a été possible d’isoler et d’identifier le calceolarioside B (VI), le calceolarioside A (VII) et l’apigenine (VIII) de la fraction acétate d’éthyle des tiges; rutine (IX) et verbascoside (X) de la fraction acétate d’éthyle des fleurs; et isorhamnetine 3-O-glucoside (XI) de la fraction butanolique des feuilles et des fleurs. L’extrait éthanolique des feuilles et fleurs a été évalué sur le potentiel cytotoxique in vitro et en modèles in vivo d’irritation oculaire et cutanée primaire sans mettre en évidence quelque type des toxicités dans les méthodes employées. Des études d’évaluation toxicologique in vitro et in vivo de l’extrait éthanolique des fleurs ont été aussi réalisées sans mettre en évidence de potentiel cytotoxique, phototoxique, mutagénique ou irritant, ceci indiquant la sécurité de son usage. Dans le but de mettre en évidence une activité pharmacologique, des essais d’activité antioxydante ont été réalisés en modèle in vitro par la méthode du DPPH et in vivo avec Saccharomyces cereviseae. Dans le modèle in vitro tous les extraits éthanoliques ont été évalués. Les meilleurs résultats ont été démontrés pour l’extrait de feuilles et fleurs. Dans la méthode in vivo employée, seulement l’extrait des fleurs a été évalué, mettant en évidence une spécificité pour les radicaux peroxyde sans démontrer activité contre les radicaux superoxyde. Tous les extraits éthanoliques de Calceolaria chelidonioides ont été aussi evalués par rapport à des activités antimicrobiennes, montrant des résultats assez intéressants contre la souche MRSA surtout pour les extraits de fleurs et ceux de feuilles; Une activité antivirale contre le vírus Herpes simplex types 1 et 2, a aussi été demontrée, avec en général une plus grande specificité pour le type 2. La fraction acetate d’ethyle des fleurs a montré la meilleure activité antivirale contre les deux types de virus. De plus, il a été possible d’attribuer au verbascoside l’activité anti HSV-2 observée pour l’extrait brut de fleurs. Basé sur les résultats du screening toxicologique et pharmacologique, et également sur la plus grande viabilité économique, l’extrait éthanolique de fleurs a été choisi comme celui présentant le plus grand intérêt pour le développement des formulations galéniques topiques. Deux formulations ont été mises au point, une nanoémulsion et une microémulsion avec 5% d’extrait normalisé en 14,5% du verbascoside, visant la prophylaxie d'infections primaires ou récurrentes à l’Herpes simplex type 2. Le pouvoir promoteur d’absorption des formulations a été évalué en utilisant le verbascoside comme marqueur de l’extrait. Parmi les produits testés, la microémulsion fut la formulation montrant les effets recherchés, c'est-à-dire l’effet réservoir du verbascoside dans l’épiderme. Grâce à ces résultats nous avons pu conclure que la microémulsion répondait aux conditions de la formulation désirée. Seront nécessaires de futures études de développement d'une méthodologie capable d'évaluer l'activité antivirale de la formulation finie, dont la réalisation n'a pas été possible dans ce travail.
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Herbein, Georges. "L'infection à Herpesvirus humain type 6 (HHV-6) chez les transplantés : une étude rétrospective de 32 patients." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR1M098.
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Laurent, Corinne. "Virus herpès de type 6 et convulsions fébriles de l'enfant." Paris 5, 1997. http://www.theses.fr/1997PA05P066.
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Costa, Fernanda Aparecida. "Detecção e monitorização do herpevirus humano tipo 6 (HHV-6) e do citomegalovirus humano (HCMV) em pacientes transplantados hepaticos." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311934.
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Orientador: Sandra Cecilia Botelho CostaDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Os herpesvírus humanos linfotrópicos, incluindo citomegalovírus (HCMV) e herpesvírus 6 (IlliV -6 A e B) são muito comuns e infectam a maioria dos humanos. Ambos pertencem à família Herpesviridae e, desta família, o HHV-6 é o que possui maior potencial neuroinvasivo. O HHV-6 é um vírus imunomodulador, predispondo o hospedeiro a efeitos patogênicos de outros vírus, como o HCMV. Esses vírus são responsáveis por uma grande variedade de doenças causadas pela infecção primária ou por reativação de infecção latente em condições de imunossupressão, especialmente após o transplante de órgãos. O transplante de figado representa a única forma efetiva de tratamento para uma série de doenças hepáticas terminais. Foram estudados prospectivamente 30 pacientes transplantados de figado do Hospital de Clínicas da Universidade Estadual de Campinas (Unicamp), durante o período de janeiro de 2002 a abril de 2004. Detectamos o DNA do HHV-6 e do HCMV em transplantados hepáticos através da "Nested-PCR" em sangue periférico; avaliamos a co-infecção e o impacto clínico causado por esses vírus nos transplantados hepáticos. A técnica de "Nested PCR" foi escolhida para aumentar a sensibilidade e especificidade da PCR e para obter resultados mais rápidos. Vinte e dois (73,3%) pacientes transplantados do sexo masculino e 8 (26,7%) do sexo feminino, com uma média de idade de 48 anos, foram estudados. Desses pacientes 22 (73,3%) e 23 (76,6%) tiveram pelo menos um resultado positivo para HCMV e HHV-6 respectivamente, durante o seguimento. Detectamos alta taxa de infecção ativa (2 ou mais reações de PCR positivas, consecutivas) para os herpesvírus estudados, 12/30 (400,10) para HHV-6; 13/30 (43,3%) para HCMV; a co-infecção ocorreu em 4/30 (13,3%) dos transplantados hepáticos. Os resultados obtidos e os inúmeros estudos sobre o impacto clínico na detecção e tratamento desses dois betaherpesvírus em pacientes transplantados hepáticos mostram a importância de estudarmos sua prevalência, métodos diagnósticos e seu impacto clínico em nosso meio. Ficar atento às manifestações neurológicas de origem desconhecida porque podem estar relacionadas à infecção ativa por HHV-6 isolado. Nossos dados demonstraram a importância da infecção por esses herpesvírus nos transplantados hepáticos
Abstract: The human lymphotropic herpesvíros that included cytomegalovírus (HCMV), and the herpesvirus 6 (HHV-6 A and B) are very common and infect the vast majority of the human population. Both viruses belong to the Herpesviridae family. In this family, the HHV-6, subfamily Betaherpesvirinae, is wath possessing the bigger neurologic potential pathogenic. The HHV-6 is an immunomodulator virus with a significant risk factor for the subsequent pathogenic effects of others virus like HCMV. Those viroses are responsible for a range of illnesses caused by the primary viral infection or for reactivation of latent infection in patients with immunosuppression, specially after transplant of organs. The transplant of tiver represents the only form effective of cure for a many terminal illnesses. The study included prospective analysis of 30 patients with transplant of the liver from Hospital of Clinics of the State University of Campinas (Unicamp), during January of 2002 to April of 2004. We dected the HHV-6 and the HCMV in tiver transplant patients by means of "Nested-PCR" in peripheral blood We also evaluate the co-infection and the clinical impact between those virus in liver transplant patients. The "Nested PCR" analysis was choosing because this method increases the sensibility and specificity of the PCR and the results are more quick. Twenty-two (73,3%) male and 8 (26,7%) female were enroled with a mean age of 48 years old. We detected in 22 (73,3%) and 23 (76,6%) patients at least a positive result to HCMV and HHV-6. We detect high rate of active infection of HHV6 12/30, (40%) and the same rate 13/30 (43,3%) for HCMV, in the study patients studied. The rate of active co-infection for HCMV and HHV-6, was 4/30 (13,3%). In two patients infected only with HHV-6, was observed neurologic alterations. Five patients was some kind of transplant rejection. Opportunist infections of fungal or bacterial etiology were observed in 14/30 (46,5%). The results show the importance of study the prevalence of these herpesvirus in liverrecipients transplanted, there approaches diagnoses and clinical impact in our environment. They stayed aware to the neurological manifestations of unknown origin because they can be related to the active infection by HHV-6 isolated.
Mestrado
Mestre em Farmacologia