Human Papillomavirus (HPV) is one of the most common causes of sexually transmitted disease worldwide. Infections by high-risk HPVs, such as HPV-18, have been associated etiologically with cervical cancer. The successful development of HPV vaccines may be beneficial to the HPV-na??ve population, but women that have already been exposed to the virus are still at risk of developing HPV-associated malignancies. A need for a systemic cure for HPV-infection therefore still exists. Gene therapies using tissue-specific promoters have been reported to be a promising tool for treating cancers; however, few studies have explored this possibility for cervical cancer. The aim of this project is to construct a gene expression vector that can specifically target HPV-infected cervical cancer cells, by making use of the activity and selectivity of the P105 promoter which is determined by transcription control elements within the HPV-18 long control region (LCR). The first part of this study involved the construction of LCR deletion plasmids, and examining the subsequent level of gene expression induced within different mammalian cell lines. The results suggest the LCR to be capable in achieving cervical cancer-specific gene expression. The 3′-end of the viral L1 gene upstream of the LCR appeared to have a repressive effect on the promoter and therefore should be excluded for maximum LCR promoter activity. The second part of the project involved site-directed mutagenesis studies performed on selected transcription factor binding sites with an attempt to further increase the level of LCR promoter activity and specificity towards HPV-infected cervical cancer cells. The results suggest that a GRE/YY1 mutation may significantly enhance promoter activity. In terms of promoter regulation, the E2BSs appeared to be responsible for promoter activation in the absence of viral E2 proteins. The findings of this study suggest a possible gene therapy approach towards the treatment of cervical cancer. By making use of the activity and specificity of the HPV-18 P105 promoter to induce cervical carcinoma-specific expression of appropriate therapeutic genes, suicidal phenotypes can be introduced selectively within HPV-positive cervical cancer cells while normal HPV-negative cells are unaffected.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 77-92).

Persistent infection of the cervix with high risk (HR) types of Human Papilloma Virus (HPV) (HR-HPV) can result in precancerous lesions and cancers. However, most HPV infections can be cleared naturally by the immune response without causing disease. Although genetic variations have long been considered as the main explanation for individual heterogeneity in cancer susceptibility, the underlying mechanisms remain unclear. In this project, a panel of routinely taken clinical samples was assessed for 32 rationally selected SNPs with allele frequency related to disease outcome using the Taqman® OpenArray® system. The panel incorporated 475 HR-HPV negative, cytologically-normal cervical samples, 413 HR-HPV positive cervical high grade squamous intraepithelial lesion (HSIL) cases and 62 HR-HPV positive cervical cancers. Two SNPs, rs2234671 and rs2623047, were found with significant differences between HR-HPV negative, cytologically-normal samples and HR-HPV positive cervical HSIL cases. In the validation step, these two SNPs were further genotyped in the same set of samples using TaqMan® SNP genotyping assay and/or LightSNiP assay and in additional samples including 83 HR-HPV positive, cytologically-normal cervical samples, 21 HR-HPV positive cervical cancer cases, 129 HR-HPV positive vulval intraepithelial neoplasia cases and 23 HR-HPV positive vulval cancer cases. Statistical analysis was then performed based on pooled and re-grouped genotyping data of the above-mentioned samples under different genetic models so as to evaluate the associations with different stages in the disease process. After validation, SULF1 rs2623047 revealed a strong significant association with the susceptibility to HR-HPV infection but not with the development of high-grade squamous intraepithelial lesion and the progression to cervical cancer. CXCR1 rs2234671, by contrast, was associated with the progression of HR-HPV-related cancers and the minor allele CXCR1 827C was significantly enriched in HPV16 positive cancers. CXCR1 is a receptor for the chemokine CXCL8/IL-8 and CXCR1 rs2234671 leads to a serine to threonine change in an extracellular loop of the receptor. Functionally, the CXCR1 827C allele was shown to enhance cell motility in response to IL-8 stimulation in a chemotaxis assay with transiently transfected fibroblasts (HEK293 cells) and also in a wound healing assay with stably transduced cervical cancer (CaSki) cells. In addition, significantly increased cell proliferation upon IL-8 treatment was observed in two cervical cancer derived cell lines, CaSki and SiHa, transduced with CXCR1-827C allele, but not in their CXCR1 827G transduced counterparts. These findings suggest that SULF1 rs2623047 and CXCR1 rs2234671 may be genetic risk factors for HR-HPV-related cervical disease and CXCR1 rs2234671 might affect HR-HPV-related cancer susceptibility by functionally altering IL-8-CXCR1 signalling. This information has potential for use in the risk stratification of HR-HPV infected women and may also suggest new therapeutic targets to be exploited for treatment of cervical cancer patients.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em Farmácia / Made available in DSpace on 2012-10-22T14:16:36Z (GMT). No. of bitstreams: 1 226939.pdf: 3454383 bytes, checksum: 7d7e59308e868c47560d7e343508b37c (MD5)

O câncer de cérvice uterina é um problema de saúde pública na maioria dos países em desenvolvimento e também nos países desenvolvidos. Não só porque acomete mulheres relativamente jovens mas também porque seria prevenível caso um programa de rastreamento fosse factível de ser implantado em grande escala. Hoje se conhece muito sobre a patogênese deste câncer e de suas lesões precursoras. É reconhecido, por exemplo, que a infecção pelo Papilomavírus Humano (HPV) é imprescindível neste processo. Porém a grande maioria das mulheres infectadas por este vírus não evolui para câncer. Fatores associados, cofatores, são importantes tanto na resposta ao agente infeccioso, na persistência da infecção, quanto na evolução de lesões precursoras para lesões invasivas. Alguns destes co-fatores já são conhecidos, fumo, alta paridade, uso de anticoncepcional oral por um longo período, co-infecção pelo HIV. Outros estão sendo investigados. Um dos fatores menos estudados são as características do hospedeiro e sua capacidade de resposta à infecção e ao processo de malignização. História familiar traduz características genéticas, ambientais e culturais de um indivíduo. História familiar de câncer é fator de risco em maior ou menor intensidade para a maioria dos cânceres. Porém, este co-fator tem sido pouco estudado em relação ao câncer de cérvice. O objetivo desta tese é examinar a associação entre história familiar de câncer e risco para câncer de cérvice. Apesar de alguns estudos de base populacional e outros em amostras hospitalares terem sido feitos, nenhuma sistematização das publicações disponíveis foi ainda feita. Uma revisão dos artigos que analisavam esta associação foi feita e confirmou um excesso de risco aproximadamente duas vezes maior entre as mulheres que tem história familiar de câncer de cérvice entre parentes de primeiro grau. Além disso, foi feita a análise de dois bancos de dados, um caso-controle na região leste dos Estados Unidos e um estudo transversal em uma região da Costa Rica. Nos dois estudos, foi evidenciada uma associação positiva de história de câncer de cervice em familiares de primeiro grau e risco para câncer de cérvice. Com isso, conclui-se que história familiar de câncer é um co-fator para câncer de cérvice uterina. / Cervical cancer is an important public health problem not only in most developing countries but also in industrialized ones. That is so not only because it is common among relatively young women but also because it could be prevented should screening programs be implemented in large scales. Nowadays, much is known about the pathogenesis of this cancer and its precancerous lesions. It is known that infection of the human papillovirus (HPV) virtually occurs in all cases. However, the majority of women infected by this virus do not develop cancer. Thus, related factors, co-factors, are very important in relation to the response to the infectious agent, to the persistence of the infection, and to the progression of precancerous lesions into invasive lesions. Some of these co-factors are well known; smoking, high parity, use of oral contraceptive for long periods, and co-infection with HIV. Other co-factors are being investigated. One of the factors least studied is the feature of the host and its capacity to respond to the infection and malignancy. Family history conveys the genetic, environmental and cultural characteristics of the individual. Family history of cancer is a greater or smaller risk factor in almost all cases of cancer. However, this co-factor has not been thoroughly studied as regarding cervix cancer. The objective of this thesis is to examine the association between family history of cancer and cervix cancer risk. Although some population-based studies as well as others - some with hospital samples – have been carried out, there is no systematic review of such studies. A systematic review of the 20 articles that analyzed this association was performed and it confirmed excess in risk, approximately two fold, among women with relatives of first degree with family history of cervix cancer. Furthermore, the analysis of two data bases, one case-control study in the east of the USA and a cross-sectional study in a region of Costa Rica. In both studies there was a positive association of history of cancer in first-degree relatives and risk for cervix cancer. Hence, this study concludes that cancer family history is a co-factor for uterine cervix cancer.

VIEIRA, Elizabeth Dell' Orto. Prevalência de HPV e lesões intraepiteliais escamosas em gestantes. 2008. 86 f. Dissertação (Mestrado em Tocoginecologia)- Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2008. / Submitted by denise santos (denise.santos@ufc.br) on 2012-10-22T12:15:59Z No. of bitstreams: 1 2008_dis_edovieira.pdf: 724191 bytes, checksum: b154be6a33652d30ec78483a6f448800 (MD5) / Approved for entry into archive by Erika Fernandes(erikaleitefernandes@gmail.com) on 2012-10-26T15:10:19Z (GMT) No. of bitstreams: 1 2008_dis_edovieira.pdf: 724191 bytes, checksum: b154be6a33652d30ec78483a6f448800 (MD5) / Made available in DSpace on 2012-10-26T15:10:19Z (GMT). No. of bitstreams: 1 2008_dis_edovieira.pdf: 724191 bytes, checksum: b154be6a33652d30ec78483a6f448800 (MD5) Previous issue date: 2008 / This work studies the prevalence (cross sectional) on infection by HPV in uterine cervical of pregnant women evaluating the subgroups of HPV more prevalents and the association in relation to the development of squamous intraepithelial lesions. The methodology was constituted of questionary applied to 272 pregnant women independent of pregnant age and of being symptomatic or not in the first medical advice of prenatal besides the collect of cervico vaginal material (vaginal walls, ectocervix and endocervix) to the achievement of conventional oncotic cytology by the method of coloration proposed by Papanicolaou and the test of Capture Hybrid II®. Then it was proceeded the identification of squamous intraepithelial lesions and the presence of HPV virus of high, low and medium oncogenic risk. The results of Capture Hybrid II® were correlated with the cytologic discoveries comparing the frequency of anormal results in both methods. It was also proceeded the association with biosocial aspects which could interfere in the possible development of squamous intraepithelial lesions. The analysis of univariable and bivariable correlations were accomplished with calculus of Qui-squared of Pearson and value p<0,05. The logistic regression was used to estimate the importance of associations. The prevalence of infection by HPV and anormal oncotic cytologies was about 32,3% and 14,0% respectively. The sub groups of HPV of high risk were more prevalent (27,6%) than the ones of low and medium risk. (18,4%) and their association showed to be statistically significant (p< 0,05). The association of genital infection by HPV of high risk with squamous epithelial lesions described on conventional oncotic cytology was more prevalent (8,5%) than with HPV of low and medium risk (5,6%) and had statistical importance (p< 0,05) / Estudo de prevalência (estudo transversal) sobre infecção por HPV em colo uterino de gestantes, avaliando o(s) subgrupo(s) de HPV mais prevalentes e a associação quanto ao desenvolvimento de lesões intraepiteliais escamosas. A metodologia constituiu-se de questionário aplicado diretamente a 272 gestantes, independente da idade gestacional e de estarem sintomáticas ou não na primeira consulta de pré-natal, além da coleta de material cérvico-vaginal (paredes vaginais, ectocérvice e endocérvice) para realização de Citologia oncótica convencional pelo método de coloração proposto por Papanicolaou e do teste de Captura Híbrida II®. Procedeu-se a seguir a identificação das lesões intraepiteliais escamosas e da presença do vírus HPV de alto, baixo e médio risco oncogênico. Os achados da Captura Híbrida II® foram correlacionados com os achados citológicos, comparando-se a freqüência dos resultados anormais nos dois métodos. Procedeu-se também a associação com aspectos biossociais que pudessem interferir na infecção produzida pelo HPV e no possível desenvolvimento de lesões intraepiteliais escamosas. Realizaram-se análises de correlação univariada e bivariada, com cálculo do Qui-quadrado de Pearson e valor p< 0,05. Utilizou-se também de regressão logística para estimar a magnitude das associações. A prevalência de infecção por HPV e citologias oncóticas anormais foi de 32,3% e 14,0 % respectivamente. Os subgrupos de HPV de alto risco foram mais prevalentes (27,6%) do que os de baixo e médio risco (18,4%) e a sua associação mostrou-se estatisticamente significativa (p<0,05). A associação da infecção genital por HPV de alto risco com lesões intraepiteliais escamosas descritas na Citologia oncótica convencional foi mais prevalente (8,5%) do que com HPV de baixo de médio risco (5,6%) e teve significância estatística (p<0,05)

LIMA, T. S. Expressão imunohistoquímica da proteína de supressão tumoral p16ink4a como marcador de adenocarcinoma de colo uterino. 2013. 46 f. Dissertação (Mestrado em Patologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2013. / Submitted by Erika Fernandes (erikaleitefernandes@gmail.com) on 2017-05-16T14:10:00Z No. of bitstreams: 1 2013_dis_tslima.pdf: 1684405 bytes, checksum: ff48676033f3dba9d10ec8eec46885f7 (MD5) / Approved for entry into archive by Erika Fernandes (erikaleitefernandes@gmail.com) on 2017-05-16T14:10:13Z (GMT) No. of bitstreams: 1 2013_dis_tslima.pdf: 1684405 bytes, checksum: ff48676033f3dba9d10ec8eec46885f7 (MD5) / Made available in DSpace on 2017-05-16T14:10:13Z (GMT). No. of bitstreams: 1 2013_dis_tslima.pdf: 1684405 bytes, checksum: ff48676033f3dba9d10ec8eec46885f7 (MD5) Previous issue date: 2013-05-08 / Objective To evaluate the diagnostic utility of the p16ink4a protein expression as a marker for adenocarcinoma of the cervix. Methods In a cross-sectional study, p16ink4a expression was evaluated in 30 cervical biopsies from patients diagnosed with invasive adenocarcinoma from 2 reference clinics in Brazil, and compared with 18 biopsies of endocervical polyps (control cases). The performance of the tests for p16ink4a was evaluated using a conventional contingency table, and the Kappa (k) index was used to evaluate the agreement of the marker with the tissue diagnosis. Results In total, 66% of the invasive adenocarcinoma cases were positive for p16ink4a. All of the adenomatous polyps cases used as negative controls were shown to be negative for p16ink4a. The marker showed a high sensitivity and a high negative predictive value. The Kappa index was good for p16ink4a (k ¼ 0.6).Conclusion Considering the strong association between the p16ink4a marker and the cervical adenocarcinoma, its use represents an important tool for reducing incorrect. diagnoses of adenocarcinoma and thereby avoiding overtreatment. / O câncer cervical é o segundo mais comum na população feminina mundial e cerca de 20% desses tumores são classificados como adenocarcinomas. O diagnóstico histopatológico do adenocarcinoma de colo uterino, por ser subjetivo pode, em determinadas situações, tornar-se desafiador, pois faltam parâmetros para a sua definição, o que indica a necessidade de um marcador que seja adjuvante nesta afirmação e, que, possivelmente, aponte para o prognóstico da lesão. A proteína inibidora de quinase, p16ink4a tem sido alvo de vários estudos, os quais apontam superexpressão como marcador de lesões cervicais induzidas pelo Papilomavírus Humano (HPV) e preditor de mau prognóstico. Esta pesquisa tem como objetivo principal avaliar a utilidade diagnóstica do biomarcador p16INK4a no adenocarcinoma de colo uterino. Em estudo de corte transversal, não intervencional, foi feita a pesquisa por imunohistoquímica de p16 em 30 blocos de parafina com diagnóstico histológico, confirmado por dois patologistas como: adenocarcinoma endocervical (19), adenocarcinoma endocervical tipo endometrióide (3), adenocarcinoma de Células Claras (2), adenocarcinoma pouco diferenciado sólido (1), adenocarcinoma seroso (1), adenocarcinoma tipo endometrióide componente viloglandular (1), adenocarcinoma endocervical associado a carcinoma epidermóide in situ (1), carcinoma adenoescamosos (1), adenocarcinoma desvio mínimo (1). Aos resultados foi aplicada tabela de contingência e teste exato de Fisher (intervalo de confiança de 95%). Para concordância diagnóstica foi aplicado o índice de Kappa. Foram considerados positivos 80% (24/30) dos casos de adenocarcinoma Invasor para a expressão da p16. Não houve expressão da p16 em nenhum dos casos de (0/18) pólipos adenomatosos utilizados como controle negativo. A performance do p16 no diagnóstico do adenocarcinoma de colo uterino, demonstrou alta sensibilidade (75%) , alta especificidade (100%) e principalmente alto valor preditivo negativo (80%). O índice de concordância diagnóstica demonstrou ser muito bom para o p16 (κ = 0,75). A forte associação do marcador p16 com adenocarcinoma do colo uterino pode representar uma importante ferramenta diagnóstica utilizada para diminuir os diagnósticos de lesões equívocas.

Combating HPV infection in males is a significant public health issue. In addition to the number of HPV-related cancers that develop each year, Palefsky (2007) reported that "HPV infection of men is of great importance given that sexual transmission is the primary mode of spread to women" (p. 261). In recent years, the development of the HPV vaccine has spurred controversy over whether or not males as well as females should obtain the vaccine against this disease. The purpose of this study was to examine male college students' intention to be HPV vaccinated and their HPV knowledge, attitudes, subjective norms, and perceived behavioral control towards the vaccination. A descriptive, correlational, cross-sectioned research design was employed. Two hundred and eight (208) male college students at a mid-sized public university participated in the study and completed an in-class questionnaire. The results of the descriptive statistics showed that, on average, the sample of 208 male college students had correct responses on only half of the 15 questions regarding knowledge about HPV based on the mean scores. Respondents had positive attitudes towards HPV vaccination, greater sense of control over being HPV vaccinated, and favorable intention to be HPV vaccinated. Subjective norms and perceived behavioral control were significant predictors of male college students' behavioral intention to be HPV vaccinated. Subjective norms and perceived behavioral control had a positive influence on male college students' behavioral intention to be HPV vaccinated. Lastly, male college students' level of HPV knowledge was not significantly correlated to their behavioral intention to be HPV vaccinated